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Keywords:

  • Epilepsy;
  • Infantile spasms;
  • TTX;
  • Hypsarrhythmia;
  • Animal model

Summary

  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. References

Purpose: Infantile spasms is one of the most severe epileptic syndromes of infancy and early childhood. Progress toward understanding the pathophysiology of this disorder and the development of effective therapies has been hindered by the lack of a relevant animal model. We report here the creation of such a model.

Methods: The sodium channel blocker, tetrodotoxin (TTX), was chronically infused into the developing neocortex or hippocampus of infant rats by way of an osmotic minipump starting on postnatal day 10–12.

Results: After a minimum of 10 days of infusion, approximately one-third of these rats began to display very brief (1–2 s) spasms, which consisted of symmetric or asymmetric flexion or extension of the trunk and sometimes involvement of one or both forelimbs. The typical ictal EEG pattern associated with the behavioral spasms consisted of an initial generalized, high amplitude, slow wave followed by an electrodecrement with superimposed fast activity. The interictal EEG revealed multifocal spikes and sharp waves, and in most animals that had spasms a hypsarrhythmic pattern was seen, at least intermittently, during NREM sleep. Like in humans, the spasms in the rat often occurred in clusters especially during sleep–wake transitions. Comparison of the ictal and interictal EEGs recorded in this model and those from humans with infantile spasms revealed that the patterns and the frequency components of both the ictal events and hypsarrhythmia were very similar.

Discussion: The TTX model of infantile spasms should be of value in furthering an understanding of the pathophysiology of this seizure disorder.

Infantile spasms (IS) is a disorder of infancy and early childhood characterized by mental retardation and epileptic spasms (Nordli, 2002; Hrachovy & Frost, 2003; Frost & Hrachovy, 2003). The spasms usually consist of sudden and brief flexions or extensions of the body and extremities which often occur in clusters during sleep–wake transitions. Another hallmark of IS is the interictal EEG pattern called hypsarrhythmia, which consists of high amplitude slow waves intermixed with multifocal spikes. The fundamental cause of this disorder is not known and as many as 200 associated conditions have been identified (Lacy & Penry, 1976; Frost & Hrachovy, 2003). These range from brain insults such as hypoxia/ischemia, and intraventricular hemorrhage to congenital malformations such as tuberous sclerosis and lissencephaly. The lack of an animal model has severely hampered an understanding of the biological basis for this disorder as well as a means to develop therapies (Stafstrom & Holmes, 2002; Stafstrom et al., 2006). Several attempts have been made to develop animal models but none have been able to completely recapitulate the human condition (Brunson et al., 2001a; Velisek et al., 2007).

Previously, we described an animal model of early-onset epilepsy where recurring seizures can be induced by chronic infusion of the sodium channel blocker, tetrodotoxin (TTX) into the hippocampus beginning on postnatal days 10–12 (Galvan et al., 2000; Galvan et al., 2003). Within two weeks after initiating the infusion, behavioral seizures were observed that consisted of brief flexions of the head and upper trunk. EEG recordings revealed a concurrent brief run of high frequency activity. During the course of the initial studies of this model we were aware that the behavioral and electrographic features of the seizures had features reminiscent of IS. However, since a very limited recording montage was used, we did not feel that we had enough evidence to suggest that this model was a potential model of IS.

We recently undertook a more detailed neurophysiological characterization of the animal model. In many animals TTX was infused into the developing neocortex beginning on postnatal days 10–12. In other animals our original protocol was used in which the hippocampus was infused. Moreover, in these experiments recordings were made at many sites across the cortex in order to determine if the EEG abnormalities seen in human infants were reproducible in rats. Here we report that the EEG and behavioral features seen in these animals are very similar to those seen in IS patients. Preliminary results of this work have previously been presented in abstract form (Lee et al., 2006).

Methods

  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. References

Osmotic pump implantation

A total of 43 male Wistar rats were successfully implanted with an Alzet osmotic minipump, as described previously (Galvan et al., 2000). In summary, 10- to 12-day-old pups were anesthetized with a ketamine/xylazine/acepromazine mixture, and a long midline dorsal incision was made in the skin extending from the nose to the back of the neck. The infusion pump was subsequently implanted into a subcutaneous pocket along the dorsum of the animal. The pumps were prefilled with approximately 200 μl of either a 10 μM solution of TTX dissolved in artificial CSF (n = 35) or artificial CSF vehicle alone (n = 8). A 28-gauge stainless steel cannula was stereotaxically implanted into the right dorsal hippocampus (AP: 2.0, ML: 2.2; DV: 3.2 mm) or right cortex (AP: 2.0: ML: 2.2; DV: 0.8 mm), anchored in place with dental acrylic and cyanoacrylate, and connected to the infusion pump by a section of PVC tubing. The scalp/skin incision was then sutured to cover the cannula. All surgical procedures were approved by the Baylor College of Medicine animal welfare committee and were in keeping with guidelines established by the NIH. The osmotic pump provides a continuous infusion of the TTX solution or vehicle at a rate of approximately 0.25 μl/h over a period of four weeks. During the period of time following pump implantation, and prior to EEG electrode placement, animals were visually observed at random intervals (3–6 times per week) for signs of behavioral seizures.

EEG electrode implantation

For the majority of experimental and control animals (n = 41), EEG electrodes were implanted, and the osmotic pump removed, at the end of the four-week infusion period (on PND 39–41). The EEG electrodes consisted of Teflon coated silver wires (0.005″ bare diameter—AM systems), which were soldered onto female plugs (MicroTech) that were then cemented to the skull. After removal of the infusion pump and cannula, 6–12 recording electrodes were stereotaxically implanted in the cortex and/or hippocampus of each animal, depending on the infusion site (see below). All animals were also implanted with a reference and isolated system ground electrode. The reference electrode was placed over the cerebellum or in the musculature of the neck.

Cortically infused animals were typically implanted with five cortical electrodes in each hemisphere. Figure 1 depicts the electrode recording locations, which were arranged in two ways. One of these electrodes was always implanted in the right hemispheric infusion site (marked by +). In the first arrangement (Fig. 1A), four electrodes were spaced 1.5 mm from this infusion site electrode. Contralateral electrodes were implanted in homologous sites of the left hemisphere. In order to sample from a larger area of cortex the arrangement in Fig. 1B was used in other animals. Here electrodes were spaced at 3 mm distances from the infusion site. All cortical electrodes were implanted 0.8 mm below the surface of the dura.

image

Figure 1. Drawings of rat brain and skull to depict the position of recording electrodes used when TTX was infused in developing neocortex. (A) The infusion site is marked by a + and electrodes were implanted at this location and 1.5 mm anterior, posterior, medial, and distal to the infusion site. An array of five electrodes was placed in homologous sites in the contralateral cortex. (B) In order to sample from broader areas of cortex, electrodes were positioned in other rats at 3.0 mm distances from the electrode implanted at infusion site (+). Again an additional five recording electrodes were positioned contralaterally. The location of the reference electrodes in cerebellum is depicted by an asterisk.

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Hippocampus-infused animals were implanted with both cortical and hippocampal electrodes. One of the right hippocampal electrodes was located in the infusion site. Another electrode was placed in the right ventral hippocampus. The other three electrodes on the same hemisphere were linearly aligned rostral-caudal within the cortex and spaced 1.5 or 3 mm from each other. A similar set of five electrodes was placed in homologous sites in the contralateral (left) hemisphere.

In two animals (both TTX infused) a limited number of EEG electrodes were implanted during the four-week infusion period, and within days of an observed behavioral seizure. In these animals two electrodes were implanted into the cortex of the right hemisphere—one 3 mm anterior and another 3 mm posterior to the infusion cannula. Matching electrodes were implanted into homologous sites in the left hemisphere.

Recording and analysis

The EEG and a concurrent video recording of the animal's behavior were acquired with a Nicolet Alliance Works digital instrument. The EEG signals were recorded referentially, and digitized at 250 Hz after appropriate low-pass filtering. Video/EEG was recorded continuously for periods of 2–7 h on multiple occasions (1–21 recording sessions per animal) following electrode implantation. Recordings were performed for an average of 28.5 days after electrode implantation. All video/EEG data were backed up on DVDs or external hard drives and analyzed offline. All recording sessions were reviewed by at least two of us in order to characterize the ictal and interictal EEG and behavioral events. Additional quantification of the EEG was done using computer-based power spectral analysis of selected ictal episodes and interictal periods. The program for spectral analysis was developed in Matlab by one of us (JDF).

Results

  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. References

Eleven (31.4%) of the 35 animals that received TTX infusion exhibited brief behavioral spasms that were accompanied by epileptiform EEG events. The findings were essentially the same for cortical and hippocampal infusion: Of the 19 cortical-infused animals, six (31.6%) exhibited spasm episodes. Similarly, of the 16 hippocampal-infused animals five (31.2%) exhibited epileptic spasms. None of the eight vehicle controls (five hippocampal and three cortical infusions) exhibited any behavioral or electrographic seizures during the observation period. In terms of the TTX-infused rats that exhibited behavioral spasms, the spasms were initially observed during the infusion period (as early as 11 days after pump implantation). Behavioral and electrographic spasms continued for many days to weeks after the removal of the infusion pump. For instance in one animal, spasms were observed up to 95 days of age—54 days after cessation of infusion, at which time recordings were terminated.

Spasms: behavioral features

The typical ictal behavioral event was a very brief (1–2 s duration) extensor or flexor spasm of the body musculature, which was sometimes accompanied by forelimb pawing movements. These spasms could be symmetrical or asymmetrical, with, for example, rapid extension of the trunk toward the side of the TTX infusion. The intensity of the spasms was highly variable between animals and within a given animal. The spasms could vary from a minimal jerk to an intense contraction of the body musculature, which could cause the animal to fall.

Spasms: ictal EEG patterns

The most frequent ictal EEG pattern associated with a spasm was an initial generalized, high-amplitude, slow wave transient (SW), followed by a period of generalized voltage attenuation, or electrodecrement (ED) with superimposed fast activity (FA) (Fig. 2). Various combinations of the three components have been observed. The duration of these ictal EEG episodes varied from 1 to 10 s. Ictal EEG events of this type have also been observed in association with very minimal behavioral manifestations (e.g., a minor jerk of the upper torso) and, occasionally, without any observable behavioral accompaniment. An example of our video-EEG recordings is shown as supplemental material. The similarities between these episodes and the ictal EEG pattern typically observed in human IS are illustrated in Fig. 3. As evident from these recordings, ictal fast activity was more predominant in the recordings from rats (e.g., compare the recordings at 5–50 Hz in the lower panel of Fig. 3).

image

Figure 2. An example of an ictal EEG discharge recorded from a rat on postnatal day 44, that resulted from TTX infusion into the right dorsal hippocampus beginning on day 10. The most common ictal event consisted of a generalized high amplitude slow wave transient (SW) followed by a period of generalized voltage attenuation (electrodecrement—ED) with superimposed fast activity (FA). Ten recording electrodes were used and were spaced at 3 mm distances in cortex. Labels refer to the montage employed: left frontal cortex (LF), right frontal cortex (RF), left central cortex (LC), right central cortex (RC), left posterior cortex (LP), right posterior cortex (RP), left dorsal hippocampus (LDH), right dorsal hippocampus (RDH), left ventral hippocampus (LVH), right ventral hippocampus (RVH).

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image

Figure 3. Comparison of representative ictal EEG discharges recorded in a human infant with infantile spasms and a rat that was chronically infused in neocortex with TTX beginning on postnatal day 11. The top two panels show the original recordings. In the lower panels, selective band-pass filters (0.1–0.6 Hz, 0.6–5 Hz and 5–50 Hz) were applied to the ictal recordings from both human and rat. In the recordings from the human, the ictal event consisted primarily of an electrodecremental response with some superimposed fast activity. For the rat, the ictal event was recorded on postnatal day 42 and consisted of an initial slow wave followed by an electrodecrement with superimposed fast activity. The electrodecremental response is clearly evident at frequencies of 0.6–5.0 Hz in both the human and rat. The high frequency fast activity predominates at frequencies of 5- 50 Hz. It is evident from these examples that the frequency distribution is very similar in the two cases. The montage for the rat with electrodes positioned as in Figure 1B: LF, RF—left and right frontal cortex; LC, RC—left and right central cortex; LP, RP—left and right posterior cortex; LT, RT—left and right temporal cortex; LPT, RPT—left and right posterior temporal cortex. The montage for the human corresponds to the International System of electrode placement.

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Spasms: temporal features

The majority of spasms observed in rats occurred during the awake state. However, many of these events were initiated during, or shortly following, awakening from sleep. While many events occurred in an isolated manner, clusters were also frequently observed. We define a cluster as two or more spasms occurring within a minute. During the limited recording sessions (2–7 h) seven of the 11 animals that exhibited spasms had clusters. As many as 33 ictal episodes have been recorded within a 6-min period (Fig. 4), with interspasm intervals as short as 1–2 s. Furthermore, the behavioral progression during such a long cluster was generally characterized by a waxing and waning of spasm intensity. The clustering of ictal events and the clinical progression observed in these animals are very reminiscent of the features observed in human cases of IS.

image

Figure 4. Spasms induced by TTX infusion occur in clusters. In this rat, the neocortex was infused with TTX beginning on postnatal day 11. (A) EEG recording made on postnatal day 42 showing six ictal complexes consisting of a generalized slow wave transient followed by an attenuation of the background, and variable amounts of superimposed fast activity in all regions. Arrows denote the initiation of each complex. A hypsarrhythmic pattern is present between the ictal complexes. This section was taken from a 6-min segment during which time a total of 33 spasms were recorded. (See supplemental video file). Montage same as in Fig. 3. B: Graphic depiction of spasm occurrence during a 250 min recording session. The shaded region highlights the 33 spasms associated with the recordings of the cluster shown in A.

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Interictal patterns

The interictal EEG was abnormal in all 35 of the TTX-infused animals, and was typically characterized by multifocal spike and sharp wave discharges. Typically, the spikes were more prevalent during NREM sleep and over the noninjected hemisphere. Nine of the 11 TTX-infused animals who developed spasms also exhibited a high voltage, chaotic background pattern that resembled the hypsarrhythmic pattern observed in human children with IS. This pattern occurred intermittently during NREM sleep. In many animals, there was also an asymmetry of activity in the fronto-central regions, with lower voltage present on the right side, corresponding to the infusion site. In some of these animals, the tracing could be classified as a hemihypsarrhythmia. Figure 5 compares interictal recordings from a human infant diagnosed with IS and a rat from our study. A power spectral analysis in Fig. 6 compares frequency components of interictal recording from frontal cortex in rat and human. Results indicate a high degree of similarity in the frequency components found in human cases of IS with hypsarrhythmia and the interictal EEG pattern from the present model. However, there were two differences: the amplitude of the activity was higher and the frequency components above 15 Hz were more prominent in animals compared to humans, which is similar to the differences in ictal events between rat and human mentioned above. The most likely explanation for these differences is that in humans, the EEG was recorded from scalp electrodes, whereas in these animals, the EEG was recorded from intracortical electrodes. The intervening bone and scalp tissues in the humans are known to act as a voltage attenuator as well as a high-frequency filter.

image

Figure 5. Comparison of interictal hypsarrhythmic patterns recorded in a human with infantile spasms and a rat whose neocortex was infused with TTX beginning on postnatal day 11. Recordings from the rat were obtained on postnatal day 42. The montage for the rat is the same as in Fig. 3. The montage for the human corresponds to the International System of electrode placement.

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image

Figure 6. Power spectrum analyses comparing frequency components of interictal recording from frontal cortex in a human with infantile spasms and a rat that was infused with TTX. Note the similarities in the frequency components of the discharges recorded from the human and rat model. Recordings from the rat commonly had discharges with higher frequency components. This was likely due to differences in how recordings were obtained. In the human they were from the surface of the skull but in the rat they were intracortical.

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Discussion

  1. Top of page
  2. Methods
  3. Results
  4. Discussion
  5. References

The results of this study demonstrate that infusion of TTX into the neocortex or hippocampus of rats at an early stage of postnatal development can induce an epileptic process with neurophysiological and behavioral characteristics essentially identical to those associated with human IS. As summarized in Table 1, the major similarities include (1) an interictal EEG pattern characterized by multifocal spikes and sharp waves, which in most animals resembles hypsarrhythmia, (2) ictal EEG complexes identical to those seen in human IS, (3) brief clinical extensor or flexor spasms that vary in intensity, (4) spasms may occur as isolated seizures or in clusters, (5) spasms typically occur during wakefulness, or upon arousal from sleep, and (6) ictal complexes may occur without accompanying clinical seizures. Also, it should be noted that in this model, just as in the human condition, the spasms and EEG changes do not occur acutely following a brain perturbation. Instead, there is a latent period between the infusion of TTX and the development of the behavioral and EEG abnormalities. The fact that only a third of animals infused with TTX developed spasms is also consistent with the human condition since not all infants experiencing the same apparent brain insult develop IS (Frost & Hrachovy, 2003). In addition, TTX-infused animals often develop other types of seizures later in life, just as in the human condition. In rats these consisted primarily of prolonged limbic motor seizures (Galvan et al., 2000).

Table 1.  Comparison of human and animal model
FeaturesHumanAnimal
Interictal EEG-multifocal spikes/hyps++
Ictal EEG complexes—SW, ED, FA++
Spasms++
Seizures—single or clusters++
Seizures may occur awake or on arousal++
Ictal complexes occur without clinical seizures++

Certain features of the human condition still need to be confirmed in this model. For example, it has been suggested that response to ACTH or other therapies, as well as the presence of cognitive impairment, are essential criteria for a comprehensive model of this disorder (Stafstrom & Holmes, 2002; Stafstrom et al., 2006). To evaluate response to therapy, more prolonged EEG/video monitoring sessions are required to accurately quantify spasm frequency. Experiments are currently being designed to address these issues. However, it should be noted that the diagnosis of IS in the human does not require these additional criteria.

In the current rat model, spasms begin during the four-week TTX infusion period. Thus far, the earliest we have observed spasms is P21 but long-term video EEG monitoring may reveal they begin earlier. Furthermore, it is also known that the TTX model is developmentally dependent, with chronic epileptogenesis resulting when TTX infusion is initiated on P10–12 but not later (Galvan et al., 2000). It is conceivable that if treatment was initiated during the first week of life, seizures might take place even earlier in development. Consequently, this model shares certain developmental features that are consistent with the human condition: In humans, IS typically begins within the first year of life, with a peak age of onset at 4–6 months (Hrachovy & Frost, 1989), although it can occur as early as the first week of life, or, rarely, as late as 3 years of age or longer. Stafstrom & Holmes (2002) have suggested that P13–20 in the rat represents the time window corresponding to the period when humans are susceptible to developing IS. However, it has been and continues to be very difficult to directly compare maturational processes in the human and rat brain. In any given species, different brain regions and systems exhibit different maturational rates, and these system-specific rates may vary considerably between species (Clancy et al., 2001; Avishai-Eliner et al., 2002). Commonly, P5 to P7 in the rat has been considered comparable to birth in the human and the first postnatal year of human life approximately equivalent to postnatal days 7–14 in the rat (e.g., Gottlieb et al., 1977; Avishai-Eliner et al., 2002), but recently even these interspecies comparisons have been called into question (Clancy et al., 2001).

Nonetheless, it is important to note that our model of IS is not the first in which seizures or behavioral abnormalities that occur in human infants or young children are observed in what are commonly considered more mature rodents. Indeed, in genetic animal models of neurodevelopmental disorders such as Rett, Angelmann, and Fragile X syndromes, clinically relevant behavioral abnormalities are observed in adulthood (Watase & Zoghbi, 2003). For instance, in Rett mouse models, animals appear normal until six weeks of age after which symptoms similar to those of very young girls (6–18 months of age) begin to appear (Chen et al., 2001; Guy et al., 2001). In terms of epilepsy, spike-and-wave discharges begin to be recorded in GAERS and WAG/Rij rats at one month and two to three months of age, respectively and in both strains discharging increases in intensity with age (Vergnes et al., 2003; Schridde & van Luijtelaar, 2005)—this despite the fact that human absence seizures commonly occur in childhood. Thus, comparisons between animal and human brain maturation will likely to continue to be debated but with ever-increasing intensity since this issue could impact interpretation of the underlying neuropathological mechanisms discovered in a variety animal models of neurodevelopmental disorders.

The pathophysiological basis of IS is not known, although there has been much speculation (Chugani et al., 1992; Brunson et al., 2001a; Lado & Moshe, 2002; Frost & Hrachovy, 2005; Dulac et al., 1999). Recently, we have suggested that desynchronization of two or more developmental processes could be the basis for this disorder (Frost & Hrachovy, 2005). The entire process of normal development is dependent on a complex series of interactions that is finely tuned temporally and spatially. Unanticipated disruptions in any of these processes could potentially lead to pathologic consequences. It is well known that neuronal activity plays an important role in normal neuronal development (Katz & Shatz, 1996). Numerous studies have shown that when the activity of neurons is experimentally altered early in life, the maturation of neurons and their patterns of connectivity can be drastically modified. Perhaps the visual system is the best studied in this regard where blockade of neuronal activity in the retina by infusion of TTX disrupts the formation of ocular dominance columns in visual cortex (Stryker & Harris, 1986; Antonini & Stryker, 1993). However, activity can also regulate the growth of dendrites (Wong & Ghosh, 2002), formation of synapses (Waites et al., 2005), and expression of neurotransmitter receptors (Dumas, 2005). Thus the TTX-induced blockade of neuronal activity undertaken in the present study could be expected to desynchronize the developmental processes that normally take place in neurons at the infusion site and their synaptic partners at more distant sites. The occurrence of an epileptic condition in rats that closely resembles human IS lends further credence to the developmental desynchronization hypothesis.

Our results and the desynchronization model are also consistent with the model of Chugani and colleagues (Chugani et al., 1992) who reported hypometabolic regions in neocortex in the majority of human IS patients. This observation has been confirmed independently by others (Itomi et al., 2002; Metsahonkala et al., 2002). It would also be expected, and indeed has been shown, that infusion of TTX into the hippocampus results in focal hypometabolism in the region of infusion (Galvan et al., 2000). Since focal cortical hypometabolism has been reported in the majority of patients with IS and since TTX induces a focal hypometabolism in rats that develop an epilepsy closely resembling IS, it is possible that this epilepsy results from regional neuronal inactivity early in life.

In the past, a number of attempts have been made to develop an animal model of IS. One is based on the “CRH hypothesis,” which suggests that IS results from an excessive release of CRH from limbic and brainstem regions (Brunson et al., 2001a). The hypothesis was developed based on the ability of ACTH to control IS (Hrachovy et al., 1983; Mackay et al., 2004) and the demonstration that ACTH suppresses the production of CRH in the brain (Brunson et al., 2001b). CRH has also been shown to produce seizures in infant rats (Baram et al., 1992). However, the behavioral and electrographic features of these events in rats do not resemble the human condition. A second model relies on an intraperitoneal injection of NMDA in infant mice to induce acute, flexion-like spasms that last for tens of seconds (Kabova et al., 1999; Velisek et al., 2007). EEG recordings during these spasms resemble the electrodecremental response that characterizes the ictal discharge in humans. However, these animals do not display the interictal EEG pattern (hypsarrhythmia) and the condition does not persist beyond the acute injection period. A third model was recently described by Snead et al. (2007) in which GABA receptor agonists were administered in a mouse model of Down's syndrome with resulting extensor spasms and an accompanying electrodecremental response in the EEG. However, these spasms occurred only acutely (10–25 min) following IP injection of the agent. These animals also exhibited altered behavioral patterns compared to controls. The seizures in this model were blocked or reduced by several anticonvulsants, including ACTH (Cortez et al., 2007). As in the case of the NMDA model, the condition apparently does not persist beyond the acute injection period. The crucial aspect of the TTX model of IS described here is that it recapitulates many of the features of the clinical syndrome, including spontaneous seizures that persist for weeks. Thus, it should be an especially important resource for exploring the neurobiological mechanisms that are responsible for this epilepsy of infancy.

Disclosure of conflicts of interest

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The authors do not have conflicts of interest to report. This work was supported by NIH Grants: NS 37171 and NS18309.

References

  1. Top of page
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  3. Results
  4. Discussion
  5. References
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