Introduction

The terrifying aspect of the sudden infant death syndrome (SIDS) is that it occurs in infants who seem healthy and then die without warning when put down to sleep. SIDS is not typically witnessed and it is surmized that death occurs during sleep, or during one of the many transitions to waking that occur during normal infant sleep-wake cycles (1). Multiple sleep-related mechanisms have been proposed to cause SIDS (1, 2). These mechanisms include suffocation/asphyxiation in the face-down sleep position, central and/or obstructive sleep apnea, impaired-state-dependent responses to hypoxia and/or hypercarbia, inadequate autoresuscitation, defective autonomic regulation of blood pressure or thermal responses, and abnormal arousal to life-threatening challenges during sleep.

In this chapter, we review the hypothesis and the neuropathologic evidence that SIDS is precipitated by a dentate gyrus-related seizure or a limbic-related instability that involves the central homeostatic network (CHN). We begin with an overview of this hypothesis, and then review our neuropathologic evidence for an epileptiform hippocampal lesion in the brain of a subset of SIDS infants and young children (41-50% respectively) who died suddenly and unexpectedly (3-5). We then consider the putative mechanism whereby dentate lesions cause seizures, the role of the hippocampus as part of the CHN in stress responses (such as the face-down sleep position), and the potential interactions of brainstem serotonergic (5-HT) deficits and the hippocampus in the pathogenesis of sudden death in infants. We conclude with further directions for research into the role of the hippocampus in sudden and unexpected death in early life.

The Limbic Seizure-Related Hypothesis in SIDS

In 1986, Harper suggested that some SIDS deaths may be due to a fatal seizure during sleep that arises in forebrain-limbic-related circuits (6). This hypothesis arose from the recognition of the following inter-related phenomena: limbic regions are particularly susceptible to epileptogenesis; sleep states lower the threshold for seizure; and SIDS is linked to sleep and arousal. Sleep itself is thought to be a precarious state, in part because of the loss of the major “back-up” forebrain systems of waking which influence the final common pathways in the brainstem that mediate central cardiorespiratory function during sleep. Forebrain limbic regions, such as the hippocampus and amygdala, which are part of the CHN, modulate brainstem cardiorespiratory control in a manner influenced by the sleep-waking cycles.

In line with Harper’s reasoning we propose that SIDS, or a subset of SIDS, is triggered by a seizure-like or paroxysmal event in unstable electrical circuits of the CHN, some of which originated in and are propagated from the hippocampus. The main evidence is neuropathologic observations that we identify as an epileptiform lesion in the hippocampus, a key structure of the CHN (Figure 29.1); such lesions are present in infants and young children with sleep-related sudden and unexplained death. The lesion is dentate bilamination (DB) (Figure 29.2), a morphological variant of granule cell (GC) dispersion that is recognized virtually exclusively in temporal lobe epilepsy (3).

Figure 29.1:

Schematic of the putative central homeostatic network with forebrain and brainstem nodes and interconnections. The abnormalities in SIDS reported by our laboratory are colored in red. (Authors’ own work.).

Figure 29.2:

Dentate bilamination in dentate gyrus (DG) in SIDS brain compared to control infant. Granular cell dispersion as illustrated by C Houser (bottom) (24). Top left panel: normal dentate gyrus in an infant. Top right panel: granular cell layer with diffuse (more...)

The presence of DB in cases of SIDS and sudden and unexplained death in childhood (SUDC) suggests a seizure-related mechanism of sudden death, arising from a bout of electrical instability generated from the abnormal dentate gyrus in the CHN. We propose that this electrical instability is precipitated by an exogenous stressor (e.g. hyperthermia or asphyxia), because of the epidemiological link of SIDS deaths to over-bundling and unsafe sleep environments such as the prone sleep position. Clinical seizures with abnormal movements are not usually recognized in infants dying of SIDS, either before, or at the time of, death. We have reported, however, an infant who was discovered having a seizure during sleep and whose death was deemed unexplained by a complete autopsy (7). Also, approximately 12% of SIDS cases have been associated with antecedent acute life-threatening events (ALTEs), with the ALTEs described as possible seizures in 6-16% (8). It does seem possible that some SIDS and SUDC cases arise from subclinical autonomic seizures during sleep that result in apnea, bradycardia, or other forms of cardiorespiratory dysfunction and sudden death.

The major network in the human brain that copes with stress is the CHN (9). This network comprises ascending and descending interconnections between brainstem nuclei and forebrain limbic regions, including the hippocampus, which together regulate and integrate respiratory, autonomic, immune, neuroendocrine, affective, and cognitive responses to stress during sleep or waking. Although the limbic lobe/system was historically regarded as the neuroanatomic substrate of emotion (10, 11), its role in the regulation of homeostasis has been increasingly recognized. As such, the originally defined sites have been encompassed in the central autonomic network (12-15) or “flight or fight” system of the hypothalamic-pituitary-adrenal axis (HPA) (16, 17). The biomediators of the CHN (e.g. cortisol, sympathetic and parasympathetic transmitters, 5-HT, cytokines, metabolic hormones) operate interactively, down- and up-regulating each other, depending on concentration, anatomic location, and physiological needs.

The Hippocampus, Regulation of Stress, and the CHN

The hippocampus plays an instrumental role in regulating the HPA (9, 18). Stress involves activation of the CHN to release a cascade of neurotransmitters, hormones, and other chemical messengers that induce behavioral and metabolic changes. A delayed response to stress involves the HPA axis, via activation of the hypothalamic paraventricular nucleus to release corticotrophin-releasing hormone (CRH) into the portal vasculature of the anterior pituitary gland. This stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland, which in turn triggers the release of glucocorticoids from the adrenal cortex.

All types of stress reactions operate through the HPA axis (19, 20). Through the release of glucocorticoids, the HPA axis mobilizes energy reserves in order to ensure that the organism has the resources to prepare for, and meet, a homeostatic challenge (19). The glucocorticoids exert negative feedback, regulating HPA axis activity via its own receptors (glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs)) in the hippocampus, as well as in the anterior pituitary, hypothalamus, and prefrontal cortex (19). The GRs and MRs are both ligand-gated transcription factors that alter expression of multiple genes (21). The hippocampus has the highest concentration of MRs in the brain. Higher levels of glucocorticoids (those following stress) activate lower-affinity GRs, which promotes expression of a wide variety of genes, and mediates glucocorticoid effects on neural function in the hippocampus (21).

Within the hippocampus, a critical CHN and HPA component is the dentate gyrus. The dentate gyrus is a central region of the hippocampus and is critical to its functions, which include learning and the formation of new memories. Furthermore, it is one of the major regions in the adult CNS with the capacity for constitutive neurogenesis throughout life (22). In humans, neurogenesis takes place in the subgranular zone of the dentate gyrus. Neural progenitor cells migrate from the dentate subgranular zone to the GC layer. The majority of cells are generated early in life, but new dentate GCs arise at a lower rate throughout adulthood and into late life in humans and rodents. Adult-born neurons make up about 6% of the GC layer in rats. These cells integrate into hippocampal circuitry and acquire characteristics of mature GCs, as demonstrated in part through BrdU labeling experiments (23).

Although the hippocampus mediates stress responses via the HPA axis, it is itself especially vulnerable to the deleterious effects of excessive corticoid stimulation in abnormal stress responses. In animal models, chronic stressful experiences (e.g. prolonged immobilization, housing in dominance hierarchies, early maternal separation) can remodel hippocampal neurons and result in changes in gross and microscopic morphology of the hippocampus (21). Animal model studies of the adult hippocampus have revealed mechanisms by which repeated stress causes remodeling of hippocampal circuitry. These include: [1] suppression of neurogenesis, which is ongoing in the young adult dentate gyrus; [2] shortening of dendrites; and [3] loss of spine synapses (21). Stress decreases neurogenesis by stimulating the release of adrenal corticosteroids via the HPA axis (see above); the adrenal corticosterioids then bind to the GC progenitors in the dentate gyrus and decrease cell proliferation. In certain diseases related to stress (e.g. depression or post-traumatic stress syndrome (21)), there is a subsequent decreased volume of the hippocampus.

Replacement of neurons via neurogenesis is one neuroplastic mechanism to protect against and/or to adapt to stress; however, it is also affected by excessive or dysregulated stress itself. Studies have demonstrated that the proliferation of GC precursors and production of new GCs, are dependent on the levels of circulating adrenocortiocoid steroids (20); these hormones inhibit cell proliferation in the dentate gyrus during the early postnatal period and in adulthood. The suppressive action of glucocorticoids on cell proliferation is not direct but occurs through an N-methyl-D-aspartate (NMDA) receptor-dependent excitatory pathway. Stressful experiences, which are known to elevate circulating levels of glucocorticoids and to stimulate hippocampal glutamate release, inhibit the proliferation of GC precursors. However, different experimental paradigms indicate that stress can not only decrease neurogenesis, but also increase it, depending upon the type of stress, the amount, the developmental window, and other factors.

Hippocampal Pathology in SIDS

Clinicopathologic findings in the San Diego cohort of the hippocampal study

In the San Diego cohort we found that the frequency of DB was significantly increased in the unexplained group compared to the explained group. Dentate bilamination was present in 41.2% (47/114) of the unexplained group compared to 7.7% (3/39) in the explained (p<0.001). This lesion was recognized at anterior, mid-, and posterior sections of the hippocampus in the unexplained category. The frequency of clusters of immature cells in the subgranular layer of the dentate gyrus was also significantly increased in the unexplained group (53.5% [61/114]) versus 10.3% (4/39) in the explained group, p<0.001). Immunocytochemical analysis indicated that these immature cells expressed Tuj1, a marker of early neuronal differentiation (3); these cells did not express immunomarkers for reactive astrocytes or activated microglia. The presence of DB was significantly associated with four features which were absent in cases without DB: [1] DB located in the bend of the C-shaped dentate gyrus; [2] clusters of immature cells in the subgranular layer of the dentate gyrus; [3] single ectopic GCs in the dentate gyrus molecular layer; and [4] clusters of ectopic GCs in the dentate gyrus molecular layer (3). There was no effect of increasing postconceptional age upon the frequency of DB, single/clusters of ectopic GCs, or immature cells in the subgranular layer of the dentate gyrus. Of note, in cases in which the right and left side of the hippocampus were available, we observed in some SIDS cases gross hippocampal asymmetry, which also demonstrated microscopic dentate abnormalities. We previously reported (28), for example, the case of a 10-month-old infant boy whose clinical presentation included a sleep-related death: prone position upon discovery, minor illness within two days of death, and no anatomic explanation for sudden death upon systemic autopsy. Nevertheless, neuropathologic examination revealed striking hippocampal asymmetry (Figure 29.3) and DB similar to that reported in cases in the San Diego cohort above.

Figure 29.3:

Asymmetry of the hippocampus in a 10-month-old with sudden death. The macroscopic abnormalities are restricted to the hippocampus. A: At the anterior level (level of the substantia nigra and red nucleus), the left pes appeared globular and shortened in (more...)

In the San Diego infant cohort of unexplained (SIDS) and explained (control) cases, we also examined the dentate gyrus, temporal cortex, and white matter for possible linked morphologic profiles. In the unexplained group there was no significant increase in the frequency of acquired features indicative of acute or chronic hypoxic-schemic injury. However, 64.1% (25/39) of the explained group demonstrated acquired features compared to 21.1% (24/114) of the unexplained group (p<0.001). Because ischemia is known to stimulate neurogenesis, we postulated that the frequency of DB with hypoxic features (DB-HI) (e.g. hypereosinophilic GCs with pyknosis, gliosis in dentate gyrus) was not significantly different between the explained (15.4% [6/39]) and unexplained (14.0% [16/114]) groups (p=0.80) with hypoxia-ischemia, and we found this to be the case. The presence of DB-HI was significantly associated with features indicative of acute and/or chronic injury outside of the dentate gyrus (e.g. in the temporal cortex and Ammon’s horn), whereas DB was not associated with HI changes. Thus, the morphological profile of linked features differed significantly between DB and DB-HI, indicating distinct entities, with DB almost exclusively found in the unexplained group.

Hippocampal Pathology in Sudden Unexpected Death Beyond Infancy

A major finding in children dying suddenly and unexpectedly over 1 year without explanation (e.g. SUDC) is hippocampal pathology, first reported by us in SUDC cases of the San Diego SUDC Research Project (30). A final summary of the San Diego database was published in 2015 (4, 5) in a study in which the findings in toto from 2007 to 2015 were collectively reported. We undertook analysis of a retrospective cohort of 151 cases, of which 80% (121/151) were subclassified as SUDC, 11% (16/151) as explained, 7% (10/151) as undetermined, and 3% (4/151) as seizure-related. There were no significant differences between SUDC and explained cases in postnatal, gestational, or postconceptional age, frequency of preterm birth, gender, race, or organ weights. In contrast, 96.7% (117/121) of the SUDC group were discovered during a sleep period compared to 53.3% (8/15) of the explained group (p<0.001). Of the SUDC cases, 48.8% (59/121) had a personal and/or family history of febrile seizures compared to 6.7% (1/15) of the explained group (p<0.001). Of the explained deaths, 56% (9/16) were subclassified as infection, 31% (5/16) cardiac, 6% (1/16) accidental, and 6% (1/16) metabolic. Two of the three cases specifically tested for cardiac channelopathies at autopsy based upon clinical indications had genetic variants in cardiac genes, one of uncertain significance. Two of the four seizure-related deaths were witnessed, with two of the brains from these cases showing generalized malformations. Hippocampal anomalies, including a specific combination we termed Hippocampal Maldevelopment Associated with Sudden Death (HMASD), were found in almost 50% (40/83) of the SUDC cases in which hippocampal sections were available. This study highlights the key role for the hippocampus, febrile seizures, and sleep in SUDC pathophysiology.

In the SUDC San Diego cohort, we characterized in greater detail the hippocampal pathology in 121 cases (4, 5). We performed comparative analysis on these cases, which we classified as one of the following: HMASD, SUDC with febrile seizure phenotype (SUDC-FS) but without hippocampal pathology, SUDC without hippocampal pathology or febrile seizure phenotype, and explained deaths. The frequency of each subgroup was: HMASD 48% (40/83); SUDC-FS 18% (15/83); SUDC 27% (22/83); and explained 7% (6/83). HMASD was characterized clinically by sudden, sleep-related death, term birth, and discovery in the prone position. Key morphologic features of HMASD were focal GC bilamination of the dentate gyrus with, or without, asymmetry and/or malrotation of the hippocampus associated with significantly increased frequencies of 11 other developmental abnormalities (Figure 29.4). We identified no other distinct phenotype in the unexplained categories, except for an association of febrile seizures without hippocampal maldevelopment. This finding could reflect incomplete sampling of the hippocampus with failure to detect the hippocampal lesion. Alternatively, febrile seizure without hippocampal pathology may indicate that febrile seizures are a risk factor for sudden death without a direct link to anatomically obvious hippocampal pathology.

Figure 29.4:

Developmental abnormalities in the hippocampus. Top left panel: granule cell heterotopia (asterisks) in hilus of hippocampus in SIDS. Top right panel: granule cell heterotopia (asterisks) in molecular layer of dentate gyrus in SIDS. Lower panel: scalloped (more...)

Spectrum of Dentate Anomalies before and after One Year of Life (the Age “Cut-off” for SIDS)

We first reported hippocampal abnormalities in separate cohorts of SIDS (3) and SUDC (4, 5, 30, 31) cases. In the SUDC study, in the children between 1 and 6 years of age with hippocampal maldevelopment, 62.5% (25/40) had a personal and/or family history of febrile seizures compared to the population frequency of 3-5% (4, 5). We then asked if the hippocampal anomalies were the same, or similar, in SIDS and SUDC cases. We tested this in a different cohort of 32 SIDS and SUDC brains combined, and reported that in both age groups there was a similar spectrum of anomalies in the formation of the hippocampus and/or subiculum (32). Thus this study defined, for the first time, a unifying neuropathologic entity in sudden unexplained death in pediatrics (SUDP), involving children less than, and older than, 1 year of age. This was characterized by dentate/hippocampal/subicular maldevelopment, an entity we had previously reported separately in SIDS (3) and SUDC cases (4, 5, 30, 31). We have termed this lesion “hippocampal formation maldevelopment in SUDP” (SUDP-HFM), and identified four morphological variants of the disorder: [1] DB and GC anomalies only (Pattern A); [2] DB with hippocampal asymmetry (Pattern B) (Figure 29.5); [3] DB with subicular anomalies (Pattern C) (Figure 29.6); and [4] DB with hippocampal dysplasia (Pattern D) (32). These patterns may prove to be related to specific clinical subtypes, and/or variable genetic and environmental factors involved in the pathogenesis. All patterns display focal DB, with or without asymmetry/malrotation of the hippocampus proper (dentate gyrus and Ammon’s horn). The major distinction among them is the presence of abnormal subicular folding (Pattern C) versus the absence of such folding (Patterns A, B, and D). While Patterns A, B, and D were present in all age groups, Pattern C was only observed in children older than 1 year of age. Pattern C also carried an 11-fold increase in risk of personal febrile seizures compared to Patterns A, B, and D combined, and a tendency toward larger head/brain size compared to Patterns A, B, and D combined. This latter observation needs confirmation in larger samples and comparison with parental head circumference data.

Figure 29.5:

Asymmetry of the hippocampus (abnormal globular shape) in toddler with history of seizures and sudden death. Malrotation of the hippocampus proper is notable for a rounded and upright shape (encircled hippocampus). The toddler also has abnormal folding (more...)

Figure 29.6:

Anomalies of the subiculum in two cases of SUDC between the ages of 1 and 6 years. Left panel: duplication of the subiculum is characterized by the “splitting” of CA1 of Ammon’s horn into two thick “branches” of (more...)

In addition to DB, the brains of the 32 cases of SUDP-HFM exhibited a range of microdysgenetic features in temporal and non-temporal regions. These microdysgenetic features have been shown to be associated with epilepsy (32), and include focal cortical dysplasia, heterotopia, and hamartia. In addition, we found anomalies of derivatives of the embryonic rhombic lip, including hypo- or hyperplasia of the arcuate nucleus, olivary heterotopia and dysplasia, and dispersed GCs in the molecular layer of the cerebellar cortex (32). Although the DB and associated dentate gyral anomalies are the sine qua non of the SUDP-HFM entity that we describe, the presence of developmental pathology in the cerebral cortex and rhombic lip derivatives in the majority of SUDP-HFM cases suggests that this constellation of anomalies could relate to common processes involved in the development of the different regional anlages. It is possible that in some cases these three embryonic anlages are developmentally and functionally linked, and pattern disruptions occur in the genetic regulation of a signaling molecule or transcription factor shared by all three embryonic anlages in SUDP-HM. Many of the abnormalities inside and outside the hippocampus proper are consistent with neuronal migration defects — for example, DB, focal cortical dysplasia, heterotopia, peripheralization of olivary neurons, arcuate nucleus hyperplasia, and dispersed GCs in the molecular layer of the dentate gyrus and cerebellar cortex — suggesting that genetic disturbances in shared migration factors (e.g. reelin) may occur in different parts of the brain.

The association between sudden death with personal febrile seizures in young children likely reflects the developing brain’s vulnerability between the ages of 6 postnatal months and 6 years to high fever due to brain maturational factors related to thermal sensitivity, involving the CHN (33). Under 6 months, heightened thermal sensitivity may also be present, but may manifest as putative central autonomic instability and increased risk for sudden unexplained death due to over-bundling in SIDS (33).

In the combined study of infants and children who died suddenly, brain regions, in addition to the hippocampus, were examined for pathology. Of the cases under 1 year of age, 10/13 (77%) had diffuse cerebral white matter gliosis. This declined to 6% (1/17) in young children under 6 years, and to 0% in the two cases over 6 years. The majority of cases in the first year of life had brainstem tegmental gliosis, including the dorsal raphe and olivary gliosis; both of these features were reduced by half in early childhood (32). There was sparing of gliosis and neuronal loss in the thalamus, putamen, caudate, globus pallidus, and amygdala, and relative sparing of the hypothalamus. In the hippocampus there was hilar gliosis in both the infants (0 to less than 1 year, 46% [6/13]) and young children (1 to less than 6 years old, 47% [8/17]), without obvious neuronal loss. There was neither gliosis nor neuronal loss in hippocampal CA1-3 pyramidal neurons in any age group. The degree of myelination was age-appropriate in all forebrain and brainstem regions in which myelin counter-staining with Luxol-fast-blue was available (six infants and nine children over 1 year).

The Pathogenesis of Dentate Gyral Abnormalities in SIDS/SUDC

The etiology of DB observed in the dentate gyrus in sudden and unexpected death in early life is unknown. We suggest that DB represents a developmental defect in neuronal proliferation, migration, and/or cell survival in the dentate gyrus related to [1] an unknown teratogen during gestation; [2] abnormalities in the trophic effects of 5-HT (see below); or [3] an unrecognized genetic defect in dentate gyral formation. In the SIDS cases, evidence of proliferation of GC, scalloping, and hyperconvolution of the dentate gyrus suggests an excess number of GCs packed into the undulating configuration of the dentate gyrus, which influences GC dispersion and DB, as evidenced by the excessive clusters of progenitor-like cells in the subgranular layers with markers of immature neurons (e.g. Tuj1). The strong association of DB with other features of maldevelopment in the dentate gyrus (e.g. excessive single or clustered ectopic GCs in the dentate molecular layer and hilus) and clusters of immature cells in its subgranular layer (the zone of GC neurogenesis) supports such a developmental hypothesis.

This is further supported by a lack of acquired inflammation (i.e. reactive astrocytes), activated microglia, and/or apparent neuronal loss. In the San Diego cohort study, the immature cells, labeled by Tuj1, in excessive clusters in the subgranular layer are potentially “stalled” in the subgranular layer due to impaired migration; or, alternatively, they “accumulate” in the subgranular layer due to an abnormally prolonged cell survival, a mechanism suggested in the PET1 knockout mouse with impaired 5-HT cell development (32). The undulations of the dentate gyrus and its molecular layer, particularly in the medial distribution, in Pattern D (hippocampal dysplasia) are reminiscent of the histopathologic dentate findings in the genetically engineered mutant mice which lack the non-receptor tyrosine kinase gene fyn and demonstrate impaired long-term potentiation, spatial learning, seizures, and sudden death (39, 40). The lack of fyn during hippocampal development in this mouse mutant results in an increased number of GCs in the dentate gyrus, giving it a “scalloped” or “dysplastic” appearance, as seen in our Pattern D. The increase in cells was postulated to result from over-proliferation, altered cell fates, or failure of cell death (39). Granule cell production occurs in the human dentate gyrus pre- and postnatally, with stabilization within the first three years (41). Granule cell dispersion has not, however, been observed in normal dentate development; rather, its presence is invariably considered pathologic (41).

We regard the abnormal hippocampus with Patterns A-D as primary developmental lesions because they are not associated with gliosis and/or neuronal loss in the hippocampal formation (HF), except for hilar gliosis (see below). We speculate that abnormal folding of the hippocampus proper (Pattern B), subiculum (Pattern C), and GC and molecular layers of the dentate gyrus (Pattern D) originates as the hippocampus begins to form and fold at the end of the first trimester (32). The embryonic anlage of the HF, the cortical hem, which induces the formation of the hippocampus proper and subiculum within the adjacent cortical neuroepithelium (32), may be at fault in Patterns B, C, and D. Granule cells in the dentate gyrus are generated from stem cells in the subgranular layer throughout life, and integrate into the mature hippocampal circuitry, potentially participating in the formation of new memories (22). Because neurogenesis continues after birth into adulthood (22), Pattern A, consisting of DB only, could arise pre- and/or postnatally. GC dispersion, including DB, is hypothesized to be due to increased proliferation of progenitor cells from the subgranular zone, a defect in neuronal migration upwards from the subgranular zone, and/or inhibition of programmed GC death.

We have examined the cohort histories for possible teratogens that could operate during early gestation (e.g. prenatal exposure to alcohol and cigarette smoke). Patterns A, B, and D combined demonstrated variable frequencies of borderline significance with exposure to prenatal alcohol, which is a known risk factor for SIDS (42), as is prenatal exposure to smoking (43). Pattern C, with abnormal subicular folding, was not associated with these exposures, suggesting that Pattern C may have a distinctive pathogenesis with a developmental vulnerability of the subiculum different from the hippocampus proper — a hypothesis for future testing in larger cohorts with more detailed exposure histories.

Granule Cell Dispersion in the Dentate Gyrus and its Role in the Genesis of Seizures

The dentate gyrus in the hippocampus is a well-recognized site of epileptogenesis (23), as demonstrated in genetically engineered mouse models in which dentate morphological disorganization is responsible for the origin of seizures, and not secondary to them (44). Granule cell dispersion, however, is also recognized to be secondary to seizures, with seizure activity resulting in the formation of the lesion. Thus, a role for seizures must be considered in the pathogenesis of increased GCs in SIDS cases. Data from rodent models of medial temporal lobe epilepsy show that prolonged seizures acutely increase adult GC neurogenesis (23). In the rat pilocarpine model of temporal lobe epilepsy, as assessed by the expression of Ki-67 (an endogenous cell proliferation marker) or short-pulse bromodeoxyuridine (BrdU) mitotic labeling, the dentate gyrus responds to status epilepticus (SE) by increasing cell proliferation in the subgranular zone (45).

Seizures can also induce other morphological changes in the dentate gyrus that affect dentate function. The epileptic dentate gyrus in human TLE is associated with mossy fiber sprouting, ectopically located GCs, and GCs with very prominent hilar basal dendrites (HBDs), as well as GC dispersion (23). In rodent models of status epilepticus such as the pilocarpine model, hippocampal pathways exhibit structural plasticity analogous to changes reported in humans. After SE, many dentate GCs erroneously migrate into the dentate hilus or through the granular layer into the molecular layer (23). These ectopic cells are found in rodent models of epilepsy (46), in the epileptic human hippocampus (23), and in the SIDS and SUDC cases of our studies.

One proposed cause of the aberrant migration is loss of the migration guidance cue reelin, which is expressed in the adult rodent hippocampus (23). In epileptic brains, dentate GC dispersion is thought to result in aberrant synaptic connectivity, increasing susceptibility to seizures through hyperexcitability (23). A large body of information supports the hypothesis that cellular abnormalities such as mossy fiber sprouting, ectopic dentate GCs, and HBDs contribute to epileptogenesis in experimental and human TLE. Seizures in TLE have been proposed to result from hyperexcitability due to aberrant excitatory recurrent axon collaterals between GCs in mossy fiber sprouting (23). Additionally, evidence suggests that normal gamma-Aminobutyric acid (GABA) inhibition is diminished by mossy fiber terminals, further contributing to hyperexcitability in mossy fiber sprouting. Hilar ectopic GCs themselves are also thought to be hyperexcitable (23). Timm staining and dynorphin immunoreactivity, as markers for mossy fibers, have demonstrated substantial sprouting in patients with mesial TLE that is considered secondary to chronic seizures (23). Normally, glutamatergic mossy fibers project into the dentate hilus from the GC layer and stratum lucidum of CA3 and synapse with inhibitory interneurons, hilar mossy cells, and CA3 pyramidal cells, but only very rarely with other GCs. Consequently, most GCs normally do not display functional, monosynaptic, recurrent excitation (23).

Overall, there is considerable anatomical and physiological evidence that mossy fiber sprouting creates a positive-feedback, seizure-generating circuit among GCs. In epileptic tissue, sprouted mossy fibers form excitatory synapses with ectopic GCs in the hilus, GC basal dendrites in the hilus, GC somata in the GC layer, and GC apical dendrites in the GC layer and inner molecular layer. Furthermore, mossy fiber sprouting correlates with hilar neuron loss in patients with mesial TLE (23). In our tissue sections, neuronal loss was not always visually apparent, and quantitative studies would be needed to determine subtle loss.

Speculation about the Mechanism(s) of Sudden Death associated with Dentate Gyral Abnormalities in SIDS/SUDC

The dentate gyral abnormalities are a putative morphological marker of an impaired central homeostatic network (which involves brainstem, forebrain, and limbic systems) which increases the risk of sudden infant death due to instability of modulation of brainstem cardiorespiratory-related nuclei, or to a subclinical autonomic seizure in an infant with a predisposition to epilepsy, not yet manifested as a clinical seizure. We propose that this morphological marker “identifies” a vulnerable infant at risk for sudden death during a critical developmental period (birth to 6 years) when the infant or child meets an exogenous stressor of the Triple Risk model for SIDS and now SUDC (34). The hippocampus is interconnected with other forebrain loci in the limbic network (e.g. amygdala, insula, hypothalamus), as well as the brainstem sites which directly mediate respiratory autonomic control. The hippocampus exhibits a striking propensity to seizure generation and propagation, and the seizure discharges in temporal lobe epilepsy, especially, precipitate serious cardiorespiratory events (e.g. apnea and bradycardia (35)). Autonomic seizures are a consideration in sudden infant death, since recurrent episodes of apnea, reported in infants who subsequently die of SIDS (36), may be the sole manifestation of seizures (without movement abnormalities) in infants with temporal lobe pathology (37). The association of seizures (and sudden death during sleep periods) with limbic/hippocampal pathology suggests that sleep state in some way lowers the threshold for epileptogenesis in the limbic system.

The neuropathologic findings in these children provide a plausible mechanism for sudden and unexpected death via an epilepsy-like mechanism. Seizures, known to arise in all hippocampal formation (HF) substructures (32), may be generated in the abnormal hippocampal formation in SUDP-HFM, triggered by stress (e.g. asphyxia or fever) (Figure 29.7). The dentate gyrus is a well-recognized site of epileptogenesis (23) (see below). We speculate that abnormal electrical discharges in the disorganized HF are propagated to regions of the brainstem involved in breathing and/or autonomic function during sleep, leading to lethal disruption of vital functions and sudden death during sleep, when the threshold for epileptogenesis is lowered. We agree with Noebels, who recently coined the term “epilepsy in situ” in SUDC cases with hippocampal maldevelopment as an apt “new term that may be usefully applied to a microscopic epileptiform lesion with or without evidence of actual seizures” (38) (p. 198).

Figure 29.7:

Potential mechanism of death in dentate gyral dysplasia with compromised serotonergic pathways in the brainstem. (Authors’ own work.).

Using the Connectome in living adult volunteers, we have provided evidence for connectivity between the hippocampus and caudal brainstem regions (nodes) that participate in the regulation of homeostasis in the human brain (9). These nodes, and connections between the brainstem and hippocampus and other forebrain limbic-related sites, possibly represent the CHN due to the fact that its nodes regulate not only emotion and autonomic functions, but also homeostatic functions such as respiration (paragigantocellularis lateralis) and arousal (e.g. median and dorsal raphe, and the functions of the locus coeruleus). An important question is why the abnormalities of the HF, arising during gestation and present at birth, manifest themselves as sudden death at different ages. We speculate that the timing is due to the child’s individual developmental, environmental, and genetic risk factors, which influence the underlying HF vulnerability.

Potential Relationship between Brainstem and Hippocampal Abnormalities in the Same Cases

Over the last two decades, our group has provided substantial evidence in four published independent datasets that a subset of SIDS (~40%) is characterized by 5-HT defects. These are located in cardiorespiratory- and arousal-related regions in the medulla oblongata (caudal brainstem) and were identified using neurochemical techniques in frozen brainstem tissue (47-50). In 2015, we reported the novel morphological finding in the dentate gyrus of DB in a major subset of SIDS cases (~40%) in a separate dataset, as described above. It is currently unknown whether the same SIDS cases share hippocampal DB and 5-HT brainstem pathology, or whether each of these problems defines two separate entities currently under the rubric “SIDS”. If the hippocampal and brainstem abnormalities are part of one disease process, the presence of GC dispersion in the SIDS cases suggests the possibility that sudden death is the consequence of a seizure generated from the abnormal dentate gyrus. This would be triggered by stress (e.g. asphyxia or over-bundling/hyperthermia) and cannot be compensated by activation of 5-HT pathways in the brainstem, due to the simultaneously defective brainstem-mediated protective responses (e.g. arousal), thereby resulting in death. Importantly, recent experimental evidence suggests that brainstem 5-HT systems are critical in autonomic and respiratory changes during and after seizures arising above the brainstem, with implications for seizure-related sudden death (51).

The vulnerability of the hippocampus among forebrain sites to brainstem 5-HT pathology may reflect its preferential and extensive innervation with known heavy concentrations of 5-HT terminals by the rostral raphe (52). Neuroanatomic interconnections exist between the rostral and caudal 5-HT cell domains (52) and between the caudal 5-HT domain and limbic sites (9), as we have shown in Connectome studies of adult in vivo brains. We propose that the developmental malposition of GCs in SIDS-DB is due to defective brainstem 5-HT cell domains interfering with 5-HT innervation of hippocampal Cajal Retzius (CR) cells. Serotonergic fibers enter the marginal zone of the cerebral cortex before birth, where they influence cortical development through synaptic contacts with these CR cells (53). Perturbation of these early 5-HT contacts with CR cells decreases reelin in the brains of the newborn pups, and the formation of the presubicular cortex is altered (53). This work suggests a mechanism where 5-HT deficiencies involving ascending 5-HT projections in the brainstem during hippocampal development could lead to DB — that is, via decreased 5-HT-mediated production of reelin by the CR cells and secondary migration defects in the GCs that are known to be innervated by CR cells. In regards to 5-HT brainstem pathology in SIDS and its possible link to hippocampal defects, 5-HT is released from nuclei in the rostral raphe in the caudal midbrain and upper pons to play a trophic role in neurogenesis, migration, and neuronal survival in the dentate gyrus in early development (54). Moreover, 5-HT from the rostral raphe helps regulate neurogenesis in the dentate gyrus throughout life. Serotonin dysfunction is implicated in the seizure pathogenesis, and hippocampal abnormalities of 5-HT1A receptor binding have been reported in TLE (55). Thus, the underlying vulnerability in the infant at risk for sudden death may reflect a 5-HT brainstem disorder with deficient projections from the rostral raphe to the hippocampus, or alternatively, brainstem and hippocampus disorders independent from one another. Future research is needed to determine the role of brainstem 5-HT in the dentate disorganization reported here.

Conclusions

The finding of DB, a distinctive variant of GC dispersion, in the hippocampus of infants and children with sudden unexplained death opens new avenues for research into underlying vulnerabilities of these individuals to sudden death. Given that GC dispersion is a pathologic hallmark of TLE, its presence in the brains of infants and children dying suddenly without explanation raises provocative questions about the possible role of an underlying anatomic anomaly of the hippocampal dentate gyrus in initiating sudden death through epileptogenesis or faulty modulation of the CHN. The identification of this anatomic marker of a potential vulnerability to sudden early death unifies our approach to the investigation of SIDS, SUDC, and SUDEP. The descriptive observation of DB in sudden infant and child death is a potentially critical clue towards guiding both future neuropathologic studies in human youth and mechanistic testing in developmental animal models with consideration of hippocampal-brainstem and CHN interactions. Further research is also needed to investigate the relationship between hippocampal and the previously reported brainstem pathology in sudden infant death.

This study concludes that the presence of DB neuropathology in the HF in sudden unexplained death of infants and children challenges the age-related conventions for separating SIDS and SUDC. SUDP-HFM must be carefully identified in neuropathologic examination of sudden death in infants and children by assessment of both hippocampi in more than one tissue section. We believe it is appropriate to designate SUDP-HFM as a distinct cause of death for the purposes of family counseling, vital statistics, and death certificates. In our opinion, the robustness of the clinicopathologic phenotype, and the biologic plausibility of a fatal seizure-like event triggered by a set of exogenous factors in a critical developmental period, justify this conclusion. The outcomes of our research may lead to an increased understanding of antecedent risk factors for this entity.

References

1.

Kinney HC, Thach BT. The sudden infant death syndrome. N Engl J Med. 2009;361(8):795-805. https://doi​.org/10.1056/NEJMra0803836. [PMC free article: PMC3268262] [PubMed: 19692691]

2.

Harper RM, Kinney HC. Potential mechanisms of failure in the sudden infant death syndrome. Curr Pediatr Rev. 2010;6(1):39-47. https://doi​.org/10.2174​/157339610791317214. [PMC free article: PMC3392684] [PubMed: 22792083]

3.

Kinney HC, Cryan JB, Haynes RL, Paterson DS, Haas EA, Mena OJ, et al. Dentate gyrus abnormalities in sudden unexplained death in infants: Morphological marker of underlying brain vulnerability. Acta Neuropathol. 2015;129(1):65-80. https://doi​.org/10.1007​/s00401-014-1357-0. [PMC free article: PMC4282685] [PubMed: 25421424]

4.

Hefti MM, Kinney HC, Cryan JB, Haas EA, Chadwick AE, Crandall LA, et al. Sudden unexpected death in early childhood: General observations in a series of 151 cases: Part 1 of the investigations of the San Diego SUDC Research Project. Forensic Sci Med Pathol. 2016;12(1):4-13. https://doi​.org/10.1007​/s12024-015-9724-2. [PMC free article: PMC4752958] [PubMed: 26782961]

5.

Hefti MM, Cryan JB, Haas EA, Chadwick AE, Crandall LA, Trachtenberg FL, et al. Hippocampal malformation associated with sudden death in early childhood: A neuropathologic study: Part 2 of the investigations of The San Diego SUDC Research Project. Forensic Sci Med Pathol. 2016;12(1):14-25. https://doi​.org/10.1007​/s12024-015-9731-3. [PubMed: 26782962]

6.

Harper RM. State-related physiological changes and risk for the sudden infant death syndrome. Aust Paediatr J. 1986;22 Suppl 1:55-8. [PubMed: 3790006]

7.

Kinney HC, McDonald AG, Minter ME, Berry GT, Poduri A, Goldstein RD. Witnessed sleep-related seizure and sudden unexpected death in infancy: A case report. Forensic Sci Med Pathol. 2013;9(3):418-21. https://doi​.org/10.1007​/s12024-013-9448-0. [PMC free article: PMC3897270] [PubMed: 23852931]

8.

Hewertson J, Poets CF, Samuels MP, Boyd SG, Neville BG, Southall DP. Epileptic seizure-induced hypoxemia in infants with apparent life-threatening events. Pediatrics. 1994;94(2 Pt 1):148-56. [PubMed: 8036065]

9.

Edlow BL, McNab JA, Witzel T, Kinney HC. The structural Connectome of the human central homeostatic network. Brain Connect. 2016;6(3):187-200. https://doi​.org/10.1089/brain.2015.0378. [PMC free article: PMC4827322] [PubMed: 26530629]

10.

Barger N, Hanson KL, Teffer K, Schenker-Ahmed NM, Semendeferi K. Evidence for evolutionary specialization in human limbic structures. Front Hum Neurosci. 2014;8:277. https://doi​.org/10.3389/fnhum.2014.00277. [PMC free article: PMC4033018] [PubMed: 24904348]

11.

Kaas JH. The evolution of brains from early mammals to humans. Wiley Interdiscip Rev Cogn Sci. 2013;4(1):33-45. https://doi​.org/10.1002/wcs.1206. [PMC free article: PMC3606080] [PubMed: 23529256]

12.

Beissner F, Meissner K, Bar KJ, Napadow V. The autonomic braIn: An activation likelihood estimation meta-analysis for central processing of autonomic function. J Neurosci. 2013;33(25):10503-11. https://doi​.org/10.1523/JNEUROSCI​.1103-13.2013. [PMC free article: PMC3685840] [PubMed: 23785162]

13.

Benarroch EE. The central autonomic network: Functional organization, dysfunction, and perspective. Mayo Clin Proc. 1993;68(10):988-1001. https://doi​.org/10.1016​/S0025-6196(12)62272-1. [PubMed: 8412366]

14.

Saper CB. The central autonomic nervous system: Conscious visceral perception and autonomic pattern generation. Ann Rev Neurosci. 2002;25:433-69. https://doi​.org/10.1146/annurev​.neuro.25.032502.111311. [PubMed: 12052916]

15.

Mraovitch S, Calando Y. Interactions between limbic, thalamo-striatal-cortical, and central autonomic pathways during epileptic seizure progression. J Comp Neurol. 1999;411(1):145-61. https://doi​.org/10.1002​/(SICI)1096-9861(19990816)411​:1<145​::AID-CNE11>3.0.CO;2-1. [PubMed: 10404113]

16.

Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 2009;10(6):397-409. https://doi​.org/10.1038/nrn2647. [PMC free article: PMC4240627] [PubMed: 19469025]

17.

Nicolaides NC, Kyratzi E, Lamprokostopoulou A, Chrousos GP, Charmandari E. Stress, the stress system and the role of glucocorticoids. Neuroimmunomodulation. 2015;22(1-2):6-19. https://doi​.org/10.1159/000362736. [PubMed: 25227402]

18.

van Bodegom M, Homberg JR, Henckens M. Modulation of the hypothalamic-pituitary-adrenal axis by early life stress exposure. Front Cell Neurosci. 2017;11:87. https://doi​.org/10.3389/fncel.2017.00087. [PMC free article: PMC5395581] [PubMed: 28469557]

19.

Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol. 2016;6(2):603-21. https://doi​.org/10.1002/cphy.c150015. [PMC free article: PMC4867107] [PubMed: 27065163]

20.

McEwen BS, Gianaros PJ. Central role of the brain in stress and adaptation: Links to socioeconomic status, health, and disease. Ann NY Acad Sci. 2010;1186:190-222. https://doi​.org/10.1111/j​.1749-6632.2009.05331.x. [PMC free article: PMC2864527] [PubMed: 20201874]

21.

McEwen BS, Magarinos AM. Stress effects on morphology and function of the hippocampus. Ann NY Acad Sci. 1997;821:271-84. https://doi​.org/10.1111/j​.1749-6632.1997.tb48286.x. [PubMed: 9238211]

22.

Aimone JB, Li Y, Lee SW, Clemenson GD, Deng W, Gage FH. Regulation and function of adult neurogenesis: From genes to cognition. Physiol Rev. 2014;94(4):991-1026. https://doi​.org/10.1152/physrev​.00004.2014. [PMC free article: PMC4280160] [PubMed: 25287858]

23.

Parent JM, Kron MM. Neurogenesis and epilepsy. In: Jasper’s basic mechanisms of the epilepsies. Eds Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV. 4th ed. Bethesda (MD): Oxford University Press, 2012. https://doi​.org/10.1093​/med/9780199746545.003.0038. [PubMed: 22787592]

24.

Houser CR. Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy. Brain Res. 1990;535(2):195-204. https://doi​.org/10.1016​/0006-8993(90)91601-C. [PubMed: 1705855]

25.

Armstrong DD. Epilepsy-induced microarchitectural changes in the brain. Pediatr Dev Pathol. 2005;8(6):607-14. https://doi​.org/10.1007​/s10024-005-0054-3. [PubMed: 16333693]

26.

Armstrong DD. The neuropathology of temporal lobe epilepsy. J Neuropathol Exp Neurol. 1993;52(5):433-43. https://doi​.org/10.1097​/00005072-199309000-00001. [PubMed: 8360697]

27.

Blumcke I, Kistner I, Clusmann H, Schramm J, Becker AJ, Elger CE, et al. Towards a clinico-pathological classification of granule cell dispersion in human mesial temporal lobe epilepsies. Acta neuropathol. 2009;117(5):535-44. https://doi​.org/10.1007​/s00401-009-0512-5. [PubMed: 19277686]

28.

Rodriguez ML, McMillan K, Crandall LA, Minter ME, Grafe MR, Poduri A, et al. Hippocampal asymmetry and sudden unexpected death in infancy: A case report. Forensic Sci Med Pathol. 2012;8(4):441-6. https://doi​.org/10.1007​/s12024-012-9367-5. [PMC free article: PMC3897269] [PubMed: 22864821]

29.

Task Force on Sudden Infant Death Syndrome, & Moon RY. SIDS and other sleep-related infant deaths: Expansion of recommendations for a safe infant sleeping environment. Pediatrics. 2011;128(5):1030-9. https://doi​.org/10.1542/peds.2011-2284. [PubMed: 22007004]

30.

Kinney HC, Armstrong DL, Chadwick AE, Crandall LA, Hilbert C, Belliveau RA, et al. Sudden death in toddlers associated with developmental abnormalities of the hippocampus: A report of five cases. Pediatr Dev Pathol. 2007;10(3):208-23. https://doi​.org/10.2350/06-08-0144.1. [PubMed: 17535090]

31.

Kinney HC, Chadwick AE, Crandall LA, Grafe M, Armstrong DL, Kupsky WJ, et al. Sudden death, febrile seizures, and hippocampal and temporal lobe maldevelopment in toddlers: A new entity. Pediatr Dev Pathol. 2009;12(6):455-63. https://doi​.org/10.2350/08-09-0542.1. [PMC free article: PMC3286023] [PubMed: 19606910]

32.

Kinney HC, Poduri AH, Cryan JB, Haynes RL, Teot L, Sleeper LA, et al. Hippocampal formation maldevelopment and sudden unexpected death across the pediatric age spectrum. J Neuropathol Exp Neurol. 2016;75(10):981-97. https://doi​.org/10.1093/jnen/nlw075. [PMC free article: PMC6281079] [PubMed: 27612489]

33.

Hoppenbrouwers T. Sudden infant death syndrome, sleep, and seizures. J Child Neurol. 2015;30(7):904-11. https://doi​.org/10.1177/0883073814549243. [PubMed: 25300988]

34.

Filiano JJ, Kinney HC. A perspective on neuropathologic findings in victims of the sudden infant death syndrome: The triple-risk model. Biol Neonate. 1994;65(3-4):194-7. https://doi​.org/10.1159/000244052. [PubMed: 8038282]

35.

Moseley B, Bateman L, Millichap JJ, Wirrell E, Panayiotopoulos CP. Autonomic epileptic seizures, autonomic effects of seizures, and SUDEP. Epilepsy Behav. 2013;26(3):375-85. https://doi​.org/10.1016/j​.yebeh.2012.08.020. [PubMed: 23099286]

36.

Poets CF, Meny RG, Chobanian MR, Bonofiglo RE. Gasping and other cardiorespiratory patterns during sudden infant deaths. Pediatr Res. 1999;45(3):350-4. https://doi​.org/10.1203​/00006450-199903000-00010. [PubMed: 10088653]

37.

Miyagawa T, Sotero M, Avellino AM, Kuratani J, Saneto RP, Ellenbogen RG, et al. Apnea caused by mesial temporal lobe mass lesions in infants: Report of 3 cases. J Child Neurol. 2007;22(9):1079-83. https://doi​.org/10.1177/0883073807306245. [PubMed: 17890404]

38.

Noebels J. Hippocampal abnormalities and sudden childhood death. Forensic Sci Med Pathol. 2016;12(2):198-9. https://doi​.org/10.1007​/s12024-016-9768-y. [PMC free article: PMC5535270] [PubMed: 27094436]

39.

Grant SG, O’Dell TJ, Karl KA, Stein PL, Soriano P, Kandel ER. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science. 1992;258(5090):1903-10. https://doi​.org/10.1126/science.1361685. [PubMed: 1361685]

40.

Kojima N, Ishibashi H, Obata K, Kandel ER. Higher seizure susceptibility and enhanced tyrosine phosphorylation of N-methyl-D-aspartate receptor subunit 2B in fyn transgenic mice. Learn Mem. 1998;5(6):429-45. [PMC free article: PMC311255] [PubMed: 10489260]

41.

Insausti R, Cebada-Sanchez S, Marcos P. Postnatal development of the human hippocampal formation. BerlIn: Springer, 2010. https://doi​.org/10.1007​/978-3-642-03661-3.

42.

Iyasu S, Randall LL, Welty TK, Hsia J, Kinney HC, Mandell F, et al. Risk factors for sudden infant death syndrome among northern plains Indians. JAMA. 2002;288(21):2717-23. https://doi​.org/10.1001/jama.288.21.2717. [PubMed: 12460095]

43.

Mitchell EA, Milerad J. Smoking and the sudden infant death syndrome. Rev Environ Health. 2006;21(2):81-103. https://doi​.org/10.1515/REVEH​.2006.21.2.81. [PubMed: 16898673]

44.

Pun RY, Rolle IJ, Lasarge CL, Hosford BE, Rosen JM, Uhl JD, et al. Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy. Neuron. 2012;75(6):1022-34. https://doi​.org/10.1016/j​.neuron.2012.08.002. [PMC free article: PMC3474536] [PubMed: 22998871]

45.

Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci. 1997;17(10):3727-38. [PMC free article: PMC6573703] [PubMed: 9133393]

46.

Parent JM. Adult neurogenesis in the intact and epileptic dentate gyrus. Prog Brain Res. 2007;163:529-40. https://doi​.org/10.1016​/S0079-6123(07)63028-3. [PubMed: 17765736]

47.

Panigrahy A, Filiano J, Sleeper LA, Mandell F, Valdes-Dapena M, Krous HF, et al. Decreased serotonergic receptor binding in rhombic lip-derived regions of the medulla oblongata in the sudden infant death syndrome. J Neuropathol Exp Neurol. 2000;59(5):377-84. https://doi​.org/10.1093/jnen/59.5.377. [PubMed: 10888367]

48.

Paterson DS, Trachtenberg FL, Thompson EG, Belliveau RA, Beggs AH, Darnall R, et al. Multiple serotonergic brainstem abnormalities in sudden infant death syndrome. JAMA. 2006;296(17):2124-32. https://doi​.org/10.1001/jama.296.17.2124. [PubMed: 17077377]

49.

Duncan JR, Paterson DS, Hoffman JM, Mokler DJ, Borenstein NS, Belliveau RA, et al. Brainstem serotonergic deficiency in sudden infant death syndrome. JAMA. 2010;303(5):430-7. https://doi​.org/10.1001/jama.2010.45. [PMC free article: PMC3242415] [PubMed: 20124538]

50.

Kinney HC, Randall LL, Sleeper LA, Willinger M, Belliveau RA, Zec N, et al. Serotonergic brainstem abnormalities in Northern Plains Indians with the sudden infant death syndrome. J Neuropathol Exp Neurol. 2003;62(11):1178-91. https://doi​.org/10.1093/jnen/62.11.1178. [PubMed: 14656075]

51.

Zhan Q, Buchanan GF, Motelow JE, Andrews J, Vitkovskiy P, Chen WC, et al. Impaired serotonergic brainstem function during and after seizures. J Neurosci. 2016;36(9):2711-22. https://doi​.org/10.1523/JNEUROSCI​.4331-15.2016. [PMC free article: PMC4879214] [PubMed: 26937010]

52.

Azmitia EC, Gannon PJ. The primate serotonergic system: A review of human and animal studies and a report on Macaca fascicularis. Adv Neurol. 1986;43:407-68. [PubMed: 2418648]

53.

Janusonis S, Gluncic V, Rakic P. Early serotonergic projections to Cajal-Retzius cells: Relevance for cortical development. J Neurosci. 2004;24(7):1652-9. https://doi​.org/10.1523/JNEUROSCI​.4651-03.2004. [PMC free article: PMC6730467] [PubMed: 14973240]

54.

Djavadian RL. Serotonin and neurogenesis in the hippocampal dentate gyrus of adult mammals. Acta Neurobiol Exp. 2004;64(2):189-200. [PubMed: 15366252]

55.

Savic I, Lindstrom P, Gulyas B, Halldin C, Andree B, Farde L. Limbic reductions of 5-HT1A receptor binding in human temporal lobe epilepsy. Neurology. 2004;62(8):1343-51. https://doi​.org/10.1212/01​.WNL.0000123696.98166.AF. [PubMed: 15111672]