Subtle Morphological Abnormalities Research Articles

Hypoglossal Nerve Abnormalities as Biomarkers for Central Nervous System Defects in Mouse Lines Producing Embryonically Lethal Offspring.

An essential step in researching human central nervous system (CNS) disorders is the search for appropriate mouse models that can be used to investigate both genetic and environmental factors underlying the etiology of such conditions. Identification of murine models relies upon detailed pre- and post-natal phenotyping since profound defects are not only the result of gross malformations but can be the result of small or subtle morphological abnormalities. The difficulties in identifying such defects are compounded by the finding that many mouse lines show quite a variable penetrance of phenotypes. As a result, without analysis of large numbers, such phenotypes are easily missed. Indeed for null mutations, around one-third have proved to be pre- or perinatally lethal, their analysis resting entirely upon phenotyping of accessible embryonic stages.To simplify the identification of potentially useful mouse mutants, we have conducted three-dimensional phenotype analysis of approximately 500 homozygous null mutant embryos, produced from targeting a variety of mouse genes and harvested at embryonic day 14.5 as part of the “Deciphering the Mechanisms of Developmental Disorders” www.dmdd.org.uk program. We have searched for anatomical features that have the potential to serve as biomarkers for CNS defects in such genetically modified lines. Our analysis identified two promising biomarker candidates. Hypoglossal nerve (HGN) abnormalities (absent, thin, and abnormal topology) and abnormal morphology or topology of head arteries are both frequently associated with the full spectrum of morphological CNS defects, ranging from exencephaly to more subtle defects such as abnormal nerve cell migration. Statistical analysis confirmed that HGN abnormalities (especially those scored absent or thin) indeed showed a significant correlation with CNS defect phenotypes. These results demonstrate that null mutant lines showing HGN abnormalities are also highly likely to produce CNS defects whose identification may be difficult as a result of morphological subtlety or low genetic penetrance.

Ubiquitin ligase COP1 coordinates transcriptional programs that control cell type specification in the developing mouse brain

The E3 ubiquitin ligase CRL4COP1/DET1 is active in the absence of ERK signaling, modifying the transcription factors ETV1, ETV4, ETV5, and c-JUN with polyubiquitin that targets them for proteasomal degradation. Here we show that this posttranslational regulatory mechanism is active in neurons, with ETV5 and c-JUN accumulating within minutes of ERK activation. Mice with constitutive photomorphogenesis 1 (Cop1) deleted in neural stem cells showed abnormally elevated expression of ETV1, ETV4, ETV5, and c-JUN in the developing brain and spinal cord. Expression of c-JUN target genes Vimentin and Gfap was increased, whereas ETV5 and c-JUN both contributed to an expanded number of cells expressing genes associated with gliogenesis, including Olig1, Olig2, and Sox10. The mice had subtle morphological abnormalities in the cerebral cortex, hippocampus, and cerebellum by embryonic day 18 and died soon after birth. Elevated c-JUN, ETV5, and ETV1 contributed to the perinatal lethality, as several Cop1-deficient mice also lacking c-Jun and Etv5, or lacking Etv5 and heterozygous for Etv1, were viable.

Thalamic volume reduction in drug-naive patients with new-onset genetic generalized epilepsy.

SummaryObjectivePatients with genetic generalized epilepsy (GGE) have subtle morphologic abnormalities of the brain revealed with magnetic resonance imaging (MRI), particularly in the thalamus. However, it is unclear whether morphologic abnormalities of the brain in GGE are a consequence of repeated seizures over the duration of the disease, or are a consequence of treatment with antiepileptic drugs (AEDs), or are independent of these factors. Therefore, we measured brain morphometry in a cohort of AED‐naive patients with GGE at disease onset. We hypothesize that drug‐naive patients at disease onset have gray matter changes compared to age‐matched healthy controls.MethodsWe performed quantitative measures of gray matter volume in the thalamus, putamen, caudate, pallidum, hippocampus, precuneus, prefrontal cortex, precentral cortex, and cingulate in 29 AED‐naive patients with new‐onset GGE and compared them to 32 age‐matched healthy controls. We subsequently compared the shape of any brain structures found to differ in gray matter volume between the groups.ResultsThe thalamus was the only structure to show reduced gray matter volume in AED‐naive patients with new‐onset GGE compared to healthy controls. Shape analysis revealed that the thalamus showed deflation, which was not uniformly distributed, but particularly affected a circumferential strip involving anterior, superior, posterior, and inferior regions with sparing of medial and lateral regions.SignificanceStructural abnormalities in the thalamus are present at the initial onset of GGE in AED‐naive patients, suggesting that thalamic structural abnormality is an intrinsic feature of GGE and not a consequence of AEDs or disease duration.

No Association between Cortical Gyrification or Intrinsic Curvature and Attention-deficit/Hyperactivity Disorder in Adolescents and Young Adults.

Magnetic resonance imaging (MRI) studies have highlighted subcortical, cortical, and structural connectivity abnormalities associated with attention-deficit/hyperactivity disorder (ADHD). Gyrification investigations of the cortex have been inconsistent and largely negative, potentially due to a lack of sensitivity of the previously used morphological parameters. The innovative approach of applying intrinsic curvature analysis, which is predictive of gyrification pattern, to the cortical surface applied herein allowed us greater sensitivity to determine whether the structural connectivity abnormalities thus far identified at a centimeter scale also occur at a millimeter scale within the cortical surface. This could help identify neurodevelopmental processes that contribute to ADHD. Structural MRI datasets from the NeuroIMAGE project were used [n = 306 ADHD, n = 164 controls, and n = 148 healthy siblings of individuals with ADHD (age in years, mean(sd); 17.2 (3.4), 16.8 (3.2), and 17.7 (3.8), respectively)]. Reconstructions of the cortical surfaces were computed with FreeSurfer. Intrinsic curvature (taken as a marker of millimeter-scale surface connectivity) and local gyrification index were calculated for each point on the surface (vertex) with Caret and FreeSurfer, respectively. Intrinsic curvature skew and mean local gyrification index were extracted per region; frontal, parietal, temporal, occipital, cingulate, and insula. A generalized additive model was used to compare the trajectory of these measures between groups over age, with sex, scanner site, total surface area of hemisphere, and familiality accounted for. After correcting for sex, scanner site, and total surface area no group differences were found in the developmental trajectory of intrinsic curvature or local gyrification index. Despite the increased sensitivity of intrinsic curvature, compared to gyrification measures, to subtle morphological abnormalities of the cortical surface we found no milimeter-scale connectivity abnormalities associated with ADHD.

Expanding the morphologic spectrum of differentiated VIN (dVIN) through detailed mapping of cases with p53 loss.

The pathogenesis of vulvar squamous cell carcinoma follows 1 of 2 distinct pathways. A precursor lesion in the human papilloma virus-independent pathway, differentiated vulvar intraepithelial neoplasia (dVIN), was only recently characterized in detail and is infrequently diagnosed without an associated component of invasive carcinoma. Aberrant p53 immunostaining is frequently seen in dVIN, and in approximately 25% to 30% of cases it manifests as a complete loss or a p53-null pattern. The abrupt transition between p53 loss and basal p53 expression in lesional versus nonlesional epithelium allows clear demarcation between neoplastic and non-neoplastic epithelium. For this study, 14 specimens from 10 patients were identified from the pathology archives of 2 teaching hospitals on the basis of: (1) a diagnosis of dVIN, with or without invasive carcinoma; and (2) p53-null immunostaining pattern in lesional cells. Ten specimens had associated invasive carcinoma. All sections from each specimen that showed the specimen resection margin were stained for p53 and reviewed together with all hematoxylin and eosin sections. Detailed morphologic assessment of the p53-null epithelium was made and compared with the adjacent benign squamous epithelium. The status of the resection margins based on the original pathologic assessment was compared with that assessed with p53 immunohistochemistry. One specimen showed p53 loss in the invasive carcinoma but patchy basal positivity in the region originally diagnosed as dVIN, supporting interpretation as a benign hyperplastic focus, rather than dVIN. In the remaining 13 specimens the areas originally diagnosed as dVIN, as well as the associated invasive carcinoma (if present), were p53-null. In 8 of these specimens, on the basis of the presence of p53-null immunostaining and subtle morphologic abnormalities, dVIN was more extensive than originally recognized. The spectrum of morphologic changes in p53-null regions that were in continuity with areas originally recognized as dVIN were subtle and typically consisted of an abrupt change in maturation of the squamous epithelium (loss of keratohyaline granules and parakeratosis), tinctorial alterations in the keratinocytes, with cells containing more abundant eosinophilic cytoplasm, and minimal basal nuclear atypia. Margin status changed from negative to positive in 4 of 13 specimens and from focally to more extensively positive in an additional 3 specimens. In summary, the clonal in situ component of non-human papilloma virus vulvar squamous cell carcinoma can be characterized by very subtle morphologic abnormalities that may be misinterpreted as benign change. This results in underestimation of the extent of dVIN, and, as a result, resection margin involvement may be significantly underestimated. dVIN can also be overdiagnosed in areas of reactive change. Better tools for diagnosis of dVIN are needed; until such tools are developed the limitations in the current diagnosis of dVIN should be recognized.

Aetiology of cognitive impairment in children with frontal lobe epilepsy

Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its aetiology is unknown. MRI scans often reveal no structural brain abnormalities that could explain the cognitive impairment. This does not exclude more subtle morphological abnormalities that can only be detected by automated morphometric techniques. With these techniques, we investigate the relationship between cortical brain morphology and cognitive functioning in a cohort of children with FLE and healthy controls. Thirty-four children aged 8-13 years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural brain MRI. Patients were grouped as cognitively impaired or unimpaired. Intracranial volume, white matter volume, lobular cortical volume, cortical thickness and volumes of cortex structures were compared between patients and controls, and potential correlations with cognitive status were determined. The group of cognitively impaired children with FLE had significantly smaller left temporal cortex volumes, specifically middle temporal grey matter volume and entorhinal cortex thickness. In addition, cognitively impaired children with FLE had smaller volumes of structures in the left and right frontal cortex, right temporal cortex and the left subcortical area. Cognitively impaired children with FLE have smaller volumes of various cortex structures within the frontal lobes and in extra-frontal regions, most notably temporal cortex volumes. These findings might well explain the broad scale of cognitive domains affected in children with FLE complicated by cognitive impairment and highlight that FLE impacts on areas beyond the frontal lobe.

Shared Morphology of Slipped Capital Femoral Epiphysis and Femoroacetabular Impingement in Early-onset Arthritis

A subclinical form of slipped capital femoral epiphysis (SCFE) can lead to subtle morphologic abnormalities, such as cam-type femoroacetabular impingement (FAI). Femoroacetabular impingement is a mechanical hip abnormality that typically affects young populations and leads to hip pain and premature osteoarthritis. Imaging is critical to diagnosis, whether by radiograph, magnetic resonance imaging, or computed tomography. The authors investigated the use of imaging to detect characteristics of subclinical SCFE and cam-type FAI in patients undergoing hip resurfacing. They retrospectively assessed computed tomography scans of 81 hips from 75 patients. Measurements were taken of the proximal femur and included the alpha angle, head-neck tilt, and anterior offset taken in both the conventional oblique axial plane and the radial plane. The cohort consisted of 68 men and 13 women with an average age of 52 years. Ninety percent of hips on the oblique axial view and 95% of hips on the radial view were found to have pathologically increased alpha angles. Negative correlations were found between the alpha angle and head-neck tilt and positive correlations between head-neck tilt and anterior offset ratio. Sixty percent and 68% of hips in the oblique axial and radial planes, respectively, were abnormal for the alpha angle, head-neck tilt, and anterior offset ratio, strongly suggesting SCFE morphology. This study's results show similarity in morphology between cam-type FAI and SCFE, known precursors to osteoarthritis, in an early arthritic patient population.

MEG-based identification of the epileptogenic zone in occult peri-insular epilepsy

IntroductionPresurgical work-ups of patients with pharmacoresistant epileptic seizures can require multiple diagnostic methods if magnetic resonance imaging (MRI) combined with video-EEG monitoring fails to show an epileptogenic lesion. Yet, the added value of available methods is not clear. In particular, only a minority of epilepsy centres apply magnetoencephalography (MEG). This study explores the potential of MEG for patients whose previous sophisticated work-ups missed deep-seated, peri-insular epileptogenic lesions. Patients and methodsThree patients with well documented, frequent, stereotypical hypermotor seizures without clear focus hypotheses after repeated presurgical work-ups including video-EEG-monitoring, 3Tesla (3T) magnetic resonance imaging (MRI), morphometric MRI analysis, PET and SPECT were referred to MEG source localisation. ResultsIn two out of three patients, MEG source localisation identified very subtle morphological abnormalities formerly missed in MRI or classified as questionable pathology. In the third patient, MEG was not reliable due to insufficient detection of epileptic patterns. Here, a 1mm×1mm×1mm 3T fluid-attenuated inversion recovery (FLAIR) MRI revealed a potential epileptogenic lesion. A minimal invasive work-up via lesion-focused depth electrodes confirmed the intralesional seizure onset in all patients, and histology revealed dysplastic lesions. Seizure outcomes were Engel 1a in two patients, and Engel 1d in the third. DiscussionMEG can contribute to the identification of epileptogenic lesions even when multiple previous methods failed, and when the lesions are located in deep anatomical structures such as peri-insular cortex. For epilepsy centres without MEG capability, referral of patients with cryptogenic focal epilepsies to centres with MEG systems may be indicated.

Femoroacetabular Impingement: Saving the Joint

Many factors have been linked to the development of osteoarthritis (OA) of the hip, but often, cases are still considered idiopathic. Femoroacetabular impingement (FAI) has been suggested as a possible etiologic factor for the otherwise idiopathic cases. It is theorized that the subtle morphologic abnormalities seen at the head-neck junction and acetabulum in FAI may lead to labral tears, chondral damage, and subsequent progression of OA. Prevalence of FAI has been suggested to be as high as 14% in the general population. It often presents in young active patients that subject their hip joint to repetitive micro trauma associated with impingement of the osseous deformity within normal ranges of motion. Current surgical treatment options for FAI include arthroscopy, open surgical dislocation, or mini-open direct anterior osteoplasty. All methods are directed at correcting the osseous abnormalities and associated pathologies in hopes of delaying the progression of OA and the need for hip replacement. Limited short term follow-up data has shown significant improvement in pain and function following each of the three procedures. However, long term follow-up and comparative studies are necessary to evaluate the efficacy of each of the surgical approaches in delaying the progression of osteoarthritis.

Femoroacetabular Impingement

Evidence is emerging that subtle morphologic abnormalities around the hip, resulting in femoroacetabular impingement, may be a contributing factor in some instances to osteoarthritis in the young patient. The morphologic abnormalities result in abnormal contact between the femoral neck/head and the acetabular margin, causing tearing of the labrum and avulsion of the underlying cartilage region, continued deterioration, and eventual onset of arthritis. Nonsurgical treatment typically fails to control symptoms. Surgical management involves dislocation of the hip (while preserving the blood supply to the femoral head) and femoroacetabular osteoplasty. Encouraging results have been reported following femoroacetabular osteoplasty and arthroscopic treatment of femoroacetabular impingement.

Sperm DNA Integrity From Sperm to Egg

Sperm DNA Integrity From Sperm to Egg

Femoroacetabular impingement

The two major categories of conditions that give rise to osteoarthritis (OA) of the hip are dysplasia and nondysplasia. Dysplasia, commonly with anterolateral deficiency, may account for up to 40% of OA cases in the United States and over 80% of OA cases in Japan and Italy. In a distinct category of patients, there is no identifiable cause for OA, or so-called idiopathic arthritis. There is emerging evidence that subtle morphologic abnormalities around the hip, resulting in femoroacetabular impingement, may be a contributing factor in many instances.

Developmental Consequences of Trace Mineral Deficiencies in Rodents: Acute and Long-Term Effects

Approximately 3% of infants born have at least one serious congenital malformation. In the U.S., an average of 10 infants per thousand die before 1 y of life; about half of these deaths can be attributed to birth defects, low birth weight or prematurity. Although the causes of developmental abnormalities are clearly multifactorial in nature, we suggest that a common factor contributing to the occurrence of developmental abnormalities is suboptimal mineral nutrition during embryonic and fetal development. Using zinc and copper as examples, evidence is presented that nutritional deficiencies can rapidly affect the developing conceptus and result in gross structural abnormalities. Deficits of zinc or copper can result in rapid changes in cellular redox balance, tissue oxidative stress, inappropriate patterns of cell death, alterations in the migration of neural crest cells and changes in the expression of key patterning genes. In addition to well-recognized malformations, mineral deficiencies during perinatal development can result in behavioral, immunological and biochemical abnormalities that persist into adulthood. Although these persistent defects can in part be attributed to subtle morphological abnormalities, in other cases they may be secondary to epigenetic or developmental changes in DNA methylation patterns. Epigenetic defects combined with subtle morphological abnormalities can influence an individual's risk for certain chronic diseases and thus influence his or her risk for morbidity and mortality later in life.

Infection with the oncogenic human papillomavirus type 59 alters protein components of the cornified cell envelope

Infection of the genital tract with human papillomaviruses (HPVs) leads to proliferative and dysplastic epithelial lesions. The mechanisms used by the virus to escape the infected keratinocyte are not well understood. Infection of keratinocytes with HPV does not cause lysis, the mechanism used by many viruses to release newly formed virions. For HPV 11, a type associated with a low risk of neoplastic disease, the cornified cell envelope (CCE) of infected keratinocytes is thin and fragile, and transcription of loricrin, the major CCE protein, is reduced. The effects of high-risk HPV infection on components of the CCE have not been previously reported. HPV 59, an oncogenic genital type related to HPV types 18 and 45 was identified in a condylomata acuminata lesion. An extract of this lesion was used to infect human foreskin fragments, which were grown in athymic mice as xenografts. Continued propagation using extracts of xenografts permitted growth of additional HPV 59-infected xenografts. CCEs purified from HPV 59-infected xenografts displayed subtle morphologic abnormalities compared to those derived from uninfected xenografts. HPV 59-infected xenografts revealed dysplastic-appearing cells with mitotic figures. Detection of loricrin, involucrin, and cytokeratin 10 was reduced in HPV 59-infected epithelium, while small proline-rich protein 3 (SPR3) was increased. Reduction in loricrin was most apparent in regions of epithelium containing abundant HPV 59 DNA. Compared to uninfected epithelium, loricrin transcription was decreased in HPV 59-infected epithelium. We conclude that HPV 59 shares with HPV 11 the ability to alter CCE components and to specifically reduce transcription of the loricrin gene. Because loricrin is the major CCE protein, a reduction in this component could alter the physical properties of the CCE, thus facilitating virion release.

Precursor lesions of ovarian epithelial malignancy.

Most ovarian carcinomas arise from the mesothelial surface lining of the ovaries, or from invaginations of this lining into the superficial ovarian cortex to form cortical inclusion cysts. The native ovarian surface mesothelium is of an 'uncommitted' phenotype, and has potential to modulate to epithelial or mesenchymal phenotypes in response to signals such as those associated with ovulation. The exposure of the mesothelial lining of an inclusion cyst to the ovarian stromal microenvironment may be responsible for the phenotypic change to Müllerian epithelium so commonly seen in these cysts. Müllerian metaplasia is usually to a serous phenotype, and it is possible that undefined molecular events occurring in an inclusion cyst that has undergone Müllerian metaplasia may initiate neoplastic change in these cysts. This may be the developmental pathway of most invasive serous carcinomas. Occasional rare cases of ovarian intraepithelial neoplasia, manifested by epithelial atypia in an inclusion cyst or on the surface epithelium without invasive carcinoma, are identified histologically. Serous borderline tumours represent a separate category and in most cases probably do not progress to frank carcinoma. Mucinous carcinomas may in some cases have arisen from pre-existing benign and borderline mucinous tumours. Endometriosis of the ovary is associated with genetic abnormalities and is frequently found in association with clear cell and endometrioid carcinomas, suggesting that in many cases these latter two types of carcinoma may have arisen directly from endometriotic deposits. Ovaries removed prophylactically from women with a family history of ovarian carcinoma or with a mutation in one of the genes predisposing to ovarian carcinoma should be processed in their entirety, and examined closely not just for obviously neoplastic lesions, but also for more subtle morphological abnormalities of the surface epithelium or the epithelium lining cortical inclusion cysts.

Planum temporale, planum parietale and dichotic listening in dyslexia

A reduction or reversal of the normal leftward asymmetry of the planum temporale (PT) has been claimed to be typical of dyslexia, although some recent studies have challenged this view. In a population-based study of 20 right-handed dyslexic boys and 20 matched controls, we have measured the PT and the adjacent planum parietale (PP) region in sagittal magnetic resonance images. For the PT, mean left and right areas and asymmetry coefficients were compared. Since a PP area often could not be identified in one or both hemispheres, a qualitative comparison was used for this region. The total planar area (sum of PT and PP) was also compared between the two groups. A dichotic listening (DL) test with consonant–vowel syllables was administered to assess functional asymmetry of language. The results showed a mean leftward PT asymmetry in both the dyslexic and the control group, with no significant difference for the degree of PT asymmetry. Planned comparisons revealed however, a trend towards smaller left PT in the dyslexic group. In control children, but not in the dyslexic children, a significant correlation between PT asymmetry and reading was observed. A mean leftward asymmetry was also found for the total planar area, with no difference between the groups for the degree of asymmetry. Significantly fewer dyslexic children than control children showed a rightward asymmetry for the PP region. Both groups showed a normal right ear advantage on the DL task, with no significant difference for DL asymmetry. No significant correlation was observed between PT asymmetry and DL asymmetry. The present population-based study adds to recent reports of normal PT asymmetry in dyslexia, but indicates that subtle morphological abnormalities in the left planar area may be present in this condition.

A homolog of human transcription factor NF-X1 encoded by the Drosophila shuttle craft gene is required in the embryonic central nervous system.

NF-X1 is a novel cytokine-inducible transcription factor that has been implicated in the control of immune responses in humans, presumably by regulating expression of class II major histocompatibility genes. Here we report the cloning and genetic characterization of the first reported NF-X1 homolog, which is encoded by the Drosophila melanogaster shuttle craft (stc) gene. The deduced sequence of the fly and human proteins defines a new family of molecules distinguished by a novel cysteine-rich DNA-binding motif (consisting of seven copies of the consensus sequence Cx3Cx3LxCGx0-5HxCx3CHxGxCx2Cx7-9CxC). We have identified and begun a phenotypic characterization of mutations in the stc gene. stc mutants die at the end of embryogenesis, when they appear to be incapable of coordinating the typical peristaltic contraction waves normally required for embryos to hatch into feeding first instar larvae. Preliminary evidence indicates that the resulting lethality of this behavioral defect is accompanied by subtle morphological abnormalities in the central nervous system, where in wild-type embryos, STC protein is normally localized in the nuclei of repeated cell clusters within each neuromere and brain lobe. Thus, the NF-X1 homolog encoded by the Drosophila stc gene defines a new family of putative transcription factors and plays an essential role in the completion of embryonic development. This study presents the first in vivo genetic analysis of a member of this new protein family.

Sudden Infant Death Syndrome

The brainstem and cervical spinal cord were sampled from 45 cases of sudden infant death syndrome (SIDS), from 17 control cases without neurological disease, and from three negative control cases with abnormal growth of the central nervous system (36-98 postconceptional weeks). Morphometric analyses were performed on serial Nissl sections to determine the total volumes of the pons, nucleus pontis, medulla and cervical spinal cord. Normal development was characterized by a linear increase in the volumes of these regions during the first postnatal year. Regression analysis revealed that in SIDS cases the rates of increase in the volumes of the pons and nucleus pontis were significantly greater than in controls (56% and 83%, respectively), while growth rates did not differ significantly for the medulla and cervical spinal cord. By direct comparison, there was a significant increase in the mean volumes of the pons (33%), nucleus pontis (38%) and medulla (19%) in SIDS cases when compared to controls. No evidence of excessive edema or gliosis was noted in the brainstem by light and electron microscopy to account for the increased volumes. Subtle morphological abnormalities in brainstem neurons from SIDS cases, including an increased size of Nissl bodies in the cytoplasm of large motor neurons and the presence of paranucleolar coiled bodies, were consistent with an increased synthesis and transport of ribosomal RNA, an increased synthesis of cellular proteins and neuronal hypertrophy.

Mice deficient for the glycoprotein show subtle abnormalities in myelin

Using homologous recombination in embryonic stem cells, we have generated mice with a null mutation in the gene encoding the myelin-associated glycoprotein (MAG), a recognition molecule implicated in myelin formation. MAG-deficient mice appeared normal in motor coordination and spatial learning tasks. Normal myelin structure and nerve conduction in the PNS, with N-CAM overexpression at sites normally expressing MAG, suggested compensatory mechanisms. In the CNS, the onset of myelination was delayed, and subtle morphological abnormalities were detected in that the content of oligodendrocyte cytoplasm at the inner aspect of most myelin sheaths was reduced and that some axons were surrounded by two or more myelin sheaths. These observations suggest that MAG participates in the formation of the periaxonal cytoplasmic collar of oligodendrocytes and in the recognition between oligodendrocyte processes and axons.

Technical and clinical aspects of topographic brain mapping.

TBM provides physiological and diagnostic information which is quite complementary to EEG, but does not replace the need for standard EEG recordings. For example, it does not show subtle morphologic abnormalities such as FIRDA, PLEDs or epileptiform discharges. Simultaneous EEG recording as well as impeccable technique are essential in proper recording of TBM, particularly as it can generate new forms of artifact. By prolonging the averaging time to over 180 seconds, and by application of flexible montages, a more accurate and cleaner record with less artifact can be obtained. Certain phenomena such as "centrifugal effect" and "comet effect" are examples of new problems generated by the advent of TBM. On the other hand, TBM can demonstrate subtle asymmetries, lateralization and localization effects more efficiently than a standard EEG. TBM is quite helpful clinically, when recording is done properly from a technical standpoint, in the diagnosis of post-traumatic syndrome and post-traumatic seizure disorder. It demonstrates subtle focal and lateralized asymmetries in cerebral hemispheric frequency bands in such patients. This information helps differentiate neurologic complications from psychiatric disorders. TBM plays a useful role in the differentiation and management of various other disorders, including depression, behavioral disturbances and dementias.