For the first time, the fifth edition of Jasper’s Basic Mechanisms of Epilepsy includes a section on epilepsy comorbidities. This is a milestone addition, acknowledging the rapid growth in preclinical studies exploring basic mechanisms of neurological and neurobehavioral comorbidities commonly found in individuals with seizures. Together, the major comorbidities, depression, anxiety, migraine, attention deficit, cognitive disorders, autism, and sudden death, afflict subgroups of individuals over a wide age range and to a variable degree, yet detract immensely from quality of life and pose major challenges to medical management (Kanner, 2016). They are not yet incorporated into the International League Against Epilepsy (ILAE) syndromic classification of epilepsies (Scheffer et al., 2017), possibly because some of them can be treatment induced. Since seizures can begin at any age and require lifelong treatment, the challenge of isolating the natural history of the primary disease from comorbid elements can benefit from experimental models.

Definitions vary; however, comorbidity is simply the coexpression of two deleterious phenotypes, without regard to their impact upon each other. Exploring the relationship between the two is often challenging, for two main reasons. If one is a rare finding in individuals with seizures, it may be biologically unrelated and due to chance coincidence. However, when found repeatedly, the origins must be coupled in some way, whether genetically, functionally, or environmentally. This could be due to mutation of a single gene with multiple pleiotropic phenotypes, as seen in autism and Alzheimer disease (Noebels, 2015), or of several contiguous genes. Alternatively, it could be due to other defects acquired during the lifetime, or a combination of the two.

Temporal precedence can also be misleading, since the comorbidities are not always simultaneously recognized. While there is little doubt that early-onset seizures can elicit or aggravate many developmental issues, some individuals with apparently identical seizure disorders do not share the same comorbidities; in some mouse models, seizures may appear with a later onset than the comorbid phenotypes (Massey, 2021).

The goal of basic science in this area is to functionally dissect the nervous system pathways involved and to unravel the overlapping mechanisms linking them to epileptic activity to identify new treatment approaches. Chief among these are cognitive deficits, many of which can be ascribed to seizure history and medications, but which may arise from deeper roots, as evidenced by the ever-expanding list of genes for developmental epileptic encephalopathies. In Chapter 57, Lenck-Santini and Holmes outline the approach, from single-unit firing and network oscillations, to behavioral readouts and neurotransmitter systems involved in genetic and drug-induced animal models, with strategies for future interventions. In Chapter 58, Maheshwari reviews the genetic linkage between single genes for generalized thalamocortical spike-wave absence epilepsy and attention-deficit disorder with hyperactivity, the most frequent neurological comorbidity of childhood absence epilepsy. He describes an experimental approach to mapping these overlapping pathways in mice and the search for improved pharmacological management.

Autism has long been recognized as an antecedent of seizures in children. In Chapter 59, Golshani explores severe single gene mouse models of epilepsy for their contribution to understanding shared mechanisms of social behavioral deficits. In the future, genetically engineered intersectional strategies to alter selective neural pathways in mouse models will hopefully provide meaningful insights into this complicated relationship.

Depression is the oldest and best-known comorbidity in epilepsy, which itself was for centuries considered a psychiatric illness. Both share overlapping involvement of neurotransmitter systems, and the fact that electroconvulsive therapy remains a viable treatment for the most refractory cases of depression illustrates our profound ignorance of the underlying mechanisms.

Isolating and manipulating comorbid neurobehavioral phenotypes remains a major impediment to future breakthroughs in this area, since they depend on the extreme variability in the sensitivity of the assay procedures to robustly detect, categorize, and interpret abnormal behavior in mice. In Chapter 60, Gschwind and Soltesz contribute an important review of how behavioral analysis in mouse epilepsy models can be accelerated using artificial intelligence–based deep-learning algorithms to define novel phenotypes of both the seizure disorder and its treatment, and automate their detection. This additional analytical rigor, which comes at a high computational price, nevertheless promises to revolutionize future studies in this area of translational research. In Chapter 61, Jones and Maguire describe the known mechanisms and treatments of depression across several axes of underlying molecular biological dysfunction and shared stressors to lay the groundwork for experimental exploration of these mechanisms in models of epilepsy.

The phenomenon of cortical spreading depolarization (SD) arises in an anatomical and genetic borderland with epilepsy. While neuronal behavior during a slowly propagating wave of spreading depression involves a transient period of silence rather than the near instantaneous synaptic spread of hyperexcitable bursting behavior during a cortical seizure, the two events are intimately related. The genes known to cause hemiplegic migraine aura by lowering the threshold for this self-regenerative depolarizing wave are also implicated in epilepsy phenotypes (Aiba and Noebels, 2015). In Chapter 62, Aiba thoroughly reviews the many decades of SD research and describes a new field of the neurogenetics of SD as told by monogenic mouse epilepsy models. In Chapter 63, Noebels describes the first decade of interest focusing on mechanisms underlying sudden unexpected death in epilepsy (SUDEP). This time frame combines the lessons acquired from human and animal models, both based on the seminal Mortemus study that captured the final moments of life following a generalized tonic-clonic seizure during presurgical clinical video-EEG monitoring. While rare in the epilepsy population, SUDEP is the most common cause of premature mortality in epilepsy and shows elevated risk in selected genetic populations. Accordingly, careful analysis of the final preterminal moments in several mouse SUDEP models has identified distinct gene-linked mechanisms for cardiorespiratory failure, including spreading depolarization, that may ultimately lead to enhanced risk detection and hopefully specific interventions for this tragic outcome of epilepsy.