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Medial Temporal Lobe

The medial temporal lobe, located in the temporal lobe is a collection of structures, which have been heavily associated with memory. The medial temporal lobe role is although not only limited to memory, it has been associated with long lasting pathologies such as epilepsy, Alzheimer’s disease, and schizophrenia. In addition recent evidence has suggested that the medial temporal lobe is involved in visual discriminations of objects, faces and scenes.

=Anatomy= The medial temporal lobe, located within the temporal lobe, is made up of hippocampal region and the adjacent parahippocampal gyrus. The structures contained by the hippocampal region are the dentate gyrus and the subiculum. The parahippocampal gyrus is formed by the entorhinal, perirhinal and parahippocampal cortices. The parahippocampal gyrus and the hippocampal region are connected by the entorhinal cortex, which lies medially against the subiculum.

=Function= The structures within the medial temporal lobe are generally thought to be necessary for declarative memory ; memory for facts and personal experiences. The hippocampus in particular is thought to be involved in the creation of new memories and the detection of novel stimuli. There have been suggestions that it is the perirhinal cortex which is vital for the recognition of objects, while the hippocampus is involved more in the memory of paths and places.

=Research=

Early Research
Speculations that the Medial Temporal Lobe could be linked to memory started appearing as early as the twentieth century, as such references where found in clinical material that was regarded to be more than a century old. Official documentation wasn’t recorded until systematic reports by William Beecher Scoville and Brenda Milner started to be obtained with Patient H.M. Henry Molaison, more commonly known as Patient H.M underwent surgery in 1953 in attempt to cure his severe form of epilepsy, which with increasing severity and frequency of attacks left him unable to work and lead a normal life. The surgical operation included complete bilateral removal of the hippocampal formation (entorhinal cortex), amygdala, perirhinal cortex and parahippocampal gyrus. The removal of these structures freed H.M of his seizures but left him with a profound memory impairment: anterograde amnesia - the inability to form new long-term memories for new events. H.M was not the first patient to undergo bilateral removal of the medial temporal lobe. Some patients suffering from severe psychosis, underwent similar surgeries in attempt to relieve their psychosis. However as the operation failed to relieve psychosis symptoms, the memory impairments caused by medial temporal lobe resection were not considered whereas H.M’s extensive impairment was apparent immediately after surgery.

With such new findings, evaluations of patient H.M and other patients with similar medial temporal lobe damage where drafted and helped to establish three fundamental principles about memory and the medial temporal lobe: Firstly, memory is a unique cerebral ability and it is separate from other cognitive functions such as intelligence, perception, motivation and personality. Second, only long-term memory appears to be damaged after a medial temporal lobe lesion as information can be maintained for a short interval in working memory. Lastly medial temporal lobe structures are not the only fundamental source for long-term memory because remote long-term memory – memories that have already been encoded, remains largely spared. Even though these preliminary principles were drafted, knowledge about the anatomy of the medial temporal lobes was still in its early stages and it was still not known what specific damage to the structures was responsible for H.M memory impairment.

Animal Research
Efforts to evaluate a possible non-human primate model for the medial temporal lobe were made in the attempt to elucidate medial temporal lobe involvement in memory. The process began when Scoville, the same surgeon that operated on patient H.M, performed the same surgery on monkeys’ brains. This early research was taken with skepticism especially because early efforts did not seem to replicate H.M’s memory impairments. Monkeys and other animals with medial temporal lobe lesions were able to learn tasks that appeared similar to tasks that H.M could not learn. When monkeys with medial temporal lobe lesions were tested on a visual discrimination tasks which were designed to approximate the same tasks given to H.M, the monkey’s performed normally. Application of delayed periods of response and introduction of distractor tasks saw no change in monkey performance.

Extensive work in the rodent brain carried out a decade later, also failed to reproduce H.M’s memory impairment. Rodents, like monkeys, also performed normally on visual discrimination tests. This 1960’s animal model research therefore seemed not to match human literature already gathered from memory patients. Researchers were therefore beginning to question that medial temporal lobe role in memory.

A key issue was raised in 1974 by David Gaffan, who suggested that many of the tests that were used to assess memory performance in animals with hippocampal damage did not replicate accurately the tests used on amnesic patients. Gaffan therefore developed a one-trial memory test for monkeys that would test declarative memory - memory for facts and events, which results to be impaired with medial temporal lobe damage. The task became known as ‘delayed matching to sample task’ (DMS), and was equivalent to the yes/no recognition tests that where often used to test human memory. Gaffan (1974) tested monkeys with fornix lesions that showed impaired memory functions if the delays were longer than 10 seconds. This finding even though not specifically relatable to medial temporal lobe structures was still regarded as evidence of loss of recognition memory that was closely comparable to amnesic patients.

A turning point in the development of a successful animal model was made in 1978 by Mortimer Mishkin. The experiment consisted of the training of 12 monkeys in an adapted version of Gaffan’s experiment. After training, the monkeys were lesioned in a way to resemble the damage sustained by H.M. Either combined lesioning of the hippocampus, amygdala and underlining cortex were performed, or smaller lesions to the hippocampus or amygdala both with damage to underlining cortex were performed. The results showed that hippocampal or amygdala lesions yielded a mild memory impairment whereas hippocampal, amygdala and underlining cortical lesioning resulted in a profound impairment, especially when testing with longer delays. This test along with others to follow  documented a successful replication of human amnesia in a monkey brain and therefore established an animal model for medial temporal lobe amnesia in humans. Following research would then reveal that the amygdala is not a critical component in causing a memory deficit and it was in fact the underlining cortical areas damaged during the extraction of the hippocampus and amygdala that were critically important in causing a memory deficit. Mumby et al. (1994) also extended this animal model to the rodent brain, showing that lesions in the hippocampus and underlining cortical structures produced a delay memory impairment similar to ones observed in monkeys and consisted with the ones observed for patient H.M.

New research
After the establishment of the role of the medial temporal lobe in declarative memory, the research field tried to address the question of the medial temporal lobe role as a unitary system or if each structure within it would be involved in a specific aspect of memory or other cognitive functions. Speculations of this began with a neuroanatomical prospective: information from the neocortex enters the medial temporal lobe at different points. The perirhinal cortex receives the strongest projections from the visual areas as opposed to the parahippocampal cortex, which receives prominent projections from the dorsal stream (restrosplenial cortex, area 7a of posterior parietal cortex and area 46). In monkey studies visual memory is more dependent on the peririhinal cortex (Squire & Zola-Morgan 1996) whereas spatial memory is more dependent on the parahippocampal cortex. With the development of neuroimaging techniques findings suggest that the hippocampus is more active in relation to visual and spatial memory and it also seems to have a special role in combining information from multiple sources, such as tasks that require information from specific events (episodic memory) or tasks that require remembering pairs of information (associative memory).

Research also began to branch out from the firm belief that the medial temporal lobe would only be involved in declarative memory, researchers began to investigate if the perirhinal cortex might also be involved in perceptual processing of complex visual information, specifically in the ability to identify complex objects. This concept was primarily built on lesion studies in monkeys, but this methodology presented some drawbacks: the difficulty in testing experimental animals for their ability to identify an object as opposed to their ability to learn about an object. As this could signify that some impairments attributed to a perceptual deficit could have resulted from impaired learning.

Patient studies where also examined and it was suggested that lesions to the perirhinal cortex cause an impaired ability to discriminate objects and faces but simpler visual discrimination such as distinguishing size, colour and shape remain intact. Human amnesiacs suffering from bilateral hippocampal damage showed discrimination difficulties for spatial scenes if high demand was placed on spatial configuration processing. Patients were mostly impaired if multiple scenes were blended together creating overlapping features, or if the virtual scenes were presented from different viewpoints. These findings lead to several possibilities: a possible involvement of the perirhinal cortex in processing conjunctions of complex features for objects and faces and a possible hippocampal involvement in representations of visual spatial information for scenes, particularly for combining features that represent a scene.

Functional magnetic resonance imaging was therefore proposed to test of these preliminary hypotheses. Increased cerebral activity was observed in the right perirhinal cortex and right posterior hippocampus in healthy participants when asked to perform a visual discrimination tasks, suggesting that the medial temporal lobe has a role in complex object discrimination. In a following study, peririhinal cortex activation was highest for discrimination of faces and objects whereas greatest activation for scenes resulted to be located in the posterior hippocampus. In addition posterior hippocampal activity was found for discriminations that involved different viewpoints.

=Pathology=

Epilepsy
Temporal lobe epilepsy appears to be have a profound affect on several structures within the medial temporal lobe and is often associated with hippocampal sclerosis; damage and cell loss of the hippocampus. Temporal lobe epilepsy is also associated with a substantial decrease in hippocampal neurogenesis ; the creation of new neurons within the hippocampus. Though new cells are still created, there is evidence they have trouble differentiating; specializing into the required neuron type. This is especially problematic, as the dentate gyrus within the hippocampus normally engages in neurogenesis throughout our lifespan. This inability for new neurons to properly differentiate, has been suggested as a possibility for the persistence of seizures, learning and memory dysfunction, and depression associated with chronic epilepsy. However, there can be some uncertainty about whether epilepsy is the result of damage to the hippocampus or whether the abnormalities in the hippocampus are the result of the epileptic seizures. While artificially induced epileptic seizures in animals have been shown to result in severe damage to the hippocampus and entorhinal cortex, the effect can be inconsistent and is only a small part of the mayor damage the other structures in the brain.

Alzheimer's Disease
As memory is the main function associated with the medial temporal lobe, it has been the focus of many studies relating to Alzheimer's disease. One of the regions that is particularly vulnerable and affected earlier in Alzheimer's disease, is the entorhinal cortex; part of the entorhinal-hippocampal circuit, necessary for encoding specific forms of memory. In a postmortem study counting the neurons in the entorhinal cortex of deceased individuals, it was shown that even the participants with the mildest clinically detectable form of dementia, who still retained the neuropathological diagnosis of Alzheimer's disease, already had 32% fewer neurons in their entorhinal cortex than controls. Participants with the most severe cognitive impairment had lost as much as 90% of the neurons in the entorhinal cortex necessary for the entorhinal-hippocampal circuit. It has been suggested that it is the loss of this connection between the entorhinal cortex and the hippocampus that could be responsible for memory defects associated with Alzheimer's disease.

Exercise has been shown to be able to increase the volume size of the anterior hippocampus; which can lead to improving spacial memory. Fitness is also suggested to be able to prevent volume loss of the hippocampus. One attempt to use deep brain stimulation increased the participants' spacial memory when stimulating the entorhinal cortex, rather than the hippocampus.

This strong link between the medial temporal lobe and Alzheimer's disease is believed by some to be the key to predicting Alzheimer's disease in patients. MRI studies show that a volume reduction in the entorhinal cortex, more than the hippocampus, can be an early sign of Alzheimer's disease pathology. Some suggestions have been made that entorhinal cortex, specifically in the right hemisphere, can predict the conversion rate from Mild Cognitive Impairment to Alzheimer's disease with a concordance of 93.5%.

Schizophrenia
MRI and postmortem studies indicate a reduction in the temporal lobe in patients with schizophrenia. While the causes of schizophrenia and its symptoms are still heavily debated, there are some suggestions that that the medial temporal lobe is involved; with lots of research focusing on the hippocampus. While there have been indications of a reduction of the size of the hippocampus in patients with schizophrenia, smaller hippocampal volumes have also been noted in patients showing early symptoms of schizophrenia; suggesting the size reduction is not a secondary effect of the illness or the treatment thereof. There have also been suggestions that this hippocampal volume reduction could be the result of a genetic predisposition to schizophrenia. These hippocampal anomalies could be responsible for the long-term memory impairments associated with schizophrenia. Schizophrenia appears to be associated with asymmetry in the medial temporal cortex as a result of volume reductions in various structures. Postmortem research revealed that Schizophrenia patients had lower volumes in the left hemispherical parahippocampal and fusiform gyri than their right. This is a reversal of asymmetry when compared to control subjects. Such asymmetry can also be prevalent in the entorhinal cortex. While schizophrenia correlates with volume reductions of the entorhinal cortices in both hemispheres, the right one appears to be especially effected. Asymmetric reduction of entorhinal cortex volumes, and miswiring of entorhinal connections could be contributing factors to some cognitive disturbances associated with schizophrenia.

=References=