Regular articleSelective frontal, parietal, and temporal networks in generalized seizures
Introduction
Generalized tonic–clonic seizures are among the most dramatic events that occur in the nervous system. Massive firing of neurons leads to generalized muscle contractions, autonomic and neuroendocrine outpourings, and loss of consciousness. Generalized seizures are usually classified as either secondarily generalized with local onset or primarily generalized with no clear focal onset. Regardless of onset, both types of generalized tonic–clonic seizures ultimately manifest as widespread, apparently global convulsive activity. Previous electrophysiological, blood flow, and metabolic mapping studies have suggested that virtually all neurons in the brain are involved in generalized tonic–clonic seizures Andre et al 2002, Engel et al 1978, Engel et al 1982, Handforth and Treiman 1995, Matsumoto and Marsan 1964, McCown et al 1995. However, some animal studies have shown more regional changes during generalized seizures Ackermann et al 1986, McIntyre et al 1991. Specific regions, such as the anterior piriform cortex, inferior colliculus, or substantia nigra Faingold 1999, Gale 1992, may be crucial for the initiation and propagation of generalized seizures. Moreover, following spontaneous secondarily generalized tonic–clonic seizures in patients with epilepsy, focal deficits are often present, reflecting impaired function in the regions of seizure onset (Rolak et al., 1992). Are “generalized” seizures truly generalized? Are all regions of the brain homogenously involved, or are specific networks affected most intensely, and what are the functional consequences?
Cerebral blood flow (CBF) imaging provides a powerful noninvasive measure of neural activity throughout the brain. Single photon emission computed tomography (SPECT) imaging is particularly well suited to measuring CBF during seizures Avery et al 1999, Devous et al 1990. This is because the Tc99m-linked SPECT agent is rapidly taken up by the brain after injection, and once taken up, the agent does not redistribute Andersen 1989, Devous et al 1990. This allows imaging to be done later, reflecting CBF at the time of injection. Thus, the SPECT injection is done during the seizure, but the actual imaging is done 60 to 90 min after the seizure has ended, eliminating potentially serious problems with movement artifact and the patient’s clinical stability. Recent advances in image analysis including comparison of ictal SPECT images (injected during seizures) to interictal SPECT images, and coregistration with MRI scans, have enabled precise anatomical localization of cortical and subcortical CBF changes during seizures Avery et al 1999, Chang et al 2002, Zubal et al 1995. Nevertheless, extensive analysis of CBF changes during generalized tonic–clonic seizures has so far been limited because of the unpredictable timing, variable duration, and variable seizure types seen with spontaneous seizures in epilepsy patients. These investigations would be greatly facilitated if a group of patients with homogeneous seizure type and predictable seizure timing could be studied.
Just such a population exists in patients undergoing electroconvulsive therapy (ECT) for treatment of depression. Previously misused, ECT has been modified in recent decades to become a safe treatment and is the most effective therapy available for refractory depression (American Psychiatric Association, 2001). In this treatment modality, a generalized tonic–clonic seizure is induced in a controlled setting, under general anesthesia and neuromuscular blockade (American Psychiatric Association, 2001). Bilateral frontotemporal ECT stimulation (Fig. 1A) induces a typical generalized tonic–clonic seizure, resembling generalized seizures in patients with epilepsy in both clinical and EEG manifestations (American Psychiatric Association, 2001). Seizures induced by right unilateral ECT (Fig. 1B) resemble spontaneous partial seizures with secondarily generalization Kriss et al 1978a, Kriss et al 1978b.
We used SPECT imaging of ECT-induced seizures to investigate whether specific cortical–subcortical networks are preferentially involved during generalized tonic–clonic seizures in homogeneous groups of patients. In addition, we studied the functional implications of focal network involvement by performing neuropsychology testing before and after ECT-induced seizures. Finally, to determine whether similar focal networks are involved in spontaneous seizures, we analyzed images from spontaneous secondarily generalized seizures in patients with epilepsy.
Section snippets
SPECT imaging and analysis
For ictal SPECT injections during ECT-induced seizures a technician performed an intravenous injection of 30 mCi Tc-99m labeled hexamethylpropylene amine oxime (HMPAO) (Ceretec kit supplied by Medi-Physics, Amersham Healthcare, Arlington Heights, IL, USA) within 30 s of the ECT-induced seizure onset (Fig. 2a). Uptake of the SPECT agent is nearly 100% complete within 30–60 s, reflecting CBF at the time of injection Andersen 1989, Devous et al 1990. These ictal injections were compared to
Focal CBF changes in ECT-induced seizures
Both bilateral and right unilateral ECT (Fig. 1A and B) induce generalized tonic–clonic seizures. To investigate which brain regions are involved during these generalized seizures we mapped CBF changes using Tc-99m SPECT imaging Avery et al 1999, Chang et al 2002, Zubal et al 1995. We found that focal brain regions show maximal relative CBF increases during both bilateral and right unilateral ECT-induced seizures despite the fact that generalized seizures were induced in all cases. Fig. 1 shows
Discussion
Generalized tonic–clonic seizures are often thought of as maximal events in which there is paroxysmal and ubiquitous activation of the entire nervous system. We report here instead that human generalized tonic–clonic seizures are not truly generalized, but instead involve specific regions of the brain while sparing others. By imaging CBF during ECT-induced seizures we found selective involvement of the prefrontal, parietal, and temporal association cortex. The regions showing maximal relative
Conclusion
Generalized seizures remain a major cause of disability and impaired quality of life. The identification of the specific networks involved may allow the development of specific therapies, including targeted neurostimulation, surgical disconnection procedures, or selective pharmacological interventions to improve treatment for generalized seizures. Our findings demonstrate that generalized tonic–clonic seizures are not homogeneous all-or-none events. The behavioral manifestations of tonic–clonic
Acknowledgements
We thank J.C. Brumberg, A. Luthi, K.A. McNally, and R.T. Constable for helpful comments. We also thank G. Morano and M. Corsi for nuclear medicine and neuroimaging technical assistance. This work was supported by a Dana Foundation Clinical Hypotheses in Neuroscience award.
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