Mapping relational memory deficits and their hippocampal correlates in schizophrenia

ABSTRACT (PROJECT SUMMARY)
Despite decades of research, schizophrenia remains the most devastating of all psychiatric disorders.
Schizophrenia is characterized by significant deficits in neural and cognitive processing, shortened lifespans,
and tremendous social, personal, and economic burden—for patients, their families, and society. The
development of cognitive markers that can track clinical and neural progression is a promising avenue for
monitoring illness burden and effective treatment response. Yet, despite enthusiasm for cognitive markers of
progression, clinically useful markers have proven difficult to identify. One reason for this may be the lack of
fidelity between potential cognitive markers and neuropathology. Cognitive markers that are causally linked
with brain pathology are needed to overcome this obstacle. We propose that relational memory – a form of
memory dependent on the hippocampus – is ideally suited as a marker of neuropathology in schizophrenia.
Hippocampal atrophy is one of the most significant brain abnormalities in chronic schizophrenia but is less
pronounced in the prodromal and early stage of psychosis. Progressive microstructural changes, resulting from
an excitation/inhibition imbalance advancing from the hippocampal head to encompass the hippocampal body
and tail has been identified as a plausible mechanism for the hippocampal atrophy observed over illness
stages in schizophrenia. We propose to use a novel paradigm developed and validated in hippocampal
amnesia patients to quantify performance across three types of relational memory – associative, temporal, and
spatial – in schizophrenia. As distinct relational memory types have been shown to segregate along the
hippocampal longitudinal axis, we propose that impairment within relational memory types will map to
dysfunction in distinct hippocampal divisions of the head (associative memory), body (temporal memory), and
tail (spatial memory). Further, we will test the relationship between relational memory impairments and
hippocampal pathology over illness stages. To test our hypotheses, we will examine hippocampal volume and
microstructure in patients ranging from early to chronic illness stages. The proposed combination of a multi-
type, hippocampal-dependent relational memory assessment with multi-dimensional hippocampal
neuroimaging will allow us to characterize the relationship between relational memory function and
hippocampal structural abnormalities. The establishment of a cognitive marker sensitive to hippocampal
structure will significantly improve our ability to track, intervene, and prevent the progression from early
psychosis to schizophrenia.

Grant Number: 1R21MH134061-01A1
NIH Institute/Center: NIH
Principal Investigator: Suzanne Avery