Clinical aspects of hippocampal function

1. Clinical aspects of hippocampal function MedTech West seminar April 15, 2016 Helge Malmgren

2. Plan of the seminar • Question: Are the hippocampi worth the attention they receive? • The macro- and microanatomy of the hippocampus • Its internal and external connections, and its place in larger systems • Some current clinical and scientific practices involving the hippocampus • Some intriguing findings that may well have clinical significance • Memory, 1: The Amnestic (Korsakoff) Syndrome • Spatial memory, spatial perception and the hippocampi • If there is time left: • Hippocampal time cells? • Cognition, emotion and the limbic system • Very little will be said about LTP, place cells, rhythms and epilepsy • Discussion

3. Hippocampal macro-anatomy • The hippocampi are located in the medial temporal lobes (MTL) • They border to temporal neocortex, amygdalae, lateral ventricles and the ambient cistern • They are rolled into themselves along their long axes and then curved at both ends • The mouse hippocampi are orientated differently from the human ones • Ontogenetically, the hippocampus is an advancing rostral edge of the brain Anlage, just like the prefrontal cortex (which is rolled into itself on the upper side of the CC) • Which explains the long connections between the hippocampal and prefrontal areas • The induseum griseum layer that covers the whole upper edge of the CC is included in the hippocampus proper by, e.g., Duvernoy There are two of them (in each brain)!

4. Internal hippocampal structure • The cortex of the hippocampi (cornu ammonis + gyrus dentatus) is an allocortex that has a simpler layer structure than the neocortex. • Cornu ammonis can be seen as consisting of six layers, of which the alveus is outermost • The alveus is a massive fiber (output) tract that eventually continues as the fornix • Three subregions of the cornu ammonis: CA1, CA2, CA3, (CA4), dominated by large pyramidal neurons • The output from the dentate gyrus is from granule cells • The dentate gyrus is the ontogenetically most recent part, and is the main location for adult neurogenesis

5. Internal hippocampal connections • There are few longitudinal connections within the hippocampus proper • Two main ”transversal” circuits have been distinguished: • The polysynaptic path: entorhinal cortex → dentate gyrus → CA3 → (via Schaffer collaterals) → CA1 → subiculum, EC • The direct (perforant) path: EC → dentate gyrus → (via mossy fibers) → CA1 → subiculum, EC • The Schaffer collaterals are stimulated in experiments with LTP and LTD (long-term potentiation and depression, respectively)

6. External hippocampal connections • In rodents, but not in humans, the two hippocampi have abundant interhemispheric connections • Three main ipsilateral circuits are: • The circuit of Papez: parieto-occipital cortex → entorhinal cortex → dentate gyrus → CA3 → CA1 → subiculum → (via the fornix) → mamillary bodies, septum and anterior thalamus → retrosplenial and posterior cingulate cortices • The ”direct pathway”: inferior temporal neocortex → entorhinal cortex → CA1 → subiculum → inferior and anterior temporal neocortex, prefrontal cortex • The ”limbic striatal loop”: prefrontal cortex → nucleus accumbens → dorsomedial thalamus → ventral pallidum → prefrontal cortex. The accumbent nucleus also receives input from the ventral tegmental area, amygdala and hippocampus (fornix route) https://commons.wikimedia.org/wiki/File:The_Limbic_System_and_Nearby_Structures_-_John_Taylor.jpg The entorhinal cortex, through which the main input to the hippocampus arrives, can be considered part of the anterior parahippocampal gyrus. The subiculum is the major output port of the hippocampus. It is situated between the hippocampus proper and the parahippocampal gyrus.

7. Some established convictions and practices • Hippocampal sclerosis is the most common cause of drug-resistant mesial temporal lobe epilepsy (MTLE) • MR, PET and SPECT imaging are used for diagnosis and to guide resections • The hippocampus and the larger hippocampal area are engaged early in Alzheimer’s disease, sometimes visibly so in its pre-stages • DTI, fMRI and (tau) PET are increasingly used for early diagnosis • Structural MRI with automatic or manual analysis of MTL subregions, e.g. the transentorhinal area (medial perirhinal cortex) is also a growing field • An Amnestic Disorder (DSM) results from a number of causes involving the hippocampus or other parts of the limbic system: • Bilateral temporal lobe resection (the famous case of HM) • Chronic alcoholism (cf. Wernicke-Korsakoff’s encephalopathy) • Herpes encephalitis (”limbic encephalitis”) • Anoxia, e.g. after circulatory arrest • More about this syndrome in a minute!

8. Some tentative clinical and research findings • The rodent hippocampus is highly vulnerable to radiation, and the human hippocampus most probably shares this weakness • The latter issue is important for the design of radiotherapy, but research is difficult (randomization seldom possible, many confounding factors) • The radiation effects may be due to impaired neurogenesis • Structural and/or functional MRI changes in the hippocampus have been detected in, among others: • Major depression (fairly reliably) • First-episode schizophrenia • Hypercortisolism (Cushing, cortisol medication) • ”The brain, and in particular the limbic system, is a major target area for cortisol, considering the high density of both the mineralocorticoid and glucocorticoid receptors.” • Hypothyroidism (and we are currently investigating the opposite case) • T3 receptors are distributed among all brain areas with the highest levels in the olfactory bulbs, the hippocampi, and the cerebellar cortex. • This endocrine coupling, plus that a major hippocampal output goes to the hypothalamus, points to important roles beyond memory and cognition.

9. Korsakoff’s Amnestic Disorder (KAD) • For documentation and terms see Lindqvist & Malmgren (1990, 1993) • KAD is not the most common kind of memory disorder • The memory disturbances in mild cognitive impairment (MCI) and mild traumatic brain injury (TBI) have the character of ”mental fatigue”, or astheno-emotional disorder. • KAD was excellently described by S. Korsakoff around 1880. • It has a quite specific profile: • An inability, or lowered ability, to learn new declarative knowledge. But: • Preserved immediate memory (e.g. immediate reproduction of sequences) • A memory gap stretching back from the début, and hours to many decades before it. The gap does not encompass the whole life. It includes knowledge of facts (not only episodic memory), and can regress almost completely • Disorientation and confabulation • Preserved ability for practical, associational (?) and perceptual (?) learning • KAD requires a bilateral lesion, or functional disturbance, in limbic circuits. E.g.: • Hippocampus (bilateral surgery as in the famous case of HM, circulatory arrest, …) • Mamillary bodies or anterior thalamic nuclei (alcoholism) • Bilateral? Yes, else epilepsy surgery would be almost impossible (but: reorganisation) • Memory problems after successful surgery are not of the KAD kind (please confirm) • In DSM-IV, ”dementia” and ”amnestic disorder” exclude each other. But • Alzheimer’s disease often shows early symtoms indistinguishable from a KAD. • And of course, we have bilateral limbic damage in Alzheimer’s dementia!

10. Spatial memory, spatial perception and the hippocampi • Many know the story of the London taxidrivers. But is their larger hippocampi due to better spatial memory, or to improved spatial perception? • The equally famous hippocampal place cells do not only re-play learned locations. Their defining feature is that they react to the actual location of the animal – does not that involve perception? • Of course perception is itself (continuously) learned, so the question of memory or perception may be a non-issue • There is recent evidence that (anterior) hippocampal lesions go with specific deficits of imagination: an inability to integrate individual imagined objects to a spatially consistent scene • The authors seem to suggest that the same holds for perception • There is old, direct evidence for this hypothesis in Herman Rorschach’s study (1921) of patients with alcoholic Korsakoff: these patients exhibited so-called confabulatory combinations • The present author could confirm and extend Rorschach’s finding in a study 50 years later

11. Cognition, emotion, action and the limbic system • Cognition needs motivation and emotion. Why think, if you do not need it and do not like it? • There is no completed executive functioning without motivation. Nothing will be done (no action will be executed) in the end. • The classical ”frontal lobe syndrome” encompasses changed (antisocial) emotionality, lowered motivation, passivity, bad judgment and disturbances of abstract thinking • It can occur with lesions in the frontal lobe, but also with unilateral lesions anywhere in the limbic system • The popular or semi-popular ideas that emotions are tied to the right brain, or to the amygdalae, are just wrong (Lindquist et al) • Remember also the engagement of the hippocampi with the limbic striatal (essentially motor) system • So the hippocampi are heavily involved not only in memory and perception, but also in the cognitive, emotional, motivational and final executive components of human existence • The limbic system, not the neocortex, constitutes the brain’s highest integrational level. The neocortex is just its computer.