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Title: Autoimmune encephalitis and its implications for the neuroscience of remote memory
Author: Miller, Thomas D.
ISNI:       0000 0004 6499 8033
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Since the field-defining patient HM, consistent links have been made between a region of the brain called the hippocampus and memories that can be consciously declared - so called declarative memories. Declarative memories fall into two categories (1) episodic memories, memories that are highly detailed and re-experiential, and (2) semantic memories, fact-based memories for personal and public information but that have no sense of re-experiencing. It is believed that the intrinsic anatomy of the hippocampus supports episodic memory but not semantic memory. The hippocampus consists of five regions (cornu Ammonis, CA, 1-3, dentate gyrus, subiculum) with each purported to have a specific role in episodic memory acquisition and retrieval. However, controversy surrounds the temporal extent to which episodic memories rely on the hippocampus for retrieval: current consensus suggests the hippocampus supports these memories for five-10 years post-acquisition, but some suggest that it is required for retrieval across the lifetime. Voltage-gated potassium channel-complex antibody-mediated limbic encephalitis (VGKC-complex LE) is a recently described autoimmune disease that causes chronic hippocampal atrophy and mild amnesia on standardized neuropsychological assessment. Two subfields of the hippocampus - CA1 and CA3 - contain the antigenic targets of the disease but it is unknown if specific atrophy of these subfields underlies the hippocampal damage in humans. Here, the human hippocampal subfield volumes of VGKC-complex LE patients (n = 19, mean age: 64.0±2.55; range: 24-71) were investigated using ultra-high spatial resolution MRI at 7.0-Tesla. Assessment also included standardized neuropsychology to examine the impact of the pathology on hippocampal-dependent and -independent memory performance, as well as attention, language, executive function, and perception Declarative memory assessment measured semantic and episodic memory performance across the lifespan. Manual segmentation detected lesions to just CA3, with no volume loss noted elsewhere in the hippocampus or brain. Patients were impaired on hippocampal-dependent memory domains but not the hippocampal-independent and non-memory domains. Notably, episodic memory assessment revealed episodic amnesia across the lifetime except for their earliest memories. This counters the received convention that the hippocampus has a temporally limited role in episodic retrieval. Conversely, the performance of the VGKC-complex LE patients for semantic memory, including a new test developed herein, was comparable to controls across the lifespan. It was then shown that CA3 volume predicted episodic memory performance across the lifetime. Together, the results suggest that VGKC-complex LE provides a novel model of human hippocampal subfield pathology, with which to explore the roles of hippocampal subfields in episodic memory acquisition and retrieval.
Supervisor: Butler, Chris ; Rosenthal, Clive Sponsor: Guarantors of Brain ; Patrick Berthould Charitable Trust ; Encephalitis Society
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Memory ; Neurology ; Declarative memory ; Autoimmune encephalitis ; Hippocampus