Computational models of the hippocampal region: implications for prediction of risk for Alzheimer's disease in non-demented elderly

Abstract

We have pursued an interdisciplinary research program to develop novel behavioral assessment tools for evaluating specific memory impairments following damage to the medial temporal lobe, including the hippocampus and associated structures that show pathology early in the course of Alzheimer's disease (AD). Our approach uses computational models to identify the functional consequences of hippocampal-region damage, leading to testable predictions in both rodents and humans. Our modeling argues that hippocampal-region dysfunction may selectively impair the ability to generalize when familiar information is presented in novel recombinations. Previous research has shown that specific reductions in hippocampal volume in non-demented elderly individuals correlate with future development of AD. In two previous studies, we tested non-demented elderly with and without mild hippocampal atrophy (HA) on stimulus-response learning tasks. Individuals with and without HA could learn the initial information, but the HA group was selectively impaired on transfer tests where familiar features and objects were recombined. This suggests that such generalization deficits may be behavioral markers of HA, and an early indicator of risk for subsequent cognitive decline. Converging support for the relevance of these tasks to aging and Alzheimer's disease comes from our recent fMRI studies of individuals with mild cognitive impairment (MCI). Activity in the hippocampus declines with progressive training on these tasks, suggesting that the hippocampus is important for learning new stimulus representations that support subsequent transfer. Individuals with HA may be able to learn, but in a more hippocampal-independent fashion that does not support later transfer. Ultimately, this line of research could lead to a novel battery of behavioral tests sensitive to very mild hippocampal atrophy and risk for decline to AD, allowing early diagnosis and also allowing researchers to test new Alzheimer's drugs that target individuals in the earliest stages of the disease - before significant cognitive decline. A new mouse version of one of our tasks shows promise for translating these paradigms into rodents, allowing for future studies of therapeutic interventions in transgenic mouse models of AD.

Fig. (1)

Coronal images of the human brain through the hippocampus in four individuals with increasing degrees of hippocampal atrophy (HA): 0=no atrophy, 1=questionable or mild HA, 2=mild-to-moderate HA, 3=moderate-to-severe HA. Reprinted from [6] Myers et al. (2003) Figure 3.

Fig. (2)

Concurrent visual discrimination task. (A) On each trial of the initial learning phase, the subject sees a pair of objects on the computer screen (top) and is asked to choose the left or right object. The chosen object is raised and, if the subject’s choice was correct (center) a smiley face is revealed underneath; otherwise (bottom) there is no smiley face. (B) In the transfer phase, the irrelevant feature in each object pair is altered so, in this example, mushroom still beats frame, but the (irrelevant) color has changed. Reprinted from [30] Myers et al. (2002) Figure 2.

Fig. (3)

(A) Non-demented elderly individuals with and without HA learned a series of concurrent visual discriminations at the same speed; (B) On the transfer phase, however, the HA group made significantly more errors. Reprinted from [6] Myers et al., 2002, Figure 3A, B.

Fig. (4)

Example screen events during one trial of the acquired equivalence task. (A) On each trial, the subject sees one face and two colored fish. (B) The participant responds by pressing a key to choose the left or right fish, the chosen fish is circled, and feedback is given telling the participant whether this choice was correct or incorrect. Reprinted from [6] Myers et al. (2003) Figure 4.

Fig. (5)

(A) Non-demented elderly individuals with and without HA learned at the same speed during the learning phases of our acquired equivalence task. (B) In the testing phase, both groups continued to perform well on previously-learned (old) discriminations. However, the HA group was significantly worse at transferring to novel (new) pairs, indicating they had failed to learn the acquired equivalence during the earlier phases. Reprinted from [6] Myers et al., 2003,

Fig. (6)

A montage across three slices of the SPM atlas depicting activation from a single 75 year old healthy female subject. The subject exhibited a learning-related adaptation response in the hippocampus. A region of interest analysis was used that focused on the hypothesized location of the mesial temporal lobe (outlined in the Figure).

Fig. (7)

Statistical parametric maps of adaptation during the Choose task in 13 controls and 8 MCI. The activations can be interpreted as regions where the negative slope of change over repeated trials is significantly different from zero. (A) The average slope of adaption in the controls is significant in the anterior medial temporal lobe at the point where the hippocampus and amygdala conjoin (t=4.38, p<.001; x,y,z -22, -4, -22). (B). The MCI patients do not exhibit any significant change over trials in the MTL. The group statistics in A and B are superimposed on the same standard atlas brain at the same slice location. The left side of the brain is on the left side of the image.

Fig. (8)

(A) Mouse testing apparatus. (B) Schematic of design of rodent analog of the concurrent discrimination and transfer task.

Fig. (9)

Pilot data from 9 wild-type mice showing enhanced transfer to phase 2 from phase 1 (fewer trials to criterion) when the relevant rule remains the same. A third phase with a novel cue pairing is included as a control for non-specific changes in performance.