Psychosocial functioning of caregivers of pediatric brain tumor survivors.

BACKGROUND: Assessment of caregiver needs is a recommended standard of care in pediatric oncology. Caregivers of pediatric brain tumor survivors (PBTS) are a subgroup that may be at highest psychosocial risk. This study examined psychosocial functioning of caregivers of PBTS in comparison to caregivers of youth without cancer history. We hypothesized that caregivers of PBTS would exhibit more psychological symptoms, higher caregiver burden, and lower perceptions of social support than caregivers of comparison youth. PROCEDURE: As part of a five-site study, we utilized a matched sample design to evaluate psychosocial functioning of 301 caregivers of 189 PBTS (ages 8-15) who were 1-5 years post treatment, and 286 caregivers of 187 comparison youth matched for sex, race, and age. Caregivers completed measures of psychological symptoms, caregiver burden, and perceptions of social support. Repeated measures mixed models compared outcomes between groups and examined differences based on caregiver sex. Socioeconomic status (SES) was examined as a moderator of significant main effects. RESULTS: Caregivers of PBTS reported similar levels of psychological symptoms to caregivers of comparison youth. Mothers of PBTS mothers reported higher caregiver burden and lower perceptions of social support than mothers of comparison youth. Low SES exacerbated group differences in caregiver burden. CONCLUSIONS: Mothers of PBTS may have more caregiving responsibilities and perceive less social support, but reported similar levels of psychological symptoms to comparison mothers; fathers of PBTS were similar to comparison fathers. The mechanisms involved in this complex psychosocial dynamic require further investigation.

The effects of interactive music therapy on hospitalized children with cancer: a pilot study.

BACKGROUND: The use of music therapy with children in health settings has been documented, but its effectiveness has not yet been well established. This pilot study is a preliminary exploration of the effectiveness of interactive music therapy in reducing anxiety and increasing the comfort of hospitalized children with cancer. METHODS: Pre- and post-music therapy measures were obtained from children (N = 65) and parents. The measures consisted of children's ratings of mood using schematic faces, parental ratings of the child's play performance, and satisfaction questionnaires completed by parents, children and staff. RESULTS: There was a significant improvement in children's ratings of their feelings from pre- to post-music therapy. Parents perceived an improved play performance after music therapy in pre-schoolers and adolescents but not in school-aged children. Qualitative analyses of children's and parents' comments suggested a positive impact of music therapy on the child's well-being. CONCLUSIONS: These preliminary findings are encouraging and suggest beneficial effects of interactive music therapy with hospitalized pediatric hematology/oncology patients. In future studies replicating these findings should be conducted in a randomized control trial.

[Neuronal plasticity associated with learning and epileptic seizures: LTP and KIP].

Long-term synaptic potentiation (LTP) and kindling-induced potentiation (KIP) are hypothesized to play an important role in spatial learning and kindling development, respectively, and the possible roles of LTP in spatial learning and KIP in kindling development are reviewed in this paper. Blockage of NMDA receptors, protein synthesis inhibition and knockout of alpha-CaMKII gene markedly impaired both LTP-induction and spatial learning, and destruction of the dentate granule cells with colchicine has been reported to result in severe spatial learning deficits. These findings support the hypothesis that spatial learning may depend on the neuronal input from the entorhinal cortex to dentate granule cells via perforant path and LTP-induction at perforant path-dentate granule cell synapses. However, recent studies have revealed that MPC17742, a selective NMDA receptor antagonist, and 1S, 3S-ACPD, the group II metabotropic glutamate receptor agonist, block LTP-induction at perforant path-dentate granule cell synapses, but that those drugs did not prevent rats from spatial learning. Thus, adaptable changes in the dentate granule cell discharge caused by the neuronal information from the entorhinal cortex are necessary, but LTP at perforant path-dentate granule cell synapses is not necessarily requisite for spatial learning. It has been also hypothesized that kindling development might be based on the long-lasting synaptic potentiation (the KIP/kindling hypothesis). Destruction of the dentate granule cells with colchicine retarded kindling development of amygdala or entorhinal cortex has been reported, and repeated induction of LTP at perforant path-dentate granule cell synapses, furthermore, caused anomalous mossy fiber sprouting and facilitated the subsequent kindling development. These results are in accordance with the KIP/kindling hypothesis. However, even when LTP was induced once a day for 20 days, the repeated induction of LTP failed to induce epileptic discharge. We demonstrated that KIP observed in an interictal period faded away gradually during kindling stimulation before epileptic seizures began. Furthermore, rapid kindling at an interstimulus interval of 5 min blocked completely the development of KIP, whereas the afterdischarge prolonged gradually and generalized convulsions were often observed during the late stage of rapid kindling. Thus, LTP and KIP are not indispensable for kindling development, even if LTP facilitate the subsequent kindling development. It should be noted that instead of KIP, the abnormal plasticity essential for kindling development must appear during an transition period from interictal to ictal periods.

Optical recording study of granule cell activities in the hippocampal dentate gyrus of kainate-treated rats.

In the epileptic hippocampus, newly sprouted mossy fibers are considered to form recurrent excitatory connections to granule cells in the dentate gyrus and thereby increase seizure susceptibility. To study the effects of mossy fiber sprouting on neural activity in individual lamellae of the dentate gyrus, we used high-speed optical recording to record signals from voltage-sensitive dye in hippocampal slices prepared from kainate-treated epileptic rats (KA rats). In 14 of 24 slices from KA rats, hilar stimulation evoked a large depolarization in almost the entire molecular layer in which granule cell apical dendrites are located. The signals were identified as postsynaptic responses because of their dependence on extracellular Ca(2+). The depolarization amplitude was largest in the inner molecular layer (the target area of sprouted mossy fibers) and declined with increasing distance from the granule cell layer. In the inner molecular layer, a good correlation was obtained between depolarization size and the density of mossy fiber terminals detected by Timm staining methods. Blockade of GABAergic inhibition by bicuculline enlarged the depolarization in granule cell dendrites. Our data indicate that mossy fiber sprouting results in a large and prolonged synaptic depolarization in an extensive dendritic area and that the enhanced GABAergic inhibition partly masks the synaptic depolarization. However, despite the large dendritic excitation induced by the sprouted mossy fibers, seizure-like activity of granule cells was never observed, even when GABAergic inhibition was blocked. Therefore, mossy fiber sprouting may not play a critical role in epileptogenesis.

A decrease in seizure susceptibility to lidocaine in kindled epileptic rats.

Lidocaine induces electroencephalographic seizures and generalized convulsions at large doses. It is possible that epileptic patients are more susceptible to the proconvulsant effect of lidocaine. Using a kindling model of epilepsy, we examined whether the seizure susceptibility to lidocaine increases in epileptic rats. Kindled epileptic rats were prepared by repeated, initially subconvulsive, electrical stimulations applied to the amygdala for 9-14 days through a chronically implanted electrode, resulting in the establishment of a long-lasting epileptic focus. Unexpectedly, kindled rats had significantly less susceptibility to the proconvulsant action of IV lidocaine. Lidocaine-induced convulsions were observed in 11%, 75%, and 77% of control rats at 7.5, 10.0, and 12.5 mg/kg, respectively, compared with 0%, 25%, and 37% of amygdala-kindled rats, respectively. We also demonstrated that small doses of lidocaine suppressed kindled seizures in a dose-dependent manner. We conclude that the critical mechanisms underlying lidocaine-induced seizures differ from the mechanisms underlying kindled epileptogenesis. Furthermore, the establishment of a kindled epileptic focus decreases susceptibility to the proconvulsant action of lidocaine.

[Lidocaine increases the granule cell excitability in hippocampal dentate area instead of affecting GABAergic inhibition].

Lidocaine is well known to have toxic effects on the central nervous system including the induction of electroencepharographic seizures and convulsions at high doses. Although lidocaine was reported to induce electroencepharographic seizures and behavioral convulsions by decreasing the strength of GABAergic synaptic inhibition, detailed mechanisms underlying the lidocaine-induced seizures remain unclear. To determine whether lidocaine decreases GABAergic inhibition or increases the cellular excitability instead of reducing GABAergic inhibition, in the present study, we examined effects of lidocaine on monosynaptic field potentials in the hippocampal dentate gyrus of urethane-anesthetized rats. Lidocaine (10-15 mg.kg-1, i.v.) decreased significantly the threshold for action potential generation instead of producing a significant decrease in GABAergic paired-pulse inhibition. The results suggest that lidocaine first produces the hyperexcitability of hippocampal neurons, which then decreases the hippocampal GABAergic inhibition by the so-called inhibition failure leading to the induction of seizures.

Arcadlin is a neural activity-regulated cadherin involved in long term potentiation.

Neural activity results in long term changes that underlie synaptic plasticity. To examine the molecular basis of activity-dependent plasticity, we have used differential cloning techniques to identify genes that are rapidly induced in brain neurons by synaptic activity. Here, we identify a novel cadherin molecule Arcadlin (activity-regulated cadherin-like protein). arcadlin mRNA is rapidly and transiently induced in hippocampal granule cells by seizures and by N-methyl-D-aspartate-dependent synaptic activity in long term potentiation. The extracellular domain of Arcadlin is most homologous to protocadherin-8; however, the cytoplasmic region is distinct from that of any cadherin family member. Arcadlin protein is expressed at the synapses and shows a homophilic binding activity in a Ca2+-dependent manner. Furthermore, application of Arcadlin antibody reduces excitatory postsynaptic potential amplitude and blocks long term potentiation in hippocampal slices. Its close homology with cadherins, its rapid inducibility by neural activity, and its involvement in synaptic transmission suggest that Arcadlin may play an important role in activity-induced synaptic reorganization underlying long term memory.

[Kindling induced mossy fiber sprouting has no functional significance in developing seizure discharges in rats].

It is reported that chronic electrical stimulation of perforant path (PP) produces mossy fiber sprouting in dentate granule cells and as a result new recurrent excitatory circuits are formed. It has been assumed that the circuits are responsible for the well-known lowering in the threshold required to generate seizure discharges by the electrical stimulation. The assumption was tested in the present investigation. Current source density analysis of the field potential in the dentate gyrus was carried out in control (n = 8) and kindled (n = 10) rats under pentobarbital anesthesia during seizure discharges. The field potential was produced by stimulating the PP and recorded simultaneously from 10 sites which were 50 microns apart from each other. The field potential consisted of a monosynaptic excitatory postsynaptic field current (EPSC) in the middle molecular layer followed by a population spike current (PSC). In the kindled rats, following the EPSC and PSC, a late sink appeared in the supragranular layer (SGL). The amplitude of the SGL late-sink showed a positive correlation with the density of Timm granules (r = 0.76). The latency difference between the onset of PSC and that of the SGL late-sink ranged from 0.5 to 1.5 ms. This suggested the possibility that the SGL late-sink is produced via the recurrent excitatory circuit newly formed by mossy fiber sprouting. The SGL late-sink, however, evoked no further firing in dentate granule cells. During 5 Hz PP stimulation for 10 s, the amplitude of SGL late-sink increased gradually at first, but later it decreased gradually and disappeared before seizure discharges produced. Accordingly, there was no evidence suggesting that the new recurrent excitatory circuit played any role in producing seizure discharges. During seizure discharges, the EPSC resembling the SGL late-sink appeared spontaneously only in the SGL and seemed to initiate repetitive synchronized-firing of granule cells in one of four kindled rats. The number of burst discharges and the duration of seizure discharges with the late sink, however, were not significantly different from those of seizure discharges without such a late skin. These results suggest that the newly formed recurrent circuit plays no essential role in decreasing the threshold required to generate seizure discharges or in developing them.

Is synaptic potentiation necessary for the development of kindling?

Field potentials were recorded from the dentate gyrus of freely moving rats to examine the role of synaptic potentiation in the development of seizure susceptibility during rapid kindling. Kindling stimulations (10 Hz for 10 sec) were delivered to the perforant path at every 5 min for 5 or 6 hrs. This procedure produced a sustained depression of excitatory synaptic transmission at the perforant path-granule cell synapse during and after kindling. However, the kindling procedure resulted in the prolongation of afterdischarges and the development of interictal discharges originated from granule cells, indicating an increase in the seizure susceptibility of these neurons. These results indicate that synaptic potentiation is not a critical requirement for an increase in seizure susceptibility during rapid kindling, even if it has a facilitating effect on the development of kindling as suggested in previous studies.

[Effects of pentobarbital on hippocampal dentate field potentials in unrestrained rats].

The field potential technique was used to examine the effects of pentobarbital (40 mg.kg-1, ip) on the excitatory synaptic transmission and synchronous discharge of granule cells in the hippocampal dentate area of unrestrained rats. Two components of the dentate field potential evoked by perforant path stimulation were analyzed; the population EPSP and the population spike representing an extracellular excitatory postsynaptic potential and synchronous discharge, respectively. The rate of rise (slope) of the population EPSP decreased within 5 min after an injection of pentobarbital. This depression of excitatory synaptic transmission lasted for about 2 hrs and then recovered to near the pre-drug control level within 3 hrs. The ratio of population spike amplitude to population EPSP slope (S/E ratio) was calculated to estimate the readiness of granule cells for synchronous discharge. After an injection of pentobarbital the S/E ratio increased for 2 hrs, indicating that the synchronous discharge of granule cells was facilitated by the drug in spite of the depression of excitatory synaptic transmission. Under pentobarbital anesthesia, the onset and peak latencies of population spikes were prolonged for 0.2-0.4 msec.

Time discrete model of recurrent inhibition in hippocampal dentate gyrus.

A time discrete model of recurrent inhibition in the hippocampal dentate gyrus is made and analyzed. This model assumes that (1) each granule cell can generate only one action potential in response to a single stimulation of the perforant path, (2) each interneuron receives synaptic inputs from many granule cells, and (3) an output of the interneuron is inhibitory for granule cells. Although each granule cell generates an action potential in the all-or-none fashion, the population spike is shown to be approximated by a piecewise linear function of the population excitatory post-synaptic potential (EPSP). From this model six patterns in the population spike responses to the paired-pulse stimulation are deduced. Each pattern is composed of some broken lines whose slopes and intercepts are explicitly expressed by the average and variance of the microscopic parameters and the population size of the cells. This model clarifies the relation between the measured quantity in the field potential experiment and the microscopic quantities peculiar to the granule cell and to the interneuron.

Microcomputer-controlled laboratory system for field potential experiments.

A microcomputer-controlled laboratory system for hippocampal field potential experiments was constituted. This system realized the quasi-simultaneous processing of execution of stimulation, data acquisition, data display and data analysis by means of a microcomputer for the first time. To attain this quasi-simultaneous processing, a new algorithm for drawing a tangent on the wave-form of the potential was contrived, which enabled rapid analysis of an arbitrary population spike even in the case of generation of double spikes. The system has the following functions: (1) execution of the programmed stimulation paradigm, (2) analog/digital (A/D) conversion of the evoked field potential with a sampling interval of more than 50 microseconds per channel, (3) display of the A/D converted wave-form data on a CRT and storage of the data on a floppy disk, (4) on-line analysis of the population excitatory postsynaptic potential (EPSP) and population spike, (5) more detailed off-line analysis of the field potentials, and (6) output of the wave-form data and measured values through a printer and an X-Y plotter.

Effects of LTP-inducing tetanic stimulations of the perforant path on the commissural inhibition and facilitation of dentate granule cell discharge.

Effects of diazepam (1 mg/kg, i.p.) on the commissural influences on granule cells were first examined to further assess its GABAergic inhibitory mechanism. Whereas the commissural inhibition at an interval of 5-8 ms of the contralateral dentate-perforant path (CP) combined stimulus was not enhanced by diazepam, the commissural facilitation at a CP interval of 11-20 ms was reduced, suggesting that the GABAergic inhibition is involved in rather a part of the commissural facilitation at a CP interval of 11-20 msec than a part of the 'commissural' inhibition at a shorter CP interval. Based on the results of diazepam, effects of high-frequency stimulations of the perforant path on the commissural inhibition of dentate granule cells were then examined, in relation to their effects on the dentate paired-pulse depression. These stimulations produced the long-term potentiation of the perforant path-dentate excitatory synapse and significant reduction of the paired-pulse depression. The commissural inhibition at a CP interval of 5-8 ms remained unchanged following tetanization. The commissural facilitation at a CP interval of 11-20 ms was, however, slightly enhanced by tetanic stimulations and a statistical significance was obtained at a CP interval of 19 ms. These results imply that tetanic stimulations of the perforant path selectively reduce the GABAergic component of the commissural inhibition, as well as that of the paired-pulse depression.

Long-lasting reduction of dentate paired-pulse depression following LTP-inducing tetanic stimulations of perforant path.

Effects of high-frequency stimulations of the perforant path on the dentate paired-pulse depression were examined in urethane-anesthetized rats. The tetanic stimulations produced a long-term potentiation (LTP) of the excitatory synaptic transmission at the perforant path-dentate granule cell synapses in almost all animals examined. The strength of the early paired-pulse depression at an inter-pulse interval (IPI) of 20 ms decreased significantly for at least 60 min after the tetanic stimulations, whereas the late paired-pulse depression at an IPI of 2 s remained almost unchanged. The reduction of the early paired-pulse depression was stepwise augmented by each of successive tetanic stimulations given at an interval of 10 min. A preceding antidromic stimulation of the mossy fibers depressed the population spike amplitude of perforant path response at an interval of 5-9 ms. The strength of the antidromic depression of population spike also decreased following the perforant path tetanic stimulations. These results suggest that tetanic stimulations of the perforant path produce a long-lasting reduction of the GABAergic recurrent inhibition in the dentate area associated with LTP. The possible mechanisms of the decrease in GABAergic inhibition produced by tetanic stimulations and its possible effects on the development of LTP with succeeding tetanic stimulations were discussed.