Hippocampal sclerosis (HS) may be a separate pathological entity causing epilepsy. In patients with mesial temporal lobe epilepsy (MTLE), the sclerotic hippocampus is the equivalent of an “organ” in which recurrent seizures are an important functional manifestation. The sclerotic hippocampus contains an extremely complex cellular and molecular basis for maintaining this pathophysiological state. The mechanism of hippocampal sclerosis and its epileptogenicity has been a research topic in the field of epilepsy, and this paper reviews the history and current status of this research. The most common focal epilepsy syndrome is temporal lobe epilepsy (TLE), which accounts for the majority of epilepsy surgical case reports. LTLE refers to the lateral temporal lobe neocortex outside the lateral para-sulcus, including the superior temporal gyrus (T1), middle temporal gyrus (T2), inferior temporal gyrus (T3), and sphenoid gyrus (T4, also known as the lateral temporo-occipital gyrus). MTLE refers to the medial temporal lobe structures within the lateral para-sulcus, including the parahippocampal gyrus (T5, also known as the medial temporo-occipital gyrus) and hippocampal formation (T6). formation). Temporal lobe epilepsy associated with hippocampal sclerosis (MTLE) manifests primarily as MTLE. The medial temporal lobe structures are complex and the terminology is quite confusing. The anterior part of the parahippocampal gyrus is the hook gyrus, also known as the parahippocampal hook, which contains the amygdala complex. Hippocampal structures include the hippocampus (also known as the Ammon’s horn) itself, the dentate gyrus, and the subiculum. The dentate gyrus is paleocortical and consists of three layers of cellular architecture, namely the molecular layer, the granular cell layer and the polymorphic layer. The most prominent feature is the granule cell layer, which consists of closely spaced small neurons, i.e. granule cells. The molecular layer contains mainly the parietal dendrites of the granule cells, scattered interneurons and synaptic endings of the penetrating pathways. Below the granule layer is the polymorphic layer, which consists of several types of interneurons and mossy fibers emanating from the granule cells. The hippocampus itself is paleocortical and has a three-layer cellular architecture, including a molecular layer, a pyramidal cell layer, and a polymorphic layer. Depending on the arrangement of axons and dendrites in these three layers, they can be subdivided from the ventricular bed inwards into the primordium, cone layer, radial layer, luminal layer and molecular layer. The latter three layers are roughly equivalent to the molecular layer of the neocortex. Sometimes the luminal layer and the molecular layer are together called the luminal molecular layer. The most important cells in the hippocampus are the cone cells, which are regularly arranged in the cone layer, with dendrites emanating from the base of the cell toward the beginning layer and from the tip of the cell toward the molecular layer, which are widely branched and rich in dendritic lateral spines. The dendrites from the tip are regularly arranged, thus forming a radial layer. The axons of the cone cells converge towards the ventricular bed and enter the hippocampus. The luminal molecular layer contains the terminal branches of cone cell dendrites and fibrous branches of other origin. The polymorphic layer contains small cells of various morphologies, including basket cells, whose axons enter the radial and molecular layers and whose terminals form synapses with the cytosol of cone cells. The hippocampus is divided into CA1, CA2 and CA3, and sometimes the portal region is referred to as CA4. The hypotrochium refers to the transitional region located between the hippocampal parietal gyrus cortex and the hippocampus, corresponding to the upper part of the hippocampal parietal gyrus. It is divided into inferior torus apical, inferior torus, anterior inferior torus and parietal inferior torus. The apical and inferior tracts are a direct continuation of the hippocampus and are generally subsumed in the hippocampus itself, while the parietal tract is a continuation of the internal olfactory area (area 28) of the parahippocampal gyrus. Most of them belong to the six-layer structure. The main output pathways of the hippocampal structures originate in the inferior tegmental gyrus. The most important neural circuits in the hippocampal structure are the following three synaptic loops: the penetrating fibers from the inferior torus form synapses with the parietal dendrites of the granule cells of the dentate gyrus, the mossy fiber terminals of the granule cells form synapses with the cone cells of the CA3 region of the hippocampus, and the axons of the cone cells of the CA3 region of the hippocampus form synapses with the cells of the CA2 region and the neurons in the inferior torus. The most important function of the hippocampus is to participate in recent memory. The amygdala (amygdaloid cluster, amygdaloid complex) resides in the deep part of the hippocampal parabasal gyrus hook. Most of it is located near the anterior tip of the inferior horn of the lateral ventricle, a small portion is located above the top of the inferior horn of the lateral ventricle, dorsally adjacent to the nucleus accumbens, mouth side adjacent to the anterior perineurium, and caudally connected to the caudate nucleus caudalis. The amygdala includes the medial cortical nucleus and the lateral basal nucleus. The medial cortical nucleus includes ① anterior amygdala, ② lateral olfactory bundle nucleus, ③ medial amygdala, and ④ cortical amygdala. The medial cortical nuclei are connected to the oblique gyrus through the anterior amygdala and adjacent to the nonsense, shell and caudate nuclei on the dorsal side. The anterior amygdala has fibers entering and leaving the amygdala cluster and is poorly differentiated. The cortical amygdala corresponds to the cortical area on the floor of the brain and is composed of pyramidal cells and polymorphic cells. In humans, the lateral olfactory tract nucleus is the least developed of the medial cortical nuclei. The basolateral nuclei include (1) the lateral amygdala; (2) the basal amygdala; and (3) the parabasal amygdala. Afferent connections: from the olfactory bulb, anterior olfactory nucleus, dorsal medial thalamic nucleus, midline nucleus, intralaminar nucleus, dorsal median suture nucleus, blue spot, parabrachial nucleus, substantia nigra, solitary nucleus and ventral medial hypothalamic nucleus, as well as the inferior temporal gyrus, orbitofrontal cortex, cingulate gyrus and other cerebral cortex. Efferent fibers: The dorsal efferent pathway is mainly the terminal stripe. The terminal striatum is the most important efferent fiber of the amygdala, which mainly originates from the medial cortical nuclei and projects to the nucleus terminalis (located in the lateral fornix and dorsal anterior commissure), the anterior hypothalamus, preoptic area, ventral medial nucleus, and septal nucleus. The ventral efferent pathway is the basolateral nucleus cluster of the amygdala cluster to the lateral preoptic area, hypothalamus, septal area, Broca’s oblique band, dorsomedial thalamic nucleus, affecting substantia nigra, central gray matter of the midbrain, reticular formation, arcuate fascicular nucleus, vagal dorsal nucleus, and prefrontal lobe. The main functions of the amygdala cluster Stimulation of the amygdala cluster elicits the following responses: (1) Immediate cessation of automatically performed movements for objects that appear to draw attention, similar to escape, as in the early stages of the defense response. Different types of involuntary movements can be elicited, including head and eye turning to the opposite side; complex rhythmic activities such as chewing, tongue swallowing and swallowing associated with us and eating. (2) Vegetative reactions include changes in respiration, frequency, rhythm and irritability, increase or decrease in arterial pressure, increase or decrease in heart rate, increase or decrease in gastrointestinal motility and endocrine secretion, defecation and urination, changes in pupil size, and hair standing. Secretion of certain pre-pituitary hormones, etc. (ACTH ↑, gonadotropin ↑, lactation ↑) After bilateral amygdala cluster removal in monkeys, excessive probing of objects with the mouth, loss of fear, reduced aggression, marked reduction in anger and fear, becoming docile and tame, change in eating habits, even herbivores can eat meat, marked hypersexuality, the so-called Kluver-Bucy syndrome. 2, the basic pathological features of hippocampal sclerosis: hippocampal sclerosis ( Hippocampal sclerosis (HS), also known as inscisural sclerosis, medial temporal sclerosis (MTS), is a pathological condition in which the hippocampus becomes smaller, atrophied and hardened, often involving the hook gyrus, amygdala and parahippocampal gyrus at the same time. Histologically, it shows selective neuronal loss and astrogliosis, characterized by CA1, CA4 and anterior inferior tract. 3. Historical review of the process of understanding HS formation and its relationship with MTLE: The process of understanding the relationship between hippocampal sclerosis and epilepsy can be divided into three stages: (1) discovery of the presence of hippocampal sclerosis in patients with epilepsy; (2) recognition that hippocampal sclerosis may be the cause of epilepsy, not just the result of seizures; (3) recognition that hippocampal sclerosis may be a disease-independent entity whose most basic manifestation is seizures and began to explore its etiology, pathogenesis, and molecular pathology and molecular biology features. Early understanding was based mainly on controlled clinicopathological analysis, mid-term on surgical and deep recordings, and recent developments in imaging and molecular biology have provided unprecedented conditions to deepen the understanding of hippocampal sclerosis. More than 100 years ago, Hughlings Jackson (1) had a patient with a typical psychomotor seizure (complex partial seizure) by current criteria. After death, an autopsy revealed sclerotic manifestations in the medial temporal lobe structures. This first led to the recognition of a correlation between psychomotor seizures and medial temporal lobe lesions. By the 1950s a large number of controlled clinicopathological analyses had accumulated, essentially indicating that hippocampal sclerosis was the most common pathological finding in epilepsy, not only as a result of seizures, but also as a possible cause of epileptogenesis (2). When people started surgical treatment of epilepsy, it was basically extratemporal lobe epilepsy, mainly traumatic epilepsy. By the late 1930s temporal lobectomy was being performed to treat temporal lobe epilepsy. Clinical surgery and intracranial recording studies have shown that medial temporal lobe structures are the predominant temporal lobe epileptogenic focus, that surgical outcome correlates with the degree of resection of medial temporal lobe structures, and that hippocampal sclerosis is the most common temporal lobe epilepsy surgical pathology seen (3, 4). The concept of incisural sclerosis was introduced by Penfield at the Montreal Neurological Institute in Canada, where a total of 149 cases of temporal lobe epilepsy were treated by temporal lobectomy between 1939 and 1952 (68 cases in the first 10 years and 81 cases in the last 3 years), during which it was gradually found that the epileptogenic foci in temporal lobe epilepsy were most commonly found in the medial temporal lobe structures, and the concept of incisural sclerosis was introduced. The concept of incisural sclerosis was introduced, and it was believed that incisal sclerosis was the most common cause of temporal lobe epilepsy, and that the occurrence of incisal sclerosis was related to birth injury, and that enhanced resection of medial temporal lobe structures during surgery could improve the outcome. The concept of notch sclerosis is similar to medial temporal lobe sclerosis or hippocampal sclerosis. This recognized hippocampal sclerosis as an important cause of temporal lobe epilepsy from a clinicopathological perspective and suggested that the occurrence of hippocampal sclerosis was associated with an early brain injury event (birth injury) and prompted an emphasis on asking for a history of birth injury in clinical work. During this period, the theory of hippocampal sclerosis and temporal lobe epilepsy was “birth injury → hippocampal sclerosis → temporal lobe epilepsy”. The concept of primary pro-injury was developed: In the 1990s, UCLA workers used quantitative analysis techniques to perform quantitative pathology on temporal lobectomy specimens performed between 1961 and 1992. The medical histories of all cases were reviewed to explore possible susceptible etiologies prior to the onset of temporal lobe seizures. Any event involving loss of consciousness for more than 30 minutes or cognitive changes for more than 4 hours was termed an initial precipitating injury (IPI). All IPIs were further divided into epileptic and non-epileptic events. Forty-one percent of IPIs involved prolonged epileptic seizures or persistent states, 16% had a history of traumatic brain injury without a history of epileptic seizures, 12% had a history of nonprolonged febrile seizures, 7% had a history of birth injury, and another 10% had cerebral hypoxia or encephalitis between IPIs without motor epileptic seizures. The results showed that patients with IPI presented severe neuronal deficits in the form of hippocampal sclerosis, while cases without IPI showed only mild diffuse neuronal damage. The cases were divided into three groups: those with IPI but no occupying lesions, those without IPI and occupying lesions, those with occupying lesions, and those with IPI but no occupying lesions, with hippocampal neuronal loss exceeding 40% in 88.2% of cases and neuronal loss exceeding 40% in only 15.8% of cases without IPI and occupying lesions (p