Cortical Wildfires
Ancient Mesopotamian archives are a treasure trove of humanity’s earliest and most iconic written documents. These texts cover a wide range of topics, including literature, mythology, history, law, and medicine. A 4,000-year-old Akkadian record describes the symptoms of a patient suffering from an intriguing ailment: “his neck turns left, his hands and feet are tense and his eyes wide open, and from his mouth froth is flowing without having any consciousness.” Identified with the “hand of Sin,” the Mesopotamian moon god, this condition was believed to have afflicted even the demigod Herakles, which is why it was also known as the Herculean disease. Before the 5th century BC, ancient Greeks attributed it to the moon goddess Selene (or Mene). However, Hippocrates of Kos was the first to refute its celestial source, ascribing it instead to the brain’s inner workings. Yet, the belief in its lunar association prevailed well into the 19th century. Fyodor Mikhailovich Dostoevsky, the Russian wordsmith who suffered from debilitating bouts of the disease, related the advice of his physician in a letter to his older brother: “In general, he advised me to beware of the new moon.” Even the verb “moonstruck,” indicating an inability to think clearly, derives from the alleged power of the moon over the mind. Moritz Heinrich Romberg, the German neurologist who may have briefly counseled Dostoevsky on his disorder, wrote in 1853: “The planetary influence of the moon (especially of the new and full moon) upon the course of epilepsy, was known to the ancients, and although here and there doubts have been raised against this view, the accurate observations of others have established its correctness…”
Epilepsy is a catch-all term for non-communicable neurological disorders characterized by recurrent episodes of excessive electrical activity in a group of neurons that may spread to other parts of the brain. These cortical wildfires, known as seizures, vary in intensity and duration, affecting approximately 50 million people globally and making epilepsy one of the most prevalent neurological conditions worldwide. Before the early 19th century, the moon was the primary source of light in the night sky, playing a major role in regulating the sleep-wake cycle. The full moon often led to reduced sleep, sometimes triggering seizures in individuals prone to them. In fact, sleep deprivation is a regularly used pre-surgical diagnostic tool to elicit sequential epileptic fits in patients to examine interictal epileptiform discharges (IEDs), which are atypical patterns of brain activity occurring between seizures. IEDs are generally assessed in the context of seizure semiology (e.g., the study and interpretation of signs and symptoms associated with seizures) using a combination of video recordings and intracranial electroencephalography (EEG) over several days. With the commercialization of modern lighting, the impact of lunar phases on sleep diminished, especially in cities where most studies on the moon’s effect on the mind were conducted in the 20th century. While science has failed to validate claims of epilepsy’s heavenly origin, relegating them to mythology and superstition, it has nonetheless vindicated Hippocrates by recognizing the brain’s role in its causation.
While most patients manage their seizures with antiepileptic drugs (AEDs), between 30% and 40% will not respond to pharmacological treatments, eventually requiring resective brain surgery to remove the epileptogenic zone. A majority of these individuals with “pharmacoresistant” epilepsy will be diagnosed with temporal lobe epilepsy (TLE), which, as the name suggests, involves the structures of the temporal cortex. The International League Against Epilepsy (ILAE), a leading organization founded in 1909, aims to support health professionals globally by providing top-tier resources, enhancing expertise in epilepsy prevention and care, and promoting research. According to the ILAE, there are two main forms of TLE: medial TLE (mTLE), which affects internal parts of the temporal lobe, such as the hippocampus, parahippocampus, and amygdala; and lateral TLE (lTLE), a less common form that implicates its external neocortex. TLE seizures fall into three categories: (1) simple partial seizures (SPS) or “auras,” associated with mild disturbances to consciousness; (2) complex partial seizures (CPS), where perturbations to awareness become more apparent; and (3) generalized tonic-clonic seizures or “grand mal,” presenting with greatly impaired attention and even complete loss of consciousness, during which uncontrolled bodily convulsions and foaming at the mouth may occur. If these extreme symptoms persist for more than 5 minutes, the patient may enter a life-threatening state known as “status epilepticus,” requiring immediate medical intervention. Extratemporal epilepsies (ETEs), in which the epileptic focus is outside the temporal cortex, are other common pharmacoresistant forms of the disease. For instance, subtypes of focal cortical dysplasia (FCD), congenital malformations of neurons and cell layers in extratemporal regions, along with mTLE, account for up to 80% of pre-op patients in tertiary care.
In Tavakol et al. (2019), my first published review on the topic in Epilepsia, the official journal of the ILAE, my co-authors and I discussed how the recent integration of high-resolution multimodal neuroimaging data with advanced brain connectivity analyses (connectomics) has begun to reconcile the classic view of epilepsy as a localized brain disease with a more holistic understanding of large-scale neural dynamics. For example, we pointed to modern studies showing how the degree of local hippocampal pathology is anticorrelated with the strength of hippocampal connections to the default mode network (DMN). Findings demonstrate that low hippocampal-DMN connectivity, associated with lesions to the hippocampus, is a strong cerebral biomarker of memory dysfunction. Much of what we know today about impairments in human memory comes from experiments with TLE patients, starting with Brenda Milner’s seminal works in the 1950s at the Hartford Hospital in Connecticut, US, and the Montreal Neurological Institute (MNI) in Quebec, Canada. Since then, with over 70 years of clinical and neuroimaging studies, TLE has become a classic model of memory dysfunction in humans. At the MNI, where I conducted my PhD projects, one of my main objectives was to develop a state-of-the-art cognitive assessment platform for examining relational memory—see my first article for a discussion on relational memory:
I designed, programmed, piloted, and validated a novel, comprehensive Python-based memory assessment battery. With the publication of Tavakol et al. (2021) in Cerebral Cortex, we introduced the “integrated Relational Evaluation Paradigm” (iREP), a user-friendly memory assessment software specifically calibrated for the MRI environment, allowing for the examination of episodic, semantic, and spatial memory with high sensitivity while brain activity is measured with precision neuroimaging. In Tavakol et al. (2024), my follow-up study published in Epilepsy & Behavior, we used the iREP to investigate differences in memory function between healthy individuals and TLE patients. Compared to the control group, the patient cohort showed significant deficiencies in episodic memory and, to a lesser extent, spatial memory. Semantic memory was relatively spared in individuals with TLE, suggesting a resilience of the brain in sustaining this cognitive domain in spite of hippocampal sclerosis. This graded pattern of deficits was linked to variations in age and hippocampal volume, where older TLE patients with smaller hippocampi exhibited the most pronounced impairments.
Today, science helps illuminate certain aspects of the human condition that cannot be easily probed by other enterprises. In Classical Greece, narrative played a similar function. In the tragedy of Herakles, Euripides recounts the hero’s morbid fate upon his return to Thebes after completing his twelve labors, assigned by Eurystheus. The protagonist learns that, during his absence, the usurper Lycus overthrew Creon and resolved to kill Megara, Herakles’ wife. The hero wastes no time in ending Lycus’ life instead. The goddess Hera, who disdained Herakles, sends her minions to madden him before his reunion with his wife and three sons: “And as their father lingered, his children looked at him; and lo! he was changed; his eyes were rolling; he was distraught; his eyeballs were bloodshot and starting from their sockets, and foam was oozing down his bearded cheek.” In what resembles an epileptic fit, Herakles murders his wife and sons, mistaking them for Eurystheus and his kin. Violent behaviors in patients with epilepsy, which may occasionally occur, are poorly understood, with cognitive deficits, age, and medication likely playing a role. Even so, most patients do not experience the Herculean disease as its namesake did. In fact, seizures are sometimes barely noticeable from an outsider’s perspective. I recall an episode during my doctoral studies where a patient displayed telling behavioral signs. We had recruited the gentleman to participate in our neuroimaging study on memory. He was an in-patient at the time, so I met him at the ward before taking him to the brain imaging center. Initially, everything went as expected; I explained the study objectives and the MRI procedures. Upon arriving at the destination, we entered the side room next to the scanner, where I typically instruct participants on how to fill out the consent forms and questionnaires, in addition to administering a mock version of the iREP. Once seated, I gave him a pen and asked him to complete the first sheet. His demeanor suddenly changed – subtly, but noticeably. It was as if he had been holding a pen for the first time. He seemed tentative, unable to fill out the first line. He started murmuring as he finally managed to write his name. I asked if he was doing well; his answer was unclear, his gaze, blank. I gave him a moment to recollect himself, but he continued to appear out of touch with his surroundings. I immediately contacted his attending neurologist, describing his symptoms. It turned out to be an epileptic aura. I discontinued the session and escorted him back to the ward, and that was the end of it. That evening, as I gazed out my apartment window at the night sky, I thought, “What a beautiful full moon…”
References
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Magiorkinis, Emmanouil, Kalliopi Sidiropoulou, and Aristidis Diamantis. "Hallmarks in the history of epilepsy: from antiquity till the twentieth century." Novel aspects on epilepsy (2011): 131-156.
Moore, J. Layne, et al. "Sleep and epilepsy: a focused review of pathophysiology, clinical syndromes, co-morbidities, and therapy." Neurotherapeutics 18.1 (2021): 170-180.
Orrego-Gonzalez, Eduardo, Ana Peralta-Garcia, and Leonardo Palacios-Sanchez. "Heracles and epilepsy: the sacred disease." Arquivos de Neuro-Psiquiatria 78.10 (2020): 660-662.
Otte, Willem M., et al. "Web-search trends shed light on the nature of lunacy: relationship between moon phases and epilepsy information-seeking behavior." Epilepsy & behavior 29.3 (2013): 571-573.
Raison, Charles L., Haven M. Klein, and Morgan Steckler. "The moon and madness reconsidered." Journal of affective disorders 53.1 (1999): 99-106.
Romberg, Moritz Heinrich. A manual of the nervous diseases of man. Vol. 2. Sydenham Society, 1853.
Tavakol, Shahin, et al. "Neuroimaging and connectomics of drug‐resistant epilepsy at multiple scales: From focal lesions to macroscale networks." Epilepsia 60.4 (2019): 593-604.
Tavakol, Shahin, et al. "A structure–function substrate of memory for spatial configurations in medial and lateral temporal cortices." Cerebral Cortex 31.7 (2021): 3213-3225.
Tavakol, Shahin, et al. "Differential relational memory impairment in temporal lobe epilepsy." Epilepsy & Behavior 155 (2024): 109722.
Note: The highlighted first author “Tavakol, Shahin” is Shahin Zagros (myself).