The limbic system

The term 'limbic system' was coined by Maclean (1952) to designate a series of structures originally delineated by Broca (1878) and Papez (1937), plus the amygdala and its connections, which were believed to play a crucial role in mediating the exchange of information between the thinking brain (cortex) and the more primal animal brain (diencephalon and brain stem). Broca first described the limbic lobe as the area of brain making up the rim of the cortex, including the hippocampus, cingulate cortex and certain frontal lobe structures. Papez more precisely defined circuits that connected these structures, including the septal area, mamillary bodies, and parts of the thalamus and hypothalamus. The addition of the amygdala and its connections by Maclean provided the functional substrate for human emotional behaviours now attributed to the limbic system (Figure 3.1). The hippocampus, amygdala and their projection fields are central to the concept of the limbic system, and also are the most epileptogenic regions of the mammalian brain. The perirhinal and piriform regions of the parahippo-campal cortex, along with the central nucleus of the amygdala, are the most rapidly kindled structures in the brain (Mclntyre and Plant, 1993), and an area of deep piriform complex, area tempesta, has the lowest threshold in the brain to seizures induced by local application of antagonists to gamma amino butyric acid (GABA), the primary inhibitory neurotransmitter in the brain (Piredda and Gale, 1985). The limbic system, therefore, is uniquely susceptible to the development of epileptiform abnormalities, not only as a result of hippocampal sclerosis, but due to any irritating disturbance. Furthermore, distant epileptogenic lesions which preferentially project to mesial temporal structures also have a high propensity to induce mesial temporal epileptiform activity resulting in both temporal lobe seizures and their behavioural consequences (Williamson and Engel, 1997).

Entorhinal Cortex Schematic

Second generalization

Figure 3.1. Diagrammatic representation of the human limbic system and its afferent and efferent connections. Note the major connections between the hippocampus, entorhinal cortex and amygdala (NA), and the components of the Papez circuit, described in the text. SMA, supplementary motor area; HIPP, hippocampus; ENTO, entorhinal cortex; PARAHIPP, parahippocampal gyrus; CC, corpus callosum; VHC, ventral hippocampal commissure; DHC, dorsal hippocampal commissure; AC, anterior commissure. (With permission, adapted from Wieser, 1988.)

Second generalization

Figure 3.1. Diagrammatic representation of the human limbic system and its afferent and efferent connections. Note the major connections between the hippocampus, entorhinal cortex and amygdala (NA), and the components of the Papez circuit, described in the text. SMA, supplementary motor area; HIPP, hippocampus; ENTO, entorhinal cortex; PARAHIPP, parahippocampal gyrus; CC, corpus callosum; VHC, ventral hippocampal commissure; DHC, dorsal hippocampal commissure; AC, anterior commissure. (With permission, adapted from Wieser, 1988.)

Ventral Hippocampus

Figure 3.2. Illustration of the intrinsic circuitry of the hippocampal formation. The primary focus of this illustration is the trisynaptic circuit. The first synapse consists of the mossy fibre to CA3 pyramidal cell connection derived from the granule cells of the dentate gyrus. The second synapse is the connection of the CA3 cell output via the Schaffer collaterals to CA1, and the third, not shown, is the CA1 axonal output to subiculum and entorhinal cortex. Entorhinal cortex also provides the initial input to the dentate gyrus. (With permission from O'Keefe and Nadel, 1978.)

Figure 3.2. Illustration of the intrinsic circuitry of the hippocampal formation. The primary focus of this illustration is the trisynaptic circuit. The first synapse consists of the mossy fibre to CA3 pyramidal cell connection derived from the granule cells of the dentate gyrus. The second synapse is the connection of the CA3 cell output via the Schaffer collaterals to CA1, and the third, not shown, is the CA1 axonal output to subiculum and entorhinal cortex. Entorhinal cortex also provides the initial input to the dentate gyrus. (With permission from O'Keefe and Nadel, 1978.)

Hippocampus Normal structure

The hippocampus is perhaps the most studied region of the mammalian brain, due in part to its highly organized laminar structure, and its propensity for plastic change, such as long-term potentiation and long-term depression, which may underlie mechanisms of normal learning and memory (Gloor, 1997; Schwartzkroin and McIntyre, 1997). The hippocampal formation consists of the dentate gyrus and the hippocampus proper or cornu ammonis (CA), which is divided into CA1, CA2 and CA3 (Figure 3.2). The major excitatory hippocampal input is glutaminergic from the entorhinal cortex via the perforant path, which terminates on the distal two-thirds of granule cell dendrites in the dentate gyrus. The medial portion of the entorhinal cortex projects predominantly to the middle third of the granule cell dendritic layer (middle molecular layer), while the lateral ento-rhinal cortex projections, which also contain opioids, terminate on the distal third of granule cell dendrites (outer molecular layer). These latter projections may play a role in epileptogenicity due to the opioid disinhibitory effect on granule cell excitability (Xie et al., 1992). The neuronal structure of the dentate gyrus provides the substrates for strong feed-forward and feedback inhibition which resists the propagation of epileptiform activity, leading to its designation as the 'dentate gate' (Lothman et al., 1991).

The classical excitatory trisynaptic pathway through the hippocampus is glutam-atergic and utilizes NMDA and non-NMDA receptors, while inhibitory interneu-rons are GABAergic. The pathway begins with the dentate granule cell axons, called mossy fibres, which project through the dentate hilus to area CA3. Mossy fibres contain two types of terminals: the first type are the large, complex mossy terminals which give the fibres their name, and the second type are small terminals and filo-podia extending from the mossy terminals. The primary target of the mossy terminals are the CA3 pyramidal cells, with which they form multiple excitatory synapses, while the primary target of the small terminals and filopodia are GABAergic inter-neurons. The ratio of dentate granule axon terminals contacting GABAergic inter-neurons to those terminals contacting pyramidal and mossy cells (excitatory neurons in the dentate hilus) has been estimated at approximately 5:1, which means that the major postsynaptic targets of granule cells are inhibitory neurons (Acsady et al., 1998). Although the large proportion of granule cell output which activates interneurons has a significant inhibitory effect, the mossy terminals exciting CA3 pyramidal cells are quite powerful. Because CA3 pyramidal cell intrinsic connections support recurrent excitation, focused discharge of specific CA3 pyramidal cells can occur. Excitation is further supported by granule cell activation of mossy cells in the dentate hilus, which in turn project back onto the proximal one-third of the granule cell dendrites (inner molecular layer). This excitatory feedback loop is offset by similar inhibitory feedback loops via a variety of hilar inhibitory neurons. CA3 pyramidal cells have a unique propensity to burst synchronously, thus excitatory epileptiform input that traverses the dentate gate activates synchronously bursting pacemaker cells in CA3, giving rise to interictal spikes (Wong and Traub, 1983).

The second segment of the hippocampal trisynaptic pathway consists of the Schaffer collaterals, CA3 pyramidal cell axons which terminate on CA1 pyramidal neurons. Under epileptogenic conditions, synchronous bursting in CA3 can produce continuous discharges in CA1, the usual site of ictal onset in the hippo-campal slice preparation. CA2 is a transition zone that does not appear to participate in the transmission of epileptiform discharges in the nonsclerotic hippocampus. However, pyramidal cells in this region are relatively spared in the process of neuronal loss that characterizes hippocampal sclerosis (Mathern et al.,

1997), and these remaining neurons may play a more important role in mesial temporal lobe epilepsy (Williamson and Spencer, 1994).

The third segment of the hippocampal trisynaptic pathway is its primary output, from CA1 to the adjacent subiculum. The subiculum in turn projects back to the entorhinal cortex, completing a closed hippocampal excitatory loop. This pathway is not absolutely unidirectional, however; there are also significant connections from entorhinal cortex to CA1, and some fibres even reach CA3. The subiculum predominantly projects to perirhinal and piriform cortex, but also to the mamil-lary bodies. The perirhinal cortex has connections with frontal motor cortical areas, whereas the piriform cortex projects reciprocally to olfactory areas and the brain stem. These projections are predominantly responsible for mediating the clinical manifestations of temporal lobe seizures; ictal discharges confined to the hippocampus may have no overt signs and symptoms (Sperling and O'Connor, 1990). Parahippocampal areas may also become an important site of seizure generation; success in eliminating seizures by amygdalohippocampectomy, performed to treat medically intractable temporal lobe epilepsy, appears to depend upon the amount of parahippocampal tissue removed (Siegel et al., 1990).

CA1 axons also project via the fimbria and fornix along the traditional Papez circuit to the septal area, midline thalamus, amygdala, hypothalamus and brain stem autonomic centres. The amygdala, hypothalamic and brain stem projections mediate aspects of emotional behaviours, and the hippocampus may play a role in the adreno-hypothalamic-pituitary axis, in view of the fact that adrenal steroid receptors are abundant in the hippocampus (Gould et al., 1991).

The hippocampus also receives direct cholinergic and GABAergic input from the septal area, which mediates the classical hippocampal theta rhythm, and these projections may have disinhibitory as well as inhibitory influences on epileptic activity. With respect to brain stem afferents, direct noradrenergic input to the hippocampus from the locus coeruleus can be excitatory (Madison and Nicoll, 1986), while serotonergic input from the raphe nucleus and dopaminergic input from the substantia nigra and ventral tegmental area are predominantly inhibitory (Andrade and Nicoll, 1987), but biogenic amine effects can be varied, depending on the postsynaptic target. Indirect afferent influences on the hippocampus, via entorhinal cortex, derive from a large area of neocortex, including frontal limbic regions responsible for goal-directed behaviour, cingulate cortex influencing memory, all sensory cortical areas for integration of polymodal sensory information, and perirhinal and piriform cortex, as well as from amygdala.

Hippocampal sclerosis

Much is known about the structural and functional abnormalities that exist in the epileptic hippocampus, due in part to the ready availability of human tissue from epilepsy surgery programmes, and in part to numerous animal models of this condition; however, the cause of these abnormalities, and the reasons why these abnormalities should result in spontaneous seizures, are not well understood. The characteristic finding in hippocampal sclerosis is cell loss, most prominent in the dentate hilus and CA1, but it is also marked in CA3 and, to a lesser extent, the dentate gyrus and subiculum (Mathern et al., 1997). Although specific hilar inter-neurons are lost, namely those containing somatostatin and neuropeptide Y, in general there is relative preservation of hippocampal inhibitory interneurons, compared to principal cells (Babb, 1992). The greatest proportion of hilar cell loss is from mossy cell death, which results in loss of excitatory inputs to dentate granule cell proximal dendrites, and consequent mossy fibre sprouting. These collateral granule cell axons, which can easily be seen with Timm's stain, reinnervate the inner molecular layer, but most likely end on inhibitory interneurons, as well as on granule cell dendrites (Figure 3.3). There is also evidence of inhibitory interneuron sprouting (Babb, 1992). Electrophysiological studies in patients have confirmed that inhibition is actually increased, interictally, in the epileptiform sclerotic hippocampus (Wilson et al., 1998). This enhanced inhibition may act to suppress seizure generation; however, it has been postulated that such enhanced inhibition together with enhanced excitation, brought about by pathological neuronal reorganization, results in a predisposition to abnormal neuronal hypersynchronization (Figure 3.4). In addition, single input fibres sprout to innervate wider targets, and reduction of the dendritic domain places more excitatory input closer to the soma and axon hillock. Hypersynchronization underlies interictal epileptiform EEG spikes, but is also the hallmark of the typically hypersynchronous hippocampal ictal EEG onset (Velasco et al., 2000). Consequently, enhanced inhibition in the sclerotic hippocampus may contribute to its epileptogenicity (Engel et al., 1997). During the process of epileptogenesis, once the local anatomical substrate for abnormal hyper-synchrony has been established, these hypersynchronous discharges may act to kindle distant structures responsible for the manifestation of ictal behaviour.

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