Functional anatomy of limbic epilepsy: a proposal for central synchronization of a diffusely hyperexcitable network
Introduction
Functional anatomy in neurological processes is a complex concept that refers to all of the areas in the brain that support a particular activity. The functional anatomy may include the local and regional neuronal circuits that initiate, modulate, synchronize and propagate a specific activity (e.g. movement). In sequential processes (such as movement) each of these steps (initiation, modulation, etc.) is associated with a distinct region that contributes primarily to one aspect of net function. In a pathological condition such as epilepsy, there are similar stages through which seizures evolve, such as initiation, synchronization and propagation, and each stage may be associated with (supported by) activity in a particular brain region. Understanding the functional anatomy of seizure initiation and synchronization is important because it will allow us to focus on the areas that are involved in this critical transition from interictal to ictal states. The determination of such substrates for primarily generalized seizures—involving reverberatory circuitry between the cortex and the thalamus—laid a basis for the discovery of the altered calcium currents that are the presumed molecular basis for the condition (Avoli and Gloor, 1982, Avanzini et al., 1993, Snead, 1995).
Mesial temporal lobe epilepsy (MTLE) is a common epilepsy syndrome that is frequently intractable to medical intervention. Because of the distinct pathology of hippocampal sclerosis, much attention has been focused on this structure and the anatomical and physiological changes in it that are associated with the epileptic condition. However, the true functional anatomy of seizure initiation in this condition is unknown, and information from the surgical literature suggests that the essential substrate may involve additional areas in the mesial temporal lobe (So, 1991, Goldring et al., 1992, Spencer and Spencer, 1994). Defining the functional anatomy is complicated by the multifocal pathology that has often been described in the pathological studies of this syndrome (Margerison and Corsellis, 1966, Bruton, 1988, Du et al., 1993, Hudson et al., 1993), the physiology studies showing multifocal or synchronized regional seizure onset (So, 1991, Spencer and Spencer, 1994), and the functional imaging studies (PET scans) that have shown broad regional hypometabolism in the mesial temporal structures ipsilateral to the site of presumed seizure onset (Henry et al., 1990, Sperling et al., 1990, Ryvlin et al., 1991). The observation of regional onset, involving multiple limbic sites (e.g. amygdala, hippocampus and entorhinal cortex) essentially simultaneously raises the issue of how these structures can be synchronized over such a relatively large area. In previous work (Lothman et al., 1991), we had suggested several possibilities for the functional anatomy of seizures in the limbic system. In these scenarios it was hypothesized either that the seizures arose within the reverberatory connections of the hippocampal-parahippocampal loop, or that the hippocampus acted as an amplifier that was switched into seizure activity through the synaptic connections from another structure. The seizure activity subsequently spread from the hippocampus to other limbic sites through its connections to the entorhinal cortex and beyond. This hypothesis was based on and supported by valuable work that demonstrated the nature of the anatomic connections within the loop (Van Groen and Wyss, 1990, White and Price, 1993) and the significant changes that occur in physiology of the hippocampus and entorhinal cortex during acute seizures (Collins et al., 1983, Jones and Heinemann, 1988, Jones, 1989, Witter et al., 1989, Pare et al., 1992, Rafiq et al., 1993, Jones, 1994) and in the epileptic condition (Masukawa et al., 1992, Uruno et al., 1994, Lothman et al., 1995, Mangan et al., 1995, Rempe et al., 1995, Bear et al., 1996, Wuarin and Dudek, 1996).
Recent observations in humans with MTLE and in the animal models for this condition (So, 1991, Spencer and Spencer, 1994, Bertram, 1997) suggest multifocal seizure onset (i.e. seizures that begin focally within different limbic structures with each seizure) as well as synchronized regional seizure onset (i.e. presumed simultaneous seizure initiation). These observations, together with multifocal physiological and anatomical changes in the animal models (Ben-Ari et al., 1980, Cavalheiro et al., 1991, Bertram et al., 1990, Bertram and Lothman, 1993, Du et al., 1993, Bertram and Cornett, 1994, Wuarin and Dudek, 1996, Smith and Dudek, 1997), have raised the possibility of a widely distributed neural network that supports limbic seizures. These findings could lead to several possible hypotheses regarding seizure initiation. For example, seizures may begin at a here-to-fore unrecognized site that has broad excitatory projections to other areas, and the seizure activity spreads to these other regions essentially at the same time. In another scenario, the seizures truly begin over a broad area simultaneously. In the latter instance, it is possible that a subcortical input with broad connections to all the areas would play the role of synchronizer. The midline thalamic nuclei are good candidates to serve in this role. In a number of studies using different models for limbic status epilepticus, a consistent finding with 2-deoxyglucose mapping of metabolic activity has been clear involvement of the midline thalamic nuclei (Lothman and Collins, 1981, Clifford et al., 1987, VanLandingham and Lothman, 1991, Handforth and Treiman, 1995). In addition several investigators have been able to alter the course of limbic status epilepticus or limbic kindling by pharmacologic manipulation of various midline nuclei (Patel et al., 1988, Miller et al., 1989, Miller and Ferrendelli, 1990, Hirayasu and Wada, 1992). There have been several reports describing a significant excitatory influence of the midline thalamic nuclei on the CA1 region of the hippocampus (Dolleman-Van Der Weel et al., 1997, Bertram and Zhang, 1998), and there are well described reciprocal connections between the midline thalamic nuclei and a number of limbic sites that are known to be involved in the limbic epilepsy syndrome (Herkenham, 1978, Aggleton and Mishkin, 1984, Insausti et al., 1987, Russchen et al., 1987, Su and Bentivoglio, 1990, Wouterlood et al., 1990, Turner and Herkenham, 1991, Kuroda et al., 1992, Sadikot et al., 1992, Dolleman-Van Der Weel and Witter, 1996). For these reasons, the potential for strong physiological interactions between these areas exists, and these regions may form a critical substrate for the initiation or synchronization of seizure activity.
The purpose of this initial study was to examine the potential hyperresponsive changes in areas of the limbic system (amygdala and piriform cortex) in an animal model of MTLE (Bertram and Cornett, 1994) and to explore the potential role of the midline thalamic nuclei in seizure activity and the epileptiform hyperexcitability in the limbic structures. Finding widely distributed alterations of physiology in the limbic system, together with an enhanced excitatory effect of thalamic stimulation on limbic targets, would support the hypothesis that the functional anatomy of limbic epilepsy includes the midline thalamus.
Section snippets
Materials and methods
The procedures for the preparation of animals, the induction of status epilepticus and the documentation of chronic spontaneous limbic seizures have been well described in previous reports (Lothman et al., 1989, Bertram and Cornett, 1994). Briefly, young adult male Sprague-Dawley rats (250–325 g) received bipolar twisted pair insulated electrodes that were placed stereotactically in the mid to ventral hippocampus (−5.3 mm, AP; ±4.9 mm ML; −5.0 mm DTP) (Paxinos, 1986) for stimulation and
Results
In discussing the following experiments, our use of the terms `simultaneous' and `synchronous' is meant to imply that the temporal relationships among events in different regions are sufficiently close (within a few milliseconds) to indicate that these events are likely not occurring in a chain reaction, but rather are driven from a single site. For recurring events that depend on intact circuits, the terms are meant to convey the sense of coordinated activity (as in the rhythmic spike and wave
Discussion
There were several findings in this preliminary examination that may provide some insight into the possible functional anatomy of limbic seizures. First, at least during status epilepticus, there was good synchronization of the seizure activity among multiple sites, including the hippocampus and thalamus. Second, hyperexcitability (epileptiform responses to local stimulation) was seen in all four of the limbic structures tested in vitro from epileptic animals. Third, the stimulation of the
Acknowledgements
This grant was supported in part by NIH NINDS grants NS-23650. We thank John Williamson and Sherry Spradlin for technical assistance and Rose Powell for manuscript oversight.
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