Modulating Regional Motor Cortical Excitability with Noninvasive Brain Stimulation Results in Neurochemical Changes in Bilateral Motor Cortices.

Learning a novel motor skill is dependent both on regional changes within the primary motor cortex (M1) contralateral to the active hand and also on modulation between and within anatomically distant but functionally connected brain regions. Interregional changes are particularly important in functional recovery after stroke, when critical plastic changes underpinning behavioral improvements are observed in both ipsilesional and contralesional M1s. It is increasingly understood that reduction in GABA in the contralateral M1 is necessary to allow learning of a motor task. However, the physiological mechanisms underpinning plasticity within other brain regions, most importantly the ipsilateral M1, are not well understood. Here, we used concurrent two-voxel magnetic resonance spectroscopy to simultaneously quantify changes in neurochemicals within left and right M1s in healthy humans of both sexes in response to transcranial direct current stimulation (tDCS) applied to left M1. We demonstrated a decrease in GABA in both the stimulated (left) and nonstimulated (right) M1 after anodal tDCS, whereas a decrease in GABA was only observed in nonstimulated M1 after cathodal stimulation. This GABA decrease in the nonstimulated M1 during cathodal tDCS was negatively correlated with microstructure of M1:M1 callosal fibers, as quantified by diffusion MRI, suggesting that structural features of these fibers may mediate GABA decrease in the unstimulated region. We found no significant changes in glutamate. Together, these findings shed light on the interactions between the two major network nodes underpinning motor plasticity, offering a potential framework from which to optimize future interventions to improve motor function after stroke.SIGNIFICANCE STATEMENT Learning of new motor skills depends on modulation both within and between brain regions. Here, we use a novel two-voxel magnetic resonance spectroscopy approach to quantify GABA and glutamate changes concurrently within the left and right primary motor cortex (M1) during three commonly used transcranial direct current stimulation montages: anodal, cathodal, and bilateral. We also examined how the neurochemical changes in the unstimulated hemisphere were related to white matter microstructure between the two M1s. Our results provide insights into the neurochemical changes underlying motor plasticity and may therefore assist in the development of further adjunct therapies.

Topographic Classification of the Thalamus Surfaces Related to Microneurosurgery: A White Matter Fiber Microdissection Study.

OBJECTIVE: To describe the topographic anatomy of surgically accessible surfaces of the human thalamus as a guide to surgical exploration of this sensitive area. METHODS: Using the operating microscope, we applied the fiber microdissection technique to study 10 brain specimens. Step-by-step dissections in superior-inferior, medial-lateral, and posterior-anterior directions were conducted to expose the surfaces and nuclei of the thalamus and to investigate the relevant anatomic relationships and visible connections. RESULTS: There were 4 distinct free surfaces of the thalamus identified: lateral ventricle surface, velar surface, cisternal surface, and third ventricle surface. Each is described with reference to recognizable anatomic landmarks and to the underlying thalamic nuclei. The neural structures most commonly encountered during the surgical approach to each individual surface are highlighted and described. CONCLUSIONS: Observations from this study supplement current knowledge, advancing the capabilities to define the exact topographic location of thalamic lesions. This improved understanding of anatomy is valuable when designing the most appropriate and least traumatic surgical approach to thalamic lesions. These proposed surface divisions, based on recognizable anatomic landmarks, can provide more reliable surgical orientation.

The expression of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) and HCN2 in the rat trigeminal ganglion, sensory root, and dental pulp.

Hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) and 2 (HCN2) are abundantly expressed in primary sensory neurons and contribute to neuronal excitability and pathological pain. We studied the expression of HCN1 and HCN2 in the rat trigeminal ganglion (TG) neurons and axons in the dental pulp, and the changes in their expression following inflammation, using light- and electron-microscopic immunocytochemistry and quantitative analysis. HCN1 and HCN2 were expressed predominantly in large-sized, neurofilament 200-immunopositive (+) or parvalbumin+ soma in the TG whereas they were expressed mostly in unmyelinated and small myelinated axons in the sensory root. The expression was particularly strong along the plasma membrane in the soma. In the dental pulp, majority of HCN1+ and HCN2+ axons coexpressed calcitonin gene-related peptide. They were expressed mainly in the peripheral pulp and pulp horn where the axons branch extensively in the dental pulp. The expression of HCN1 and HCN2 in TG neurons increased significantly in rats with experimentally induced inflammation of the dental pulp. Our findings support the notion that HCN1 and HCN2 are expressed mainly by both the soma of mechanosensitive neurons in the TG and peripheral axons of nociceptive neurons in the sensory root, and may play a role in the mechanisms of inflammatory pain from the dental pulp.

Acetyl salicylic acid locally enhances functional recovery after sciatic nerve transection in rat.

Local effect of acetyl salicylic acid (ASA) on peripheral nerve regeneration was studied using a rat sciatic nerve transection model. Forty-five male healthy White Wistar rats were divided into three experimental groups (n = 15), randomly: Sham-operation (SHAM), control (SIL), and ASA-treated (SIL/ASA) groups. In SHAM group after anesthesia left sciatic nerve was exposed through a gluteal muscle incision and after homeostasis the muscle was sutured. In SIL group the left sciatic nerve was exposed the same way and transected proximal to tibio-peroneal bifurcation leaving a 10-mm gap. Proximal and distal stumps were each inserted into a silicone tube and filled with 10 µl phosphate buffered solution. In SIL/ASA group defect was bridged using a silicone tube filled with 10 µl acetyl salisylic acid (0.1 mg/ml). Each group was subdivided into three subgroups of five animals each and were studied 4, 8, and 12 weeks after surgery. Data were analyzed statistically by factorial analysis of variance (ANOVA) and the Bonferroni test for pair-wise comparisons. Functional study confirmed faster and better recovery of regenerated axons in SIL/ASA than in SIL group (p < 0.05). Gastrocnemius muscle mass in SIL/ASA was significantly more than in SIL group. Morphometric indices of regenerated fibers showed that the number and diameter of the myelinated fibers in SIL/ASA were significantly higher than in control group. In immuohistochemistry, location of reactions to S-100 in SIL/ASA was clearly more positive than in SIL group. Response to local treatment of ASA demonstrates that it influences and improves functional recovery of peripheral nerve regeneration.

Neurofeedback training induces changes in white and gray matter.

The main objective of this structural magnetic resonance imaging (MRI) study was to investigate, using diffusion tensor imaging, whether a neurofeedback training (NFT) protocol designed to improve sustained attention might induce structural changes in white matter (WM) pathways, purportedly implicated in this cognitive ability. Another goal was to examine whether gray matter (GM) volume (GMV) might be altered following NFT in frontal and parietal cortical areas connected by these WM fiber pathways. Healthy university students were randomly assigned to an experimental group (EXP), a sham group, or a control group. Participants in the EXP group were trained to enhance the amplitude of their ß1 waves at F4 and P4. Measures of attentional performance and MRI data were acquired one week before (Time 1) and one week after (Time 2) NFT. Higher scores on visual and auditory sustained attention were noted in the EXP group at Time 2 (relative to Time 1). As for structural MRI data, increased fractional anisotropy was measured in WM pathways implicated in sustained attention, and GMV increases were detected in cerebral structures involved in this type of attention. After 50 years of research in the field of neurofeedback, our study constitutes the first empirical demonstration that NFT can lead to microstructural changes in white and gray matter.

Glutamate changes in healthy young adulthood.

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system and has been associated with several cognitive functions that are known to change with age. In rodents and humans age-related glutamate changes have been found in several brain areas. In this cross-sectional study the presence and extent of age-associated glutamate changes in the medial frontal cortex of healthy young adults were measured. Proton magnetic resonance spectroscopy ((1)H-MRS) and brain imaging were performed at 7 T in a 2 × 2 × 2 cm(3) voxel in 33 participants between 18 and 31 years old. Glutamate concentrations and grey and white matter volume could be successfully determined at an ultra-high magnetic field strength. Glutamate concentrations were lower in older individuals (0.33 mM/year). This decline is in line with grey matter thinning in the medial frontal cortex, but could not be explained by cortical thinning alone. Therefore, the decrease in glutamate in young adulthood may be due to physiological changes rather than anatomical changes.

Comparative mouse brain tractography of diffusion magnetic resonance imaging.

Diffusion magnetic resonance imaging (dMRI) tractography can be employed to simultaneously analyze three-dimensional white matter tracts in the brain. Numerous methods have been proposed to model diffusion-weighted magnetic resonance data for tractography, and we have explored the functionality of some of these for studying white and grey matter pathways in ex vivo mouse brain. Using various deterministic and probabilistic algorithms across a range of regions of interest we found that probabilistic tractography provides a more robust means of visualizing both white and grey matter pathways than deterministic tractography. Importantly, we demonstrate the sensitivity of probabilistic tractography profiles to streamline number, step size, curvature, fiber orientation distribution threshold, and wholebrain versus region of interest seeding. Using anatomically well-defined corticothalamic pathways, we show how projection maps can permit the topographical assessment of probabilistic tractography. Finally, we show how different tractography approaches can impact on dMRI assessment of tract changes in a mouse deficient for the frontal cortex morphogen, fibroblast growth factor 17. In conclusion, probabilistic tractography can elucidate the phenotypes of mice with neurodegenerative or neurodevelopmental disorders in a quantitative manner.

Phospholipidosis in neurons caused by posaconazole, without evidence for functional neurologic effects.

The azole antifungal drug posaconazole caused phospholipidosis in neurons of the central nervous system, dorsal root ganglia of the spinal cord, and myenteric plexus in chronic toxicity studies in dogs. The time of onset, light and electron microscopic features, neurologic and electrophysiologic effects on the central and peripheral nervous systems, and potential for regression were investigated in a series of studies with a duration of up to one year. Nuclei of the medulla oblongata were the prominently affected areas of the brain. Neurons contained cytoplasmic vacuoles with concentrically whorled plasma membrane-like material (i.e., multilamellar bodies) morphologically identical to that commonly caused in other tissues by cationic amphiphilic drugs. Some axons in the brain and spinal cord were swollen and contained granular eosinophilic, electron-dense lysosomes. There were no features suggesting degeneration or necrosis of neurons or any associated elements of nervous tissue. The earliest and most consistent onset was in neurons of dorsal root ganglia. The observed neural phospholipidosis did not result in any alteration in the amplitude or latency of the auditory, visual, or somatosensory evoked potentials. The histopathologic changes did not progress or regress within the three-month postdose period. The results indicate that phospholipidosis can be induced in central and peripheral neurons of dogs by administration of posaconazole, but this change is not associated with functional effects in the systems evaluated.

Methods for tractography-driven surface registration of brain structures.

Registration of brain structures should bring anatomically equivalent areas into correspondence which is usually done using information from structural MRI modalities. Correspondence can be improved by using other image modalities that provide complementary data. In this paper we propose and evaluate two novel surface registration algorithms which improve within-surface correspondence in brain structures. Both approaches use a white-matter tract similarity function (derived from probabilistic tractography) to match areas of similar connectivity patterns. The two methods differ in the way the deformation field is calculated and in how the multi-scale registration framework is implemented. We validated both algorithms using artificial and real image examples, in both cases showing high registration consistency and the ability to find differences in thalamic sub-structures between Alzheimer's disease and control subjects. The results suggest differences in thalamic connectivity predominantly in the medial dorsal parts of the left thalamus.

Hypothalamospinal oxytocinergic antinociception is mediated by GABAergic and opiate neurons that reduce A-delta and C fiber primary afferent excitation of spinal cord cells.

Recent results implicate a new original mechanism involving oxytocin (OT), as a mediator via descending fibers of the paraventricular hypothalamic nucleus (PVN), in antinociception and analgesia. In rats electrical stimulation of the PVN or topical application of OT selectively inhibits A-delta and C fiber responses in superficial dorsal horn neurons, and this inhibition is reversed by a selective OT antagonist. However, little is known about the mechanisms and the spinal elements participating in this phenomenon. Here we show that topical application of bicuculline blocks the effects produced by PVN electrical stimulation or OT application. PVN electrical stimulation also activates a subpopulation of neurons in lamina II. These PVN-On cells are responsible for the amplification of local GABAergic inhibition. This result reinforces the suggestion that a supraspinal descending control of pain processing uses a specific neuronal pathway in the spinal cord in order to produce antinociception involving a GABAergic interneuron. Moreover, the topical administration of naloxone or a mu-opiate receptor antagonist beta-funaltrexamine only partially blocks the inhibitory effects produced by OT application or PVN electrical stimulation. Thus, this OT mechanism only involves opiate participation to a minor extent. The OT-specific, endogenous descending pathway represents an interesting mechanism to resolve chronic pain problems in special the neuropathic pain.

Directional colour encoding of the human thalamus by diffusion tensor imaging.

The potential of diffusion tensor imaging (DTI) in brain imaging in terms of the in vivo mapping of neuroanatomy is generally accepted. Mostly, analyses of deep brain structures were based on complex methodical backgrounds. In the present study, the delineation of groups of thalamic nuclei with similar projection characteristics was investigated in healthy human subjects using a novel differentiated colour encoding approach of DTI data without the use of statistical calculations. With the application of this directional colour encoding of the longest eigenvector of every voxel-specific tensor, at least three functional groups in the thalamus with different projection directions could be differentiated. The method displayed, furthermore, a high symmetry and stability in the analysis of the individual subjects. In summary, substantial neuroanatomical information can be gained for deep subcortical gray matter structures such as the thalamus with an improved detection and directional differentiation of voxel-specific tensors.

Fiber composition of the rat sciatic nerve and its modification during regeneration through a sieve electrode.

Recovery after peripheral nerve transection is seldom complete, the outcome depending both on lesion and repair conditions, and on the type and neurochemical properties of axons. The interposition between the stumps of a perforated, or regenerative electrode (RE) is a promising avenue in the use of chronic nerve bioimplants, but represents an additional challenge to regeneration. We applied stereological methods to ultrathin and immunostained semithin sections to examine quantitatively the axon types that make up the sciatic nerve in control adult rats, and their changes 2 months after an RE implant. The number of myelinated axons (MAx) increased proximal to RE, but fell to 10% a few millimeters distal. This decrease affected more severely motor fibers, characterized by immunoreactivity to cholinacetyltransferase (ChAT+), than sensory (ChAT-) fibers. Regenerating MAx and myelin sheaths also changed notably in thickness. Unmyelinated axons (UAx) showed a moderate reduction in number distal to the implant. This reduction affected more tyrosine hydroxylase-immunoreactive axons (mostly vaso- and pilomotor fibers), than axons expressing ChAT and/or vasoactive intestinal peptide (mostly sudomotor fibers). Taken together with previous findings [Negredo, P., Castro, J., Lago, N., Navarro, X., Avendaño, C., 2004. Differential growth of axons from sensory and motor neurons through a regenerative electrode: a stereological, retrograde tracer, and functional study in the rat. Neuroscience 128, 605-615.], this study shows that regeneration through the RE is much less successful for MAx than UAx, that motor axons regenerate more poorly than sensory axons, and that some subclasses of sympathetic fibers regenerate better than others. The study also proves the value of the combined methodological approach presented here to assess the fiber composition of a nerve under normal, pathological or experimental conditions.

Somatotopic organization of thalamocortical projection fibers as assessed with MR tractography.

PURPOSE: To prospectively evaluate the course of sensory fibers through the supratentorial brain with diffusion-tensor-based tractography. MATERIALS AND METHODS: This study was approved by the institutional review board. Informed consent was obtained. Seven healthy volunteers (five men, two women; age range, 20-55 years) underwent 1.5-T magnetic resonance imaging. Diffusion-tensor images with isotropic voxels (2 x 2 x 2 mm) were obtained by using a single-shot echo-planar imaging technique, with a motion-probing gradient in 15 orientations, a b value of 1000 sec/mm(2), and nine signals acquired. The total imaging time was approximately 30 minutes. Fiber tracking of the sensorimotor pathways was performed with the fiber assignment by continuous tracking method. RESULTS: All the pyramidal tracts rotated anteriorly as they traveled through the centrum semiovale. On the other hand, the sensory tracts rotated posteriorly as they coursed through the centrum semiovale toward the cortex. When the sensorimotor tracts were viewed as a unit, the tracts of the lower extremity formed the axis of rotation around which the other parts of the pyramidal and sensory homunculus rotated. CONCLUSION: Sensorimotor fibers of the lower extremity form an axis of rotation, around which the pyramidal fibers rotate anteriorly and the sensory fibers rotate posteriorly.

Morphological analysis of human acupuncture points through immunohistochemistry.

OBJECTIVE: At present, the functional mechanism of acupuncture is not yet fully understood. Analysis of the subanatomic morphology of acupuncture points (APs) could help compensate for this shortcoming. In immunohistochemistry, the use of specific antibodies enables in situ characterization of the molecular profile of tissue microenvironments. Thus, as proof in principle for the utility of immunohistochemistry, we determined whether the nerve density in biopsies of autopsied skin of a selected standard AP differed from that of a control point (CP). DESIGN: We analyzed pairs of skin samples from nine autopsy cases and studied the presence and density of soluble protein 100 (S-100), neuron-specific enolase (NSE), and neurofilament (NF) as markers of peripheral nerve structures. Cross-sections of nerves were counted by conventional microscopy and normalized to millimeters squared of subcutaneous fat, followed by statistical analyses for formal comparisons. RESULTS: Immunohistochemistry could clearly identify myelinated peripheral nerves. The number of nerve structures expressing S-100 protein was significantly reduced in APs compared with CPs (0.020 1 0.005 vs. 0.061 +/- 0.014; P < 0.006). The same pattern was seen in staining of NSE (AP: 0.011 +/- 0.003 vs. CP: 0.045 +/- 0.011) and NF (AP: 0.011 +/- 0.004 vs. CP: 0.054 +/- 0.015; both P < 0.007). CONCLUSIONS: In this study, we introduce immunohistochemistry as a suitable technology for acupuncture research. In addition, our findings demonstrate that a human AP is not necessarily associated with an increased but, rather, a significantly decreased number and density of subcutaneous nerve structures compared with skin biopsies from locations not recognized as effective for acupuncture. This pilot study, executed on a limited number of individuals and skin samples, justifies the application of immunohistochemistry on a larger collection of biopsy material.

Thalamo-cortical connectivity in children born preterm mapped using probabilistic magnetic resonance tractography.

Our aim was to investigate the feasibility of studying white matter tracts and connections between the thalamus and the cortex in 2-year-old infants who were born preterm by probabilistic magnetic resonance (MR) tractography. Using this approach, we were able to visualize and quantify connectivity distributions in a number of white matter tracts, including the corticospinal tracts, optic radiations, fibers of the genu and splenium of the corpus callosum, superior longitudinal fasciculus and inferior fronto-occipital fasciculus, and to map the distribution within thalamus of fibers connecting to specific cortical regions. In eleven infants with no MR evidence of focal cerebral lesions and appropriate neurodevelopment as shown by general quotient (GQ) scores above 100, we mapped cortical connections to the thalamus that appeared similar to those reported in adults. However, in a proof-of-principle experiment, we examined one further child with marked white matter abnormalities and found that the volume and pattern of thalamo-cortical connections were severely disrupted. This technique promises to be a useful tool for assessing connectivity in the developing brain and in infants with lesions.

[The effects of eucommia ulmoides oliv on catching action of diabetic rats and myelinated nerve fibers in penile tissues].

OBJECTIVE: To explore the pharmacodynamic and pathological mechanism of eucommia ulmoides oliv in improving erectile function. METHODS: Thirty male diabetic rats were randomly divided into three groups: group A (n = 10, escipient group), group B (n = 10, sildenafil group), group C (n = 10, eucommia ulmoides oliv group) and group D (n = 10, the normal control group). After gavage for four weeks, the catching behaviors of all rats were observed, and ultrastructure of myelinated nerve fibers in penile tissue was examined by transmission electron microscope. The expression of neuronal nitric oxide synthase (nNOS) in penile tissues was examined by two steps immunohistochemistry method. RESULTS: Compared with group A, catching frequency of the rats in group C was notably increased (P < 0.05) and the expression of nNOS in penile tissue was significantly (P < 0.001). The examination by transmission electron microscope showed that in the rats' penile tissue of group A, myelinated nerve fibers were irregularly arranged and partially degenerated, and myelin sheaths lamella were splited and exhibited vacuoles or network forms. In group C, there were regular arrangements of myelinated nerve fibers, in which the formation of lamella was clear. CONCLUSION: By remitting the impairement of myelinated nerve fibers and enhancing the expression of nNOS in penile tissue, eucommia ulmoides oliv can improve erectile function of diabetic rats.

Traumatic axonal injury in the perisomatic domain triggers ultrarapid secondary axotomy and Wallerian degeneration.

Traumatic axonal injury (TAI) arising from diffuse brain injury (DBI) results in focally impaired axonal transport with progressive swelling and delayed disconnection over several hours within brainstem axons. Neocortical DBI-mediated perisomatic axotomy does not result in neuronal death, suggesting that a comparably delayed axotomy progression was responsible for this unanticipated response. To evaluate delayed perisomatic axotomy, the current study was initiated. Rats received intracerebroventricular 10-kDa dextran followed by moderate midline/central fluid percussion injury (FPI) or FPI alone. At 15, 30, 60, and 180 min post-injury, light and transmission electron microscopy identified impaired axonal transport via antibodies targeting amyloid precursor protein (APP), while double-label fluorescent microscopy explored concomitant focal axolemmal alterations via dextran-APP co-localization. At 15 min post-injury, perisomatic TAI was identified with LM within dorsolateral and ventral posterior thalamic nuclei. Using TEM, many sustaining somata and related proximal/distal axonal segments revealed normal ultrastructural detail that was continuous with focal axonal swellings characterized by cytoskeletal and organelle pathology. In other cases, axotomy was confirmed by loss of axonal continuity distal to the swelling. By 30 min post-injury, perisomatic axotomy predominated. By 60-180 min, somatic, proximal axonal segment, and swelling ultrastructure were comparable to earlier time points although swelling diameter increased. Distal axonal segment ultrastructure now revealed the initial stages of Wallerian degeneration. The site of perisomatic axotomy did not internalize dextran, suggesting that its pathogenesis occurred independent of altered axolemmal permeability. Collectively, this DBI-mediated ultrarapid perisomatic axotomy and its sequelae further illustrate the varied axonal responses to trauma.

Postnatal development of alkaline phosphatase activity correlates with the maturation of neurotransmission in the cerebral cortex.

We have shown previously that the tissue nonspecific alkaline phosphatase (TNAP) is selectively expressed in the synaptic cleft of sensory cortical areas in adult mammals and, by using sensory deprivation, that TNAP activity depends on thalamocortical activity. We further analyzed this structural functional relationship by comparing the developmental pattern of TNAP activity to the maturation of the thalamocortical afferents in the primate brain (Callithrix jacchus). Cortical expression of alkaline phosphatase (AP) activity reflects the sequential maturation of the modality-specific sensory areas. Within the visual cortex, the regional and laminar distribution of AP correlates with the differential maturation of the magno- and parvocellular streams. AP activity, which is transiently expressed in the white matter, exhibits a complementary distributional pattern with myelin staining. Ultrastructural analysis revealed that AP activity is localized exclusively to the myelin-free axonal segments, including the node of Ranvier. It was also found that AP activity is gradually expressed in parallel with the maturation of synaptic contacts in the neuropile. These data suggest the involvement of AP, in addition to neurotransmitter synthesis previously suggested in the adult, in synaptic stabilization and in myelin pattern formation and put forward a role of AP in cortical plasticity and brain disorders.

Visualization of thalamic nuclei on high resolution, multi-averaged T1 and T2 maps acquired at 1.5 T.

The ability to differentiate noninvasively between the primary nuclear divisions of the thalamus has immediate clinical applicability for surgical planning and guidance of functional stereotactic procedures. Comparison of prior qualitative magnetic resonance imaging (MRI) studies carried out at field strengths of 1.5 and 4 Tesla have revealed contrast within the thalamus that varies with field strength, suggesting possible differences in the inherent T1 and T2 relaxation times of the constituent nuclei. We investigate this hypothesis through acquisition of high-resolution, multi-averaged deep-brain T1 and T2 maps of a healthy volunteer. Fourteen nuclei were identified using their center-of-mass coordinates (in Talairach space) and average T1 and T2 values obtained from regions of interest placed within each. Results from this analysis revealed significant differences in T1 and T2 between the nuclei with a T1 range from 700 to 1,400 ms and a T2 range from 89 to 122 ms, allowing visual discrimination between the major nuclei groups. Furthermore, the high-resolution images showed distinct borders of T1 and T2 hypointensity surrounding each nucleus, revealing structure not reported previously. These results confirm our hypothesis and demonstrate the potential high-resolution quantitative imaging for nucleus visualization and surgical planning.

Sequence of oligodendrocyte development in the human fetal telencephalon.

Oligodendrocytes (OL), cells that myelinate axons in the CNS, differentiate from early to late oligodendrocyte progenitor cells (OPC) to become mature OL. Unlike the case in the rodent brain, myelin formation starts prenatally in the human brain, but the sequence of OL development and the onset of myelination are not well understood. We studied the human fetal forebrain at midgestation (17-23 gestational weeks, g.w.) using OL lineage-specific antibodies and mRNA probes. Early OPC were present in a gradient from the subventricular zone to the cortical plate. Their close apposition to radial glia fibers suggests a possible role of these fibers in OPC migration. Late OPC reached peak density in the subplate layer, whereas multipolar cells with the morphology of mature OL were restricted to the emerging white matter. At 20 g.w., myelinated axons were observed in the diencephalon, but not in the telencephalon, consistent with caudal-to-rostral progression of myelination. Interestingly, in organotypic slice cultures of the same gestational ages, the subventricular zone contained a considerably greater number of the mature OL cells, suggesting the presence of inhibitory signals in vivo. Overall, in addition to considerable similarities with rodents, important differences in temporal and spatial distribution and regulatory signals for OL differentiation exist in the human brain.