Recent Advances in Human Neurophysiology

Comparative Analysis using VEPs showed many abnormalities in autistic respect to healthy children

Recent Advances in Human Neurophysiology.
March 1998. Okazaki, Japan.

AGUILAR L. C., MARTIN R., CRUZ S., ROSIQUE P., ISLAS A.AND ALFAROF.

Instituto de Investigaciones en Neuroplasticidad y Desarrollo Celular. Departamento de Biologia Celular y Molecular de la Universidad de Guadalajara. Guadalajara, Jalisco MEXICO.

Contents

Introduction
Methods
Results
Discussion and Conclusion
References

INTRODUCTION

The knowledge about the neural sources of some components of the flash VEPs and the normal sequence of these components is limited. Anatomical and physiological studies has shown visual projections to areas outside the occipital lobe (Von Essen 1979, Kuypers et al. 1965, Bignall and Imbert 1969, Boyd et al. 1971) indicating cortico-cortical connections from visual association areas to parietal lobe, premotor, prefrontal cortex and to middle and inferior temporal gyri. Recordings in humans (Walter and Walter 1949; Brazier 1964) have shown VEPs in frontal and temporal regions. Studies performed by Hammond et al. 1989, showed that the topographic flash VEPs can provide data on the location of lesions remote from the occipital area, where usually the components were asymmetrical, caused by a depression or enhancement of some component. In other hand the flash VEPs are in many cases of children with mental retardation and autism, the only possibility to perform a visual evoked potential study, for there is not patient collaboration for performing the study which has to be performed in sleep stage. We performed a prospective topographic flash VEPs study in normal and autistic children in order to know the normal sequence of components, the grade of interhemispheric symmetry for each area and the comparison with autistic children.

METHODS

Topographic flash VEPs were recorded from a control group (n=40) and from autistic patients (DSM IV, n=103), both sexes, between 3 and 13 years. The stimulation was performed using a white stroboscopic xenon flash (Grass PS22). All stimuli were presented binocularly with a variable repetition rate during sleep (stage II), 16 electrodes were placed according to 10-20 international system, amplifier bandpass filters 1-35 Hz, 200 epochs were averaged and obtained twice. Symmetry analysis of each area was performed using Pearson Coefficient (PC) to know the linear correlation and energy ratio (ER) to know the symmetry in area below the curve, for 50-200 and 200-400 milliseconds (ms) segments, the result of each area on a specific segment of time of every autistic child was compared with a control group using Z transform (p<0.025) for knowing the significant deviations.

RESULTS

The following sequence of negative components was observed in normal controls: The initial response was detected in frontopolar regions (FP1-FP2), followed by occipitals (O1-O2), continuing with parietals (P3-P4), then temporals (T5-T6), followed by frontopolars, frontals (F3-F4), centrals (C3-C4), followed by occipitals, parietals and temporals (Fig.1 and 2). The linear correlation analysis showed high symmetry with a values higher to 0.70 (Pearson coefficient) for p<0.025. The symmetry analysis of ABC studied through ER showed in control group values of one side respect to contra lateral no higher than 2.5 times and no lower than 0.4 times., this for a P<0.025 (Fig. 1 and 2), only the frontopolars (Fp1-Fp2) in the 50-200 ms segment, the frontolaterals (F7-F8) and anterior temporals (T3-T4) showed low symmetry in this parameters, observing a grate dispersion in the values of these regions.

Fig. 1.- Flash VEPs of a control child, female 12 years old. Notice the sequence of negative components and the high symmetry in linear correlation and area below the curve studied by energy ratio

Fig. 2.- Flash VEPs of a 6 month old male. Observe the high symmetry quantified by Pearson coefficient (PC) (Linear correlation) and energy ratio (ER), only the T3-T4 and F7-F8 and FP1-FP2 in 50-200 ms segment showed low PC and ER.

In autistic children the sequence of components showed many abnormalities including depression, enhanced of components, like to previous observations in patients with brain damage reported by Hammond et al 1989 (Fig. 3 and 4), or premature apparition of a specific component like the negative component (NC) in parietal (Fig. 4) that usually appears after the occipital N100 (Fig. 1 and 2) in controls, this abnormalities were observed mainly in right posterior regions ; the reduction of voltage (mainly in P4,T6 and O2) was mostly seen (Fig. 3). The symmetry analysis shows many deficiencies in linear correlation where parietals (P3-P4) presented significant low PC (p<0.025) in 63% of patients and 66 % in T5-T6 for the 200-400 ms segment.

Also the autistic group showed significant asymmetries of ER (p<0.025) in 56% of the patients in P3-P4, 40 % in O1-O2 and 39 % in T5-T6 for the 200-400 ms segment.

Fig. 3.- Flash VEPs of autistic child, 6 year old male. Notice the great reduction of voltage in 02, T6 and P4, and the very low Pearson coefficient in the mentioned areas

Fig. 4.- Observe the premature response of negative component in P4, which appear prior to N100 in O2, also the Pearson coefficient and energy ratio are very low in P3-P4 and T5-T6.

DISCUSSION AND CONCLUSIONS

The mentioned results indicate that there is a normal sequence of responses after a flash stimulation that can be reflecting the cognitive process. The symmetry analysis in the control healthy group showed that the high symmetry observed in frontal, central, parietal, occipital and temporal posterior regions was no age-dependent, this symmetry was high including in a 6 month old normal child (Fig. 2). The study of mentioned sequence in autistic children and the symmetry analysis through PC and ER that contributed greatly to perform a more objective and reliable study, indicated that parietal and temporal regions are frequently affected in autism, only 2 autistic children of 103 did not show some abnormality of Flash VEPs in this areas, but one of them showed in the EEG spikes in both temporal lobes (T3 and T4) and the second one showed spikes in frontal regions and seizures every week. These results strongly suggest that the parietal and temporal regions are affected in autistic children and according to Hammond et al. 1989, these asymmetries can be reflecting lesion or damage.

The neuropsychological analysis performed in the autistic group showed that the language and visual motor skills were the most deficient functions. This functions are related with temporal (Mc Carthy and Warrington 1990) and parietal ( Perenin and Vighetto, 1988) regions. We conclude that parietal and temporal regions are high frequently affected in autism.

REFERENCES

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  3. Bignall KE. Imbert M. 1969. Polisensory and corticocortical projections to frontal lobe of squirrel and rhesus monkeys. Electroencephallogr Clin Neurophysiol 26: 206-215.
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  7. Hammond EJ. Barber CP. Wilder BJ. 1989. Flash Visual Evoked Potential Topographic Mapping: Normative and Clinical Data. In: Topographic Brain Mapping of EEG and Evoked Potentials. (Maurer K Ed) Springer-Verlag.
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The Fibroblast Growth Factor 2 (FGF2) Improves VEPs in Autistic Children.

Recent Advances in Human Neurophysiology.
March 1998. Okazaki, Japan.
AGUILAR L. C., CRUZ S., MARTIN R., ROSIQUE P., ALFARO F., ISLAS A., AND CANTU J.M.

Instituto de Investigaciones en Neuroplasticidad y Desarrollo Celular . Departamento de Biologia Celular y Molecular de la Universidad de Guadalajara. CIBO, IMSS. Guadalajara, Jalisco, MEXICO A.P. 3920.

Contents

Introduction
Methods
Results
Discussion and Conclusion
References

INTRODUCTION

FGF2 is a protein that has shown neurotrophic effect in many areas of the embryonic (Eckenstein et.al., 1990. Weise et. al., 1993), foetal (Walicke et. al., 1986. Morrison et. al., 1986. . Deloulme, et. al., 1991) and adult brain( Matsuda et al. 1990). Its in vitro effects include survival, neurite extension (Peulve P. Et. al., 1994), increase in choline acetyltransferase (CAT) activity, dopamine levels (Aguilar et. al. 1994a).

In several animal models of brain damage as trauma (Mocchetti et. al. 1995, Anderson et. al., 1988), hypoxia/ischemia (Aguilar et. al., 1994ª, Nakata et. al., 1993), kainic acid (Rudge et. al., 1995), and pathway sections (Koshinaga et. al., 1993), etc.) have shown that the FGF2 is capable of diminishing the degree of lesion. Studies in which FGF2 was administered after damage (Anderson et. al., 1988), showed a significant improvement in morphological, neurochemical (Otto, D. and Unsicker, K. 1990.) and neurophysiological (Aguilar et. al. 1994a) parameters. Previous clinical studies in intellectual disabilities showed a significant improvement in mental retardation (Aguilar et. al., 1993) and language disabilities (Aguilar et. al.,1994b).

Symmetry analysis of Flash VEPs, in previous studies carried out by our group, demonstrates to be a reliable and objective procedure for quantifying abnormalities in autistic children, when using Pearson Coefficient (PC) to analyse interhemispheric linear correlation and Energy Ratio (ER) to compare the voltage generated in a specific segment of time(area below the curve) in both hemispheres.

METHODS

With the purpose of improving the impairment of autistic children, FGF2 was used, applied subcutaneously at dosage of 0.2 mg/kg, every two weeks during 12 months. The autistic group (n=29, both sexes between 3 and 8 years of age), was studied using flash VEPs, with 16 electrodes placed according to 10-20 international system. VEPs were analysed in 2 segments, 50-200 and 200-400 ms through PC and ER, PC was expressed as a value between 1 and –1, the values lower than 0.7, were considered as significant deviations (p<0.025) when compared to control healthy group (CHG) and ER was expressed as a ratio in which the higher value of one area ( any side) was normalised to 1 and the contra lateral as a ratio, the values lower 0.4 were significant deviated (p<0.025) of a CHG indicating asymmetry. The areas that in the initial study showed significant deviations (P<0.025) respect to normal group were totalled and compared before vs. after 12 month of treatment, trough t-test.

RESULTS

The symmetry of area below the curve or ER in P3-P4 and O1-O2 showed significant increase (p<0.004) in segment 50-200 ms (Fig. 1) and in 200-400 ms segment, P3-P4 and T5-T6 (P<0.004) increase after 12 months of treatment (Fig. 1). P3-P4 and T5-T6 showed in the initial study the grater number of asymmetries in PC mainly in 200-400 ms segment and after FGF2 treatment a significant reduction (p<0.01) was observed in all areas in both segments (Fig. 2).

Fig. 1. Energy Radio (ER) before and after FGF2 Therapy in Autistic Children. Observe the significant increase

Fig. 2. Deviations in Pearson Coefficient (PC) before and after 12 months of FGF2 Therapy in Autistic Children. Observe the significant reduction (P<0.01)

DISCUSSION AND CONCLUSIONS

The parietals (P3-P4) improved significantly in ER and less in PC (p<0.08), this probably due to the fact, that first the number of responding neurones increase and then the functional organisation, in general the improvement was higher in ER that in PC. T5-T6 increase significantly in 200-400 ms in both symmetry analysis (ER and PC) indicating improvement in the late components of this regions, probably related to the fact that the best response in neuropsychological evaluation was in language, function highly related with temporal regions (Head, H. 1926).

TWe conclude that FGF2 improves flash VEPs mainly in parietal, temporal and occipital regions of autistic children after 12 months of treatment (Fig 3 a, 3 b, 4 a and 4 b), this correlated with improving in language, visual motor maturation and social behaviour, areas that showed the best evolution in the neuropsychological evaluation. The most noticeable improvement was the recovery of the area below the curve in many patients in which the initial study showed absence or very low response in parietal, temporal and occipital regions mainly in the right side (Fig. 3 a and 3 b).

Fig. 3 a. Notice the absence of response in O2 and reduction of voltage in T6 and P4, respect to contra lateral regions in autistic child ( male, 4 years old).

Fig. 3 b. Notice the recovery in voltage and area below the curve in O2, T6 and P4, also observe that the Pearson coefficient increase in the same autistic patient after 12 months of FGF2 therapy.

Fig. 4 a. Observe the low Pearson coefficient and the asymmetries in area below the curve in P3-P4, O1-O2 and T5-T6.

Fig. 4 b. Notice the increase in Pearson coefficient and reduction of asymmetries in voltage (energy ratio) in P3-P4, O1-O2 and T5-T6 after 12 months of FGF2 treatment.

REFERENCES

  1. Aguilar_LC; Islas_A; Rosique_P; Hernandez_B; Portillo_E; Herrera_JM; Cortes_R; Cruz_S; Alfaro_F; Martin_R; et_al Psychometric analysis in children with mental retardation due to perinatal hypoxia treated with fibroblast growth factor (FGF) and showing improvement in mental development. J Intellect Disabil Res, 1993 Dec, 37 ( Pt 6):, 507-20
  2. Aguilar, L.C., Islas, A., Morales, A., Alfaro, F., Cruz, S., Martin, R., and Cantu, J.M. 1994a. Estudios preclinicos de la administración del Factor de Crecimiento Fibroblástico en daño cerebral. Capitulo VI. 83-94. En Avances en la Restauración del Sistema Nervioso. Aguilar-Rebolledo, F. Ed. Vicova Editores.
  3. Aguilar, L.C., Rosique, P., Cruz, S., Martin, M., Alfaro, F., Islas, A., and Cantu, J.M. 1994b. Administración del factor Fibroblástico de Crecimiento en disfunciones neurológicas consecutivas a hipóxia-isquemia perinatal. Capitulo VII. 95-106. En Avances en la Restauración del Sistema Nervioso. Aguilar-Rebolledo, F. Ed. Vicova Editores.
  4. Anderson, K.J., Dam, D., Lee, S. and Cotman, C.W. 1988. Basic fibroblast growth factor prevents death of lesioned cholinergic neurons in vivo. Nature. 332:360-361.
  5. Deloulme_JC; Baudier_J; Sensenbrenner_M Establishment of pure neuronal cultures from fetal rat spinal cord and proliferation of the neuronal precursor cells in the presence of fibroblast growth factor. J Neurosci Res, 1991 Aug, 29:4, 499-509.
  6. Eckenstein_FP; Esch_F; Holbert_T; Blacher_RW; Nishi_R Purification and characterisation of a trophic factor for embryonic peripheral neurons: comparison with fibroblast growth factors.
    Neuron, 1990 Apr, 4:4, 623-31.
  7. Head, H. (1926). Aphasia and kindred disorders of speech. Cambridge; Cambridge University Press.
  8. Koshinaga_M; Sanon_HR; Whittemore_SR Altered acidic and basic fibroblast growth factor expression following spinal cord injury. Exp Neurol, 1993 Mar, 120:1, 32-48
  9. Matsuda, S., Saito, H. and Nishiyama, N. 1990. Effect of basic growth factor on neurons cultured from various regions of postnatal rat brain. Brain Res. 520: 310-316.
  10. Mocchetti_I; Wrathall_JR Neurotrophic factors in central nervous system trauma. J Neurotrauma, 1995 Oct, 12:5, 853-70
  11. Morrison, R.S., Sharma A., de Vellis, J. and Bradshaw
  12. R.A. 1986. Basic fibroblast growth factor supports the survival of cerebral cortical neurons in primary culture. Proc. Natl. Acad. Sci. USA. 83:75377541.
  13. Nakata_N; Kato_H; Kogure_K Protective effects of basic fibroblast growth factor against hippocampal neuronal damage following cerebral ischemia in the gerbil. Brain Res, 1993 Mar 12, 605:2, 354-6
  14. Otto, D. and Unsicker, K. 1990. Basic FGF reverses chemical and morphological deficits in the nigrostriatal system of MPTP-treated mice. J. Neurosci. 10:1912-1921.
  15. Peulve_P; Laquerriere_A; Hemet_J; Tadie_M Comparative effect of alpha-MSH and b-FGF on neurite extension of fetal rat spinal cord neurons in culture. Brain Res, 1994 Aug 22, 654:2, 319-23
  16. Rudge_JS; Pasnikowski_EM; Holst_P; Lindsay_RM Changes in neurotrophic factor expression and receptor activation following exposure of hippocampal neuron/astrocyte cocultures to kainic acid. J Neurosci, 1995 Oct, 15:10, 6856-67
  17. Walicke, P., Cowan, W.M., Ueno, N., Baird, A. and Guillemin R. 1986. Fibroblast growth factor promotes survival of dissociated hippocampal neurons and enhances neurite extension. Proc. Natl. Acad. Sci. USA. 83:3012-3016.
  18. Walicke, P.A. 1988. Basic and acidic fibroblast growth factors have trophic effects on neurons from multiple CNS regions. J. Neurosci. 8:2618-2627.
  19. Weise_B; Janet_T; Grothe_C Localization of bFGF and FGF-receptor in the developing nervous system of the embryonic and newborn rat. J Neurosci Res, 1993 Mar 1, 34:4, 442-53

 

The FGF2 Improves VEPs in Dyslexic Children (DCh).

Recent Advances in Human Neurophysiology.
March 1998. Okazaki, Japan.

L. C. AGUILAR, P. ROSIQUE, F. ALFARO, R. MARTIN, S. CRUZ, A. ISLAS, AND J. M. CANTU.

IINEDEC, a.p. 3920, Guadalajara, Jal, Mexico. IFC. CUCBA. U.de G. Div. de Genetica, CIBO.IMSS.

Contents

Introduction
Results
Discussion and Conclusion
References

INTRODUCTION

The FGF 2, is a neurotrophic factor, with effect on CNS neurons (cortex, hippocampus (HP), striatum (ST), thalamus, etc.( Eckenstein et. al., 1990, Weise et. al., 1993, Walike et. al., 1986, Deloulme, et. al., 1991) showing in vitro increase of survival and neurite outgrowth (Walicke, 1988); in vivo increases CAT activity in HP and ST and dopamine levels in ST (Aguilar et.al., 1994a). FGF 2 reverses morphological deficits in dopaminergic neurons after MPTP (Otto and Unsicker, et.al. 1990), and ameliorates learning deficits in basal-forebrain lesioned mice (Ishihara, et.al., 1992). In mentally retarded patients FGF 2 improves mental development (Aguilar et al., 1993). Also improves language disabilities and visomotor deficits in children with these pathologies (Aguilar, et.al. 1994b).

We report here, the effect of FGF 2 therapy in children with dyslexia in whom phonological, semantic and visual-spatial deficits were observed. 41 patients of both sexes, in ages between 8 and 12 years of age, separated in two groups were examined. Topographic flash VEPs were recorded from a treated group (TG) n=26 and from untreated group (n= 15), both sexes, between 8 and 12 years. The stimulation was performed using a white stroboscopic xenon flash (Grass PS22). All stimuli were presented binocularly with a variable repetition rate during awake state, 16 electrodes were placed according to 10-20 international system, amplifier bandpass was 1-35 Hz, 200 epochs were averaged and obtained twice. Symmetry analysis of each area was performed using Pearson coefficient (PC) to know the linear correlation and energy ratio (ER) to know the symmetry in energy (comparison of the area below the curve of one region respect to contra lateral), for 50-200 and 200-400 milliseconds (ms) segments, the result of each area in a specific segment of time of every dyslexic child was compared with a control group (n=25, age matched) using Z transform (p<0.025) in order to know the significant deviations.

FGF2 was administered at dosage of 0.2 mg/kg of body weight every 2 weeks during 12 months to TG, the UG received only neurophsycological therapy.

RESULTS

The VEPs showed in the initial study that the PC was significantly (p<0.025) reduced in 58 % of dyslexic respect to normal controls in at least one segment and the 48 % in the 200-400 ms segment. In ER 48% of patients showed asymmetries at least in one segment, a great reduction of voltage and area of N100 component on left occipital and temporal regions was observed in 28 % of dyslexic children (Fig. 1 a and 2 a ), causing the mentioned asymmetries in ER and PC, in occipital regions only the 26 % showed asymmetries.

After 12 months of treatment with FGF2, a significant (p<0.01) improvement in PC was observed in T5-T6 (Fig. 3) in 200-400 ms segment, the ER improved significantly (p<0.01) in both segments of T5-T6 (Fig. 3 ),. The UG did not show significant changes.

Fig. 1 a.- Case one, before treatment. Observe the reduction in voltage and area below the curve in O1 and T5 respect to contralaterals, in dyslexic child (male, 7 years old).

Fig. 2 a.- Case two, before treatment. Observe the reduction of area below the curve in O1 and T5 respect to contralaterals in dyslexic child (male 9 years old).

Fig. 3.- Notice the significant increase in Pearson coefficient (p<0.01) in 200-400 ms. and energy ratio in 50-200 and 200-400 ms segments (p<0.01) of T5-T6 after 12 months of FGF2 therapy

DISCUSSION AND CONCLUSIONS

The improvement in ER was associated with the increase of voltage (area below the curve) on the regions in which previously was reduced ( Fig. 1 b and 2 b), this occurs more frequently on left occipital and temporal regions. This correlates with neurophsycological studies in which several authors demonstrate anatomical deficits on these regions of dyslexic children (Greenblat, 1973, Ajax et al.1977, Staller et al. 1978).. The above mentioned suggests an increase on the number of the responding neurons of these regions, probably due to new pathways formation between geniculate lateral nucleus and area IV of occipital cortex as well as between occipital and temporal cortex, there was also an increase in the activity of neurons of the mentioned areas.

The VEPs improvement in PC suggest a better synchrony and organisation.
We conclude that the flash VEPs are useful for detecting the neurophysiological abnormalities in dyslexic patients and for monitoring the effects of treatments like the one with FGF2, in which a significant improvement of dyslexic children was observed in neuropsychological and neurophysiological parameters.

Fig. 1 b.- Case one, after 12 months treatment. Notice the recovery in area below the curve, Pearson coefficient and energy ratio in O1 and T5.

Fig. 2 b.- Case two, after treatment. Observe the improvement in energy ratio of T5-T6 and O1-O2 in 50-200 ms. segment.

REFERENCES

  1. Aguilar_LC; Islas_A; Rosique_P; Hernandez_B; Portillo_E; Herrera_JM; Cortes_R; Cruz_S; Alfaro_F; Martin_R; et_al Psychometric analysis in children with mental retardation due to perinatal hypoxia treated with fibroblast growth factor (FGF) and showing improvement in mental development. J Intellect Disabil Res, 1993 Dec, 37 ( Pt 6):, 507-20
  2. Aguilar, L.C., Islas, A., Morales, A., Alfaro, F., Cruz, S., Martin, R., and Cantu, J.M. 1994a. Estudios preclinicos de la administración del Factor de Crecimiento Fibroblástico en daño cerebral. Capitulo VI. 83-94. En Avances en la Restauración del Sistema Nervioso. Aguilar-Rebolledo, F. Ed. Vicova Editores.
  3. Aguilar, L.C., Rosique, P., Cruz, S., Martin, M., Alfaro, F., Islas, A., and Cantu, J.M. 1994b. Administración del factor Fibroblástico de Crecimiento en disfunciones neurológicas consecutivas a hipóxia-isquemia perinatal. Capitulo VII. 95-106. En Avances en la Restauración del Sistema Nervioso. Aguilar-Rebolledo, F. Ed. Vicova Editores.
  4. Ajax, E.T., Schenkenberg, T., & Kasteljanetz, M. (1997). Alexia without agraphia. Archives of Neurology (Chicago), 17, 645-652.
  5. Deloulme_JC; Baudier_J; Sensenbrenner_M Establishment of pure neuronal cultures from fetal rat spinal cord and proliferation of the neuronal precursor cells in the presence of fibroblast growth factor. J Neurosci Res, 1991 Aug, 29:4, 499-509.
  6. Eckenstein_FP; Esch_F; Holbert_T; Blacher_RW; Nishi_R Purification and characterisation of a trophic factor for embryonic peripheral neurons: comparison with fibroblast growth factors.
    Neuron, 1990 Apr, 4:4, 623-31 .
  7. Greenblatt, S.H. (1973). Alexia without agraphia or hemianopia; anatomical analysis of autopsied case, Brain, 96, 307-316.
  8. Ishihara, A., Saito, H., and Nishiyama, N. 1992. Basic Fibroblast Growth Factor ameliorates learning deficits in basal forebrain lesioned mice. Jpn. J. Pharmacol. 59: 7-13.
  9. Otto, D. and Unsicker, K. 1990. Basic FGF reverses chemical and morphological deficits in the nigrostriatal system of MPTP-treated mice. J. Neurosci. 10:1912-1921.
  10. Staller, J., Buchanan, D., Singer, M., Lappin, J., & webb, W. (1978), Alexia without agraphia: An experimental case study, Brain and Language, 5, 378-387.
  11. Walicke, P., Cowan, W.M., Ueno, N., Baird, A. and Guillemin R. 1986. Fibroblast growth factor promotes survival of dissociated hippocampal neurons and enhances neurite extension. Proc. Natl. Acad. Sci. USA. 83:3012-3016.
  12. Walicke, P.A. 1988. Basic and acidic fibroblast growth factors have trophic effects on neurons from multiple CNS regions. J. Neurosci. 8:2618-2627.
  13. Weise_B; Janet_T; Grothe_C Localization of bFGF and FGF-receptor in the developing nervous system of the embryonic and newborn rat. J Neurosci Res, 1993 Mar 1, 34:4, 442-53
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