Evaluación de un programa de intervención prenatal en embarazadas con fetos pequeños para la edad gestacional

La prematuridad y el retraso de crecimiento intrauterino constituyen actualmente los problemas más importantes de la Medicina Fetal y de la Neonatología y son las causas más frecuentes de la morbilidad y mortalidad perinatal en los países desarrollados. OBJETIVO. Valorar la eficacia de un programa de intervención de apoyo prenatal (creado ex-novo) dirigido a madres gestantes de fetos Pequeños para la Edad Gestacional (PEG): detectar si este procedimiento mejora el desarrollo físico y neuroconductual del neonato, el estado emocional de la madre y el vínculo entre ambos. METODOLOGÍA. Estudio quasiexperimental tipo ensayo clínico controlado y sin asignación aleatoria de la intervención realizado en el área Materno-fetal de BCNatal (corporación del Servicio de Medicina Maternofetal del Hospital Clínic y el Hospital Sant Joan de Déu de Barcelona). El tamaño final de la muestra fue de 158 embarazadas, de las cuales 65 formaron parte del grupo intervención y 93 formaron parte del grupo control. RESULTADOS. Al finalizar el programa se observa que el feto y el neonato muestran una mayor ganancia de peso y mayor perímetro craneal en el grupo intervención. En cuanto a las capacidades y competencias del neonato, valoradas con la Escala de Brazelton, los del grupo intervención obtienen unos resultados discretamente superiores en casi todos los parámetros estudiados, destacando una mayor capacidad de habituación ante los estímulos auditivos. En relación a la embarazada, los resultados más relevantes al finalizar el programa son una disminución de la ansiedad (valorada con el cuestionario STAI) y una mayor vinculación afectiva materno-filial (valorada con la escala EVAP). CONCLUSIONES. Para las madres gestantes de fetos PEG, el hecho de haber participado en un programa de intervención de apoyo prenatal tiene un resultado beneficioso para ambos, madre e hijo, presentando menos ansiedad materna, mejores condiciones para establecer el vínculo así como una mejora en el desarrollo físico e indicios de mejores capacidades neuroconductuales en el neonato.Prematurity and intrauterine growth restriction are currently the most important problems in Fetal Medicine and Neonatology and also are the most frequent causes of perinatal morbidity and mortality in developed countries.The Objectives were to evaluate the effectiveness of a prenatal support program (created ex-novo) aimed at pregnant mothers of small fetuses for Gestational Age (PEG): to detect if this procedure improves the physical and neurobehavioral development of the neonate, the emotional state of the mother and the bond between them. This was a quasiexperimental study of a controlled clinical trial and without random assignment of the intervention performed in the Maternal-fetal area of BCNatal (Hospital of the Maternal-Fetal Medicine Service of Hospital Clínic and Sant Joan de Déu Hospital in Barcelona). The final sample size was 158 pregnant women, of whom 65 were part of the intervention group and 93 were part of the control group. At the end of the program, it is observed that the fetus and the neonate show a greater weight gain and greater cranial perimeter in the intervention group. As for the abilities and competences of the newborn, evaluated with the Brazelton Scale, those in the intervention group obtained slightly better results in almost all the studied parameters, emphasizing a greater capacity of habituation before the auditory stimuli. In relation to the pregnant woman, the most relevant results at the end of the program are a reduction of anxiety (valued with the STAI questionnaire) and a greater maternal-filial affective attachment (valued with the EVAP scale). In conclusion, for pregnant mothers of PEG fetuses, having participated in a prenatal support intervention program has a beneficial outcome for both mother and child, with less maternal anxiety, better bonding conditions, and improved development physical and signs of better neurobehavioral abilities in the neonate

Mean-field analysis of firing rate equilibria, in homogeneous networks with overlapping short-term synaptic properties and no long-term plasticity.

<p>Panel <b>A</b> represents the sketch of a recurrent network where a clear segregation between subpopulations of depressing- or facilitating-only synapses does not occur. A neuron has a probability of connecting to its postsynaptic target by a depressing synapse, and of connecting to its target by a facilitating synapticapse. Panel <b>B</b> plots the location of the equilibria of the firing rate , under distinct external inputs conditions and for increasing values of . For the same parameters of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084626#pone-0084626-g004" target="_blank">Fig. 4</a>, stable equilibria move as a function of , taking intermediate values between the two extreme cases, i.e., and ; compare to panels <b>D–F</b> of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084626#pone-0084626-g004" target="_blank">Figs. 4</a> .</p

Mean-field simulation of a heterogeneous network with short- and long-term plasticity.

<p>The firing rate evolution of a heterogenous recurrent network, including both short-term facilitating and depressing synapses (<b>A</b>), was estimated by numerically solving the corresponding mean-field equations. The average synaptic efficacies among and across populations, indicated by , , , and , undergo long-term modification. Panels <b>B, D</b> show the long-term changes of an isolated synapse (decoupled from recurrent interactions) depending on pre- and postsynaptic spike timing (i.e., , ) and frequencies (i.e., , ). When and are varied independently, long-term potentiation (LTP) and depression (LTD) emerge as in associative Hebbian plasticity. This suggests that and will become significantly stronger than and (<b>C</b>) and that such a configuration will be retained indefinitely. This was confirmed by simulations (<b>E–F</b>) plotting the temporal evolution of the firing rates (black trace) and (grey trace), and of the mean synaptic efficacies (<b>F</b>). The heterogeneity occurs by separation of emerging firing rates (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084626#pone-0084626-g004" target="_blank">Fig. 4</a>), as emphasized by the grey shading. Parameters: , msec, with initial conditions for the maximal synaptic efficacies , and . Please note that without loss of generality we fix .</p

Emergence of connectivity motifs in a toy model network.

<p>Unidirectional (reciprocal) strong excitatory connections are indicated (<b>A</b>) as dashed (continuous) line segments, representing the topology of the network (<b>B</b>). Each model neuron receives periodic spatially alternating depolarizing current pulses, strong enough to make it fire a single action potential. Synapses among connected neurons display (<b>C</b>) short-term facilitation of postsynaptic potential amplitudes. Spike-Timing Dependent Plasticity (STDP) leads to strengthened connections and results in a largely reciprocal topology (<b>D</b>). Modifying the short-term plasticity profile into depressing (<b>F</b>) leads to a largely unidirectional topology shaped by STDP(<b>G</b>). Distinct motifs of strong connections arise from short- and long-term plasticities, due to distinct firing patterns (compare <b>E</b> and <b>H</b>), under identical external stimulation and initial connections. Parameters: pA, and Methods.</p

STDP key features for motif emergence.

<p>The pair-based STDP model, with temporal window shown in panel <b>A</b> and matching exactly <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084626#pone-0084626-g002" target="_blank">Fig. 2 A</a>, exhibits a different frequency dependency (panel <b>C</b>) than the triplet-based STDP model (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084626#pone-0084626-g002" target="_blank">Fig. 2 B</a>). Modifying the triplet-based STDP parameters to <i>ad hoc</i> invert its temporal window (e.g., as in anti-STDP, panel <b>B</b>, compare to panel <b>A</b>), yet leaves its frequency dependency and the LTD-reversal (grey shading) unchanged (panel <b>D</b>). Repeating the study of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084626#pone-0084626-g002" target="_blank">Fig. 2</a> with these two modified models, we find that (i) the pair-based STDP fails to account for motif emergence (panels <b>E</b>, <b>G</b>, compare to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084626#pone-0084626-g002" target="_blank">Fig. 2</a>), while (ii) anti-STDP succeeds (panels <b>F</b>, <b>H</b>, compare to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084626#pone-0084626-g002" target="_blank">Fig. 2</a>).</p

Results from numerical simulations of large recurrent networks of model neurons with short- and long-term plasticity.

<p>Homogeneous and heterogeneous recurrent networks made of Integrate-and-Fire model neurons were numerically simulated, under identical conditions. Panel <b>A</b> shows the comparison of the emergence of weak or no connectivity pairs (indicated as “-, -”), of unidirectional strong connectivity pairs (“”, “D, -”), and of reciprocal strong connectivity pairs (“”, “D, D”) for a homogeneous network of neurons connected by depressing synapses: strong unidirectional depressing connections significantly outnumber reciprocal depressing ones. The fractions of emerged motifs (black) is significantly different than the null hypothesis (white) of random motifs occurrence. Panel <b>B</b> repeats this quantification for a homogeneous network with facilitating synapses: strong connections are found only on reciprocal connectivity pairs (“”, “F, F”) and all emerging motifs are non-random. Panel <b>C</b> repeats the same quantification for a heterogeneous network with both short-term facilitating and depressing synapses. Emerging motifs display highly non-random features and confirm that reciprocal facilitatory motifs (“”, “F, F”) outnumber unidirectional facilitatory motifs (“”, “F, -”), and that unidirectional depressing motifs (“”, “D,-”) outnumber reciprocal depressing motifs (“”, “D, D”). Panels <b>D–F</b> display the steady-state firing rate distributions, corresponding to homogeneous depressing, homogeneous facilitating, and heterogeneous networks respectively. The plots confirm that heterogeneity in connectivity motifs is accompanied by bimodal firing rates above and below the <i>critical</i> frequency, represented here by a grey shading.</p

Strong external inputs may drive neurons to high firing rate and induce reciprocal motif emergence even in depressing networks.

<p>As in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084626#pone-0084626-g002" target="_blank">Fig. 2</a>, the synaptic connectivity matrix of a network of ten neurons was randomly initialized and pruned (<b>A, B</b>, i.e., pruning is indicated by the “X” symbols). An external weak input, in addition to internally generated activity, contributes to the emergence of non-random unidirectional motifs, resulting in an asymmetric matrix W (<b>C, D</b>). However, if five units of the same network (grey circles) are externally stimulated above the STDP <i>critical</i> frequency, a non-random connectivity emerges, featuring reciprocal motifs and a symmetric connectivity submatrix (<b>E, F</b>; upper left corner, dashed rectangle). The values indicated above panels <b>A, C, E</b> represent the symmetry index and its significance.</p

Parameters employed in the simulations: STDP parameters are as in the <i>minimal all-to-all</i> triplet model described in Pfister and Gerstner (2006); short-term depression and facilitation parameters as in (Wang <i>et al.</i>, 2006); neuron parameters are as in (Clopath <i>et al.</i>, 2010).

<p>Parameters employed in the simulations: STDP parameters are as in the <i>minimal all-to-all</i> triplet model described in Pfister and Gerstner (2006); short-term depression and facilitation parameters as in (Wang <i>et al.</i>, 2006); neuron parameters are as in (Clopath <i>et al.</i>, 2010).</p

Symmetry breaking as a function of the recurrent projection width ().

<p>The symmetry breaking index describes the shift in the center of gravity of the L2/3 steady state activity when displacing the middle bisection line away from the bisection center (Eq. 14). Parameter values: , and the same values , , and as in the other simulations. The maximum of is at , confirming that (for a nonlinear suppression parameter between and roughly ) the optimal recurrent projection width () is in the range of the half width of the bisection stimulus ().</p

Steady state activity of the continuously distributed L2/3 neurons (Eq. 11, solid lines).

<p>Feedforward input (dashed lines) and bisection stimulus with lines positions at , and , are the same as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000617#pcbi-1000617-g002" target="_blank">Figure 2B</a>. The width of the recurrent projections () varies for the three sub panels: (A) , (B) and (C) . Symmetry breaking is strongest if is roughly half the bisection width (B, corresponding to the parameter choice in the discrete simulations). For smaller and larger (A and C), the activity to the left bisection line is not fully suppressed and the distribution is less asymmetric (as expressed by a smaller first order moment , taking on values , and from left to right).</p