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PubMed1992

Origin of orientation tuning in the visual cortex.

The results of recent experiments have thrown new light on the neuronal connections underlying orientation-selective responses in the primary visual cortex of adult animals. The pattern of afferent input from the lateral geniculate nucleus to the cortex appears to be specific for orientation, while intracortical inhibitory connections appear to be non-specific in this respect. Experimental and theoretical studies have suggested that the development of cortical cell orientation tuning is an activity-dependent process.

Animals↗
PubMed1995

Regeneration in the adult mammalian CNS: guided by development.

In the past year, the roles and mechanisms of molecules involved in cell survival (glial-derived neurotrophic growth factor), growth cone guidance (netrins and semaphorins), axonal outgrowth and sorting (neural cadherin, polysialylated neural cell adhesion molecules, and L1), and neuronal connectivity (cell adhesion molecules, dystroglycan, and agrin) have been described during development and, to a limited extent, in the mature CNS. Evidence is now emerging that some developmental events, such as the expression of polysialylated neural cell adhesion molecule and L1, are recapitulated during adult CNS regeneration. These results suggest new avenues to address more accurately the challenges of axonal regrowth in the adult mammalian CNS.

Animals↗
PubMed2004

Acute changes in cortical excitability in the cortex contralateral to focal intracerebral hemorrhage in the swine.

Injury to the cerebral cortex results in functional deficits not only within the vicinity of the lesion but also in remote brain regions sharing neuronal connections with the injured site. To understand the electrophysiological basis of this phenomenon, we evaluated the effects of a focal intracerebral hemorrhage (ICH) on cortical excitability in a remote, functionally connected brain region. Cortical excitability was assessed by measuring the somatic evoked potential (SEP) elicited by electrical stimulation of the swine snout, which is somatotopically represented in the rostrum area of the primary somatosensory (SI) cortex. The SEP was measured on the SI cortex ipsilateral to the site of ICH and on the contralateral SI cortex during the acute period (< or =11 h) after collagenase-induced ICH. The ICH rapidly attenuated the SEP on the ipsilateral cortex as we reported earlier. Interestingly, the ICH also attenuated the SEP on the contralateral SI cortex. Evoked potentials in the contralateral SI cortex showed a gradual decrease in amplitude during this acute period of ICH. We then investigated whether the interhemispheric connections shared by the contralateral SI and the lesion cortex were responsible for the diminished evoked potentials in the uninjured hemisphere after ICH. A separate group of animals underwent corpus callosal transection prior to electrocorticography (ECoG) recordings and ICH injury. Within hours of hemorrhagic injury, a gradual but marked increase in evoked potential amplitude was observed in the homotopic SI cortex of callosotomized animals as compared to pre-injection recordings. The enhancement suggests that there are additional effects of ICH on remote areas functionally connected to the site of injury. Functional deficits were present in both SI cortices within the first several hours of a unilateral injury indicating that the cessation of brain activity in the lesioned SI is mirrored in the contralateral hemisphere. This electrophysiological depression in the uninjured SI cortex is mediated in part by the interhemispheric connections of the corpus callosum.

Animals↗
PubMed2006

Magnetoencephalography and diffusion tensor imaging in gelastic seizures secondary to a cingulate gyrus lesion.

Gelastic seizures are relatively uncommon and rarely observed secondary to frontal lobe lesions. This report presents magnetoencephalography (MEG) and diffusion tensor imaging (DTI) findings in an adolescent with gelastic seizures secondary to a left anterior cingulate gyrus lesion. Ictal scalp video EEG showed bilateral frontal 4 Hz theta discharges. Interictal EEG showed left fronto-temporal spikes or sharp waves. Interictal MEG showed spike sources over bilateral temporal regions. DTI and tractography delineated slightly shifted corpus callosum posterior to the lesion, unaffected uncinate and inferior longitudinal fasciculi. The patient became seizure free for 12 months after surgical excision of a pleomorphic xanthoastrocytoma in the left anterior cingulate region. In our patient, MEG and EEG did not localize the deep-seated epileptogenic zone. The combination of DTI and neurophysiologic studies, however, possibly disclosed neuronal connections within the epileptic network and indicated that epileptic discharges propagated via the uncinate fibers from the primary epileptogenic zone in the anterior cingulate region to the mesial temporal region in this case with gelastic seizures secondary to a cingulate lesion.

Adolescent↗
PubMed2006

Dimensional complexity of neuromagnetic activity reduced during finger movement of greater difficulty.

OBJECTIVE: We investigated the variation in dimensionality (D2) of neuromagnetic activity over the primary sensorimotor cortex (SM1) in healthy adults performing motor tasks of different difficulty. METHODS: Magnetoencephalography (MEG) was used to record neuromagnetic activity during self-paced, brisk unimanual finger extension at a rate of 1 and 2 Hz using the index finger of the dominant and non-dominant hands in 16 healthy subjects. Motor task difficulty was rated by the relative difference in time measurement between 1 and 2 Hz finger movements of both hands. The relative difference in dimensionality of SM1 activity was calculated by subtracting the D2 value in 2 Hz movement from that in 1 Hz one within subjects. RESULTS: Simple regression analyses show a significantly negative relationship between the relative dimensional complexity and the relative motor task difficulty in the contralateral SM1 for the left- (p<0.05), but not the right- (p=0.447) hand movement. CONCLUSIONS: The present data suggest that a motor task of greater difficulty may engender a reduction of simultaneously active quasi-independent neuronal generators in the contralateral SM1 underpinned by stronger neuronal connectivity of a relatively low dimensionality. SIGNIFICANCE: The decrease in dimensional complexity of MEG activity associated with a motor task of greater difficulty gives new insights to motor control strategy.

Adult↗
PubMed2004

Abciximab pharmacodynamic model with neural networks used to integrate sources of patient variability.

OBJECTIVE: Our objective was to develop a computational model for predicting abciximab-induced inhibition of ex vivo platelet aggregation from the administered dose and readily available patient clinical characteristics by use of a neural network approach. METHODS: A back-propagation neural network was designed to establish the relationship between abciximab dosing, patient clinical history, and effect (inhibition of 20 micromol/L adenosine diphosphate-induced ex vivo platelet aggregation). The neural network was trained by use of data from 8 (out of 47) patients undergoing coronary angioplasty and 30 healthy individuals. Final neuron connection weights were used to evaluate significant patient covariates. The final neural network was validated via (1) predicting the effects of the validation database (remaining 39 patients) and (2) predicting the individual patient doses to achieve 20% of baseline platelet aggregation. RESULTS: The trained neural network successfully captured the complex pharmacodynamic profiles of abciximab without specifying a structural model and identified several patient covariates that significantly contribute to establishing the abciximab dose-effect relationship, including stable angina with nitrate treatment, previous myocardial infarction, and smoking. A wide distribution of individual bolus doses of abciximab was predicted, suggesting the potential for dosing individualization while improving the risk of adverse drug events. The mean predicted dose (16.9 mg) was in agreement with the results from a previously published concentration-effect relationship for abciximab (18.9 +/- 2.0 mg). CONCLUSIONS: These findings suggest the usefulness of neural network methods to individualize dosing for drugs with a narrow therapeutic index when real-time measures of drug concentration and effect are unavailable, but future clinical studies are required for prospective validation.

Abciximab↗
PubMed2003

Central nervous determination of food storage--a daily switch from conservation to expenditure: implications for the metabolic syndrome.

Here, we present a neuroendocrine concept to review the circularly interacting energy homeostasis system between brain and body. Body-brain interaction is circular because the brain immediately integrates an input to an output, and because part of this response may be that the brain modulates the sensitivity of this perception. First, we describe how the brain senses the body through neurons and blood-borne factors. Direct neuronal connections report the state of various organs. In addition, humoral factors are perceived by the blood-brain barrier and circumventricular organs. We describe how circulating energy carriers are sensed and what signals reach the brain during food intake, exercise and an immune response. We describe that the brain regulates the homeostatic process at two fundamentally different levels during the active and inactive states. The unbalanced output of the brain in the metabolic syndrome is discussed in relation with such circadian rhythms and with regional activity of the autonomic nervous system. In line with the above, we suggest a new approach for the diagnosis and therapy of the metabolic syndrome.

Animals↗
PubMed2005

The spatial resolutions of the apposition compound eye and its neuro-sensory feature detectors: observation versus theory.

For 100 years three ideas dominated efforts to understand the apposition compound eye. In Müller's theory, the eye viewed the panorama through an array of little windows without overlaps and without gaps, with no details within windows. Spatial resolution then depended on the interommatidial angle (Deltaphi) and the number of ommatidia. In the second proposal, the insect detected the temporal modulation of the light, which was limited by the aperture of the lens and the wavelength, assuming good focus. Modulation is the change of intensity in the receptor, usually caused by motion of a spatial contrast in the stimulus. Thirdly, motion was detected from the successive temporal modulations at adjacent visual axes. Recently, two more principles arose. The light-sensitive elements, called rhabdomeres, project through the nodal point of the lens to the outside world, and the resolution was limited by their grain size, like the pixels in a digital camera. Finally, detection of contrast and colour was limited by the signal/noise ratio (SNR) which was improved by brighter light and more visual pigment. These five physical principles provide satisfying explanations of eye function but they all originated from theory. Actual measurements of resolution depend on the operation of the test. The visual system of the honeybee recognizes a limited variety of simple cues, but there is no evidence that the pattern of ommatidial stimulation is re-assembled, or even seen. The known cues are: the temporal modulation of groups of receptors, the direction and angular velocity of motion, some measure of the spatial disruption of the pattern or the length of edge (related to spatial frequency and contrast), colour, the intensity, the position of the centre and the size of large well-separated areas of black or colour, the angle of orientation of a bar or grating, radial or tangential edges, and bilateral symmetry. Neurons connected to more than two adjacent ommatidia collaborate in the detection of cues, and the resolution depends on the neuro-sensory feature detectors at work at the time. Although some behavioural and electrophysiological measurements give a spatial resolution similar to the interommatidial angle, different spatial properties of neuro-sensory detectors predominate at different light intensities and with a diurnal rhythm. During the long history of this topic, the belief that the resolution ought to be Deltaphi has frequently been overturned by experimental measurement.

Animals↗
PubMed2004

Brain development during fetal life: influences of the intra-uterine environment.

The intrauterine environment can significantly affect fetal brain development. Here we review our recent findings using animal models that mimic adverse intrauterine conditions which could exist during human pregnancy. We have focused on effects of both acute and chronic hypoxic and inflammatory insults. Relatively brief periods of hypoxemic compromise can have significant effects on the fetal brain causing neuronal loss and cerebral white matter damage. Subtle brain injury can occur, for example to a particular class of neuron, and this can have a significant effect on the function of a specific system. Chronic mild placental insufficiency can result in long term deficits in neuronal connectivity affecting function postnatally as demonstrated in the auditory and visual systems. Repeated acute exposure to an inflammatory agent results in diffuse subcortical white matter damage and in some cases periventricular necrosis. We have demonstrated that the timing and severity of these prenatal insults are determinants of the outcomes, in terms of the severity of the damage and the regions of the brain affected.

Animals↗
PubMed2003

Quantitative MR image analysis in subjects with defects in the PAX6 gene.

Cerebral development is governed by genetic and environmental factors. Animal models provide much of our knowledge about genetic influences in the brain but it is not clear how similar or relevant these are to the human brain. The investigation of human subjects with mutations in genes known to be expressed in the developing brain is an alternative approach to improving our understanding of the role of genetic factors in brain development. We investigated 24 subjects with known mutations in the PAX6 gene (including representatives of all the known mutations of the gene) which are associated with characteristic ocular abnormalities in humans and animals. We have quantified MRI data using several techniques to assess qualities of cerebral structure which are difficult to interpret visually. Abnormalities were identified using voxel-based morphometry, statistical morphometrics, and measurement of corpus callosum cross-sectional area when comparing data from subjects with PAX6 abnormality and 72 age-and sex-matched control subjects. These abnormalities include grey matter changes in the cerebellum and occipital poles and white matter loss in the corpus callosum, alteration of sulcal orientation in the occipital lobe, and alteration to overall neuronal connectivity. These abnormalities complement and exceed the changes seen in the mouse models, and those seen on visual inspection alone of the human MRI data. Structural differences were also identified between the two largest genotype mutation subgroups.

Adult↗
PubMed2005

White matter fiber tracts of the human brain: three-dimensional mapping at microscopic resolution, topography and intersubject variability.

The position and extent of individual fiber tracts within the white matter of human brains can be identified in vivo using diffusion tensor imaging (DTI) and fiber tracking methods. Previous to this study, however, the lack of three-dimensional (3-D) probability maps precluded comparing the anatomical precision of MRI studies with microscopically defined fiber tracts in human postmortem brains. The present study provides 3-D registered maps of the topography, course and intersubject variability of major fiber tracts, which were identified at microscopic resolution. The analyzed tracts include the corticospinal tract, optic and acoustic radiations, fornix, cingulum, corpus callosum, superior longitudinal, superior and inferior occipito-frontal and uncinate fascicles; sources and targets of fiber tracts include the lateral and medial geniculate nuclei and mamillary bodies. Tracts and nuclei were identified in serial myelin-stained histological sections of ten postmortem brains. The sections were 3-D reconstructed and registered to a standardized stereotaxic space of an in vivo MR reference brain by means of linear and non-linear, elastic transformations. The individual fiber tracts and nuclei were superimposed in the reference space, and probability maps were generated as a quantitative measure of intersubject variability for each voxel of the stereotaxic space. This study presents the first stereotaxic atlas of the course, location and extent of fiber tracts and related nuclei based on microscopically defined localization and topographic data taken at multiple levels on each of the three orthogonal planes. The maps are useful for evaluating and identifying fiber bundles in DTI, for localizing subcortical lesions visible in anatomical MR images and for studying neuronal connectivity.

Adult↗
PubMed2004

Close homolog of L1 modulates area-specific neuronal positioning and dendrite orientation in the cerebral cortex.

We show that the neural cell recognition molecule Close Homolog of L1 (CHL1) is required for neuronal positioning and dendritic growth of pyramidal neurons in the posterior region of the developing mouse neocortex. CHL1 was expressed in pyramidal neurons in a high-caudal to low-rostral gradient within the developing cortex. Deep layer pyramidal neurons of CHL1-minus mice were shifted to lower laminar positions in the visual and somatosensory cortex and developed misoriented, often inverted apical dendrites. Impaired migration of CHL1-minus cortical neurons was suggested by strikingly slower rates of radial migration in cortical slices, failure to potentiate integrin-dependent haptotactic cell migration in vitro, and accumulation of migratory cells in the intermediate and ventricular/subventricular zones in vivo. The restriction of CHL1 expression and effects of its deletion in posterior neocortical areas suggests that CHL1 may regulate area-specific neuronal connectivity and, by extension, function in the visual and somatosensory cortex.

Animals↗
PubMed2004

Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses.

Activity-induced modification of neuronal connections is essential for the development of the nervous system and may also underlie learning and memory functions of mature brain. Previous studies have shown an increase in dendritic spine density and/or enlargement of spines after the induction of long-term potentiation (LTP). Using two-photon time-lapse imaging of dendritic spines in acute hippocampal slices from neonatal rats, we found that the induction of long-term depression (LTD) by low-frequency stimulation is accompanied by a marked shrinkage of spines, which can be reversed by subsequent high-frequency stimulation that induces LTP. The spine shrinkage requires activation of NMDA receptors and calcineurin, similar to that for LTD. However, spine shrinkage is mediated by cofilin, but not by protein phosphatase 1 (PP1), which is essential for LTD, suggesting that different downstream pathways are involved in spine shrinkage and LTD. This activity-induced spine shrinkage may contribute to activity-dependent elimination of synaptic connections.

Actin Depolymerizing Factors↗
PubMed2006

In vivo imaging reveals dendritic targeting of laminated afferents by zebrafish retinal ganglion cells.

Targeting of axons and dendrites to particular synaptic laminae is an important mechanism by which precise patterns of neuronal connectivity are established. Although axons target specific laminae during development, dendritic lamination has been thought to occur largely by pruning of inappropriately placed arbors. We discovered by in vivo time-lapse imaging that retinal ganglion cell (RGC) dendrites in zebrafish show growth patterns implicating dendritic targeting as a mechanism for contacting appropriate synaptic partners. Populations of RGCs labeled in transgenic animals establish distinct dendritic strata sequentially, predominantly from the inner to outer retina. Imaging individual cells over successive days confirmed that multistratified RGCs generate strata sequentially, each arbor elaborating within a specific lamina. Simultaneous imaging of RGCs and subpopulations of presynaptic amacrine interneurons revealed that RGC dendrites appear to target amacrine plexuses that had already laminated. Dendritic targeting of prepatterned afferents may thus be a novel mechanism for establishing proper synaptic connectivity.

Afferent Pathways↗
PubMed2003

Role of semaphorins in the adult nervous system.

In the developing nervous system, extending axons are directed towards their appropriate targets by a myriad of attractive and repulsive guidance cues. Work in the past decade has significantly advanced our understanding of these molecules and has made it increasingly clear that their function is not limited to the guidance of growing axons during embryogenesis. Axon guidance cues fulfill additional roles in angiogenesis, cell migration and the immune system, and often display sustained expression in adulthood. Here we focus on the semaphorin (Sema) family and review their proposed functions in the adult nervous system. Several semaphorin family members continue to be expressed in the adult brain and spinal cord, and increasing evidence indicates that their expression is regulated upon nervous system injury in rodents and in neuropathology in humans. The available evidence suggests that semaphorins might significantly contribute to the maintenance and stability of neuronal networks. Furthermore, semaphorins could play important roles in the regeneration, or failure thereof, of neuronal connections. In the future, genetic manipulation of semaphorins and their receptors in the adult intact and injured nervous system should provide a deeper insight into the mechanisms by which semaphorin signaling contributes to structural plasticity and regeneration in the adult brain.

Animals↗
PubMed2004

Biophysical changes in normal-appearing white matter and subcortical nuclei in late-life major depression detected using magnetization transfer.

Neuroanatomical changes have been identified in patients diagnosed with late-life major depressive disorder (MDD) compared with controls. These primarily comprise a decrease in focal brain volumes and an increase in MRI-determined high intensity lesions that are largely confined to the white matter. The physiological status of normal-appearing white matter in patients with MDD remains unknown. Magnetization transfer (MT) is a relatively new neuroimaging technique that permits us to examine the biophysical characteristics of specific brain regions. Using MT, we studied eight patients with late-life MDD and eight non-depressed controls. MT ratios (MTR), which reflect the integrity of the macromolecular protein pool, were ascertained in normal-appearing white matter and subcortical nuclei. Patients had significantly lower MTRs in the genu and splenium of the corpus callosum, the right caudate nucleus and putamen, and the occipital white matter compared with controls. The findings indicate that the structure of the macromolecular protein matrix may be compromised in normal-appearing white matter and critical subcortical nuclei in patients with late-life major depression. These changes may provide important substrates to mood disorders and have implications for neuronal connectivity and its role in the pathophysiology of late-life depression.

Aged↗
PubMed2006

Prediction of bone mass gain by bone turnover parameters after parathyroidectomy for primary hyperparathyroidism: neural network software statistical analysis.

BACKGROUND: Primary hyperparathyroidism (pHPT) is the most frequent endocrine hypersecretion disease, and parathyroidectomy is the only curative option, since pharmacologic therapy reduces hypercalcemia but does not impede parathyroid hormone hypersecretion. According to guidelines from the National Institutes of Health, parathyroidectomy is associated with bone mass increase in some asymptomatic patients, while in others bone mass is not changed after surgery. Therefore, we performed the present study in an attempt to elucidate whether a preoperative biochemical bone parameter can be predictive of a significant vertebral bone mass increase in patients with pHPT. METHODS: For each patient we analyzed the following preoperative parameters: parathyroid hormone, urinary calcium excretion, urinary type I collagen cross-linked N-telopeptide (NTX), osteocalcin, and vertebral computerized bone mineralography. All patients underwent vertebral computerized bone mineralography 12 months after the operation. Statistical analysis was carried out by a neural network program, an event-predicting software modeled on human brain neuronal connections, which is able to examine independent statistical parameters. RESULTS: The patients presenting with high preoperative bone turnover (especially high NTX levels) will have a 5% vertebral bone mass gain in 83.33% of cases after surgery, independently of the National Institutes of Health guidelines. CONCLUSIONS: A high preoperative NTX level seems to be the best predictor parameter for postoperative vertebral bone mass gain in patients with pHPT. Our study also illustrates that neural network software may be a valuable method to help elucidate which pHPT patients should undergo surgical treatment.

Aged↗
PubMed2005

Chlorpyrifos exerts opposing effects on axonal and dendritic growth in primary neuronal cultures.

Evidence that children are widely exposed to organophosphorus pesticides (OPs) and that OPs cause developmental neurotoxicity in animal models raises significant concerns about the risks these compounds pose to the developing human nervous system. Critical to assessing this risk is identifying specific neurodevelopmental events targeted by OPs. Observations that OPs alter brain morphometry in developing rodents and inhibit neurite outgrowth in neural cell lines suggest that OPs perturb neuronal morphogenesis. However, an important question yet to be answered is whether the dysmorphogenic effect of OPs reflects perturbation of axonal or dendritic growth. We addressed this question by quantifying axonal and dendritic growth in primary cultures of embryonic rat sympathetic neurons derived from superior cervical ganglia (SCG) following in vitro exposure to chlorpyrifos (CPF) or its metabolites CPF-oxon (CPFO) and trichloropyridinol (TCP). Axon outgrowth was significantly inhibited by CPF or CPFO, but not TCP, at concentrations > or =0.001 microM or 0.001 nM, respectively. In contrast, all three compounds enhanced BMP-induced dendritic growth. Acetylcholinesterase was inhibited only by the highest concentrations of CPF (> or =1 microM) and CPFO (> or =1 nM); TCP had no effect on this parameter. In summary, these compounds perturb neuronal morphogenesis via opposing effects on axonal and dendritic growth, and both effects are independent of acetylcholinesterase inhibition. These findings have important implications for current risk assessment practices of using acetylcholinesterase inhibition as a biomarker of OP neurotoxicity and suggest that OPs may disrupt normal patterns of neuronal connectivity in the developing nervous system.

Animals↗