Picture encoding studies

Using a picture encoding task, where novel scenes were contrasted with repeated scenes, greater extent of activation in the MTL regions correlated with better recognition performance but also paradoxically with greater functional impairment and faster cognitive decline in the subsequent 2.5 years in AMCI subjects (Dickerson et al., 2004). The authors recently conducted a further analysis which showed that greater magnitude of hippocampal activation at encoding correlated with greater degree and rate of subsequent cognitive decline (Miller et al., 2008). A further study by this group, using the same task, an expanded original participant group and a model-free independent component analysis of activation across the whole brain, revealed increased MTL activation in less impaired AMCI subjects and decreased activation in the more impaired AMCI subjects (Celone et al., 2006). Their findings could indicate that greater activation during a compensated state affords better recall but also heralds the onset of a period of fast decline, whereas decreased activation indicates more advanced impairment and relatively slower decline. Findings from these studies are unfortunately difficult to generalise to the AMCI population because the authors did not require objective evidence of episodic memory impairment for a diagnosis, instead they relied on subjective reports. Their patient group therefore included subjects that we would describe as suffering from subjective cognitive impairment and likely represents an even more heterogeneous group than MCI.

Finding a correlation between MTL activation and subsequent decline is of interest as a recent study that combined functional neuroimaging of encoding (picture-word pairs) and voxel-based morphometery reported a positive correlation between increased posterior MTL (hippocampus, parahippocampus, fusiform areas) activation and anterior MTL atrophy in AMCI subjects (Hamalainen et al., 2007). This

correlation was absent in controls and AD patients and the authors suggest that increased posterior MTL activation is compensatory for anterior MTL atrophy in AMCI. The magnitude of compensatory activation could therefore correlate with disease progression and differentiate between AMCI, ageing and AD. These findings could also explain the result discussed above that indicate a correlation between MTL hyperactivation and subsequent rapid decline.

An incidental, deep picture encoding task (requiring participants to decide if a stimulus was man-made or natural) demonstrated impaired memory performance associated with decreased activation in AMCI in left hemispheric PFC (BA 47), entorhinal cortex (BA 34), superior temporal cortex, extrastriate visual cortex and anterior cingulate, in right hemispheric middle temporal gyrus, lentiform nucleus (putamen) and caudate, and in bilateral medial parietal (precuneus) cortex (Mandzia et al., 2007). In this study, recognition accuracy correlated with the extent of activation in bilateral parahippocampal gyri in controls but not in AMCI subjects. The result from this study reveals altered activation across a range of areas associated with sensory processing and higher processing of stimuli. The loss of correlation between activation and performance may indicate that parahippocampal areas were already maximally activated, and/or deployment of a compensatory encoding strategy that is less dependent on parahippocampal activation.

Altered metabolism in parahippocampal and bilateral medial parietal areas has also been reported in AMCI using the recently developed perfusion fMRI method.

During picture encoding, AMCI demonstrated attenuated medial parietal (precuneus, cuneus and posterior cingulate) and absent right parahippocampal regional cerebral blood flow (CBF) increases compared to controls (Xu et al., 2007). The mean CBF in the medial parietal cluster correlated with MMSE score and more so with delayed verbal recall performance. Furthermore, when the groups were compared at rest, similar decreased medial parietal (precuneus and cuneus) perfusion persisted and again correlated with MMSE and delayed verbal recall performance. This appears to indicate a close association between activity in medial parietal areas, episodic

memory and global cognition. The medial parietal area is comprised of the precuneus, posterior cingulate and retrosplenial cortex. This area appears vulnerable to AD neuropathology as evidenced by findings of volume loss, hypoperfusion and

hypometabolism. Volumetric differences in this area are evident between normal and AMCI subjects and decreased volume in this area predicts dementia conversion. The area also suffers accelerated atrophy in progressive AMCI. Hypoperfusion and hypometabolism have been demonstrated in this area and these findings predict progression to AD from AMCI and also correlate with episodic memory performance (for a review see(Ries et al., 2008))(Xu et al., 2007). The medial parietal area receives cholinergic input from the BFCS via the medial cholinergic pathway and are the most distant area supplied via this pathway (Selden et al., 1998). Functional and structural changes could therefore be related to AD neuropathology in the BFCS affecting cholinergic innervation and therefore cholinergic regulation, first affecting the most distant areas innervated by the medial cholinergic pathway.

Impaired memory and decreased bilateral PFC and left cerebellar activation were demonstrated in AMCI on a face-name paired associates encoding task (Petrella et al., 2006). A more recent intentional picture naming encoding task revealed

decreased left PFC activation and increased right MTL activation in AMCI compared to controls specifically for successfully encoded items (Trivedi et al., 2008). This indicates that matching the performance of controls requires different contributions from PFC and MTL structures, which may be compensatory.

The available experimental data does not allow a coherent description of functional activation changes associated with encoding processes in AMCI. This is due to the small number of studies, the varying encoding tasks and the lack of consistent application of operationalised diagnostic criteria for AMCI. Generalisable results from these few studies indicate that matching the encoding performance of controls is accompanied by greater MTL activation whilst altered PFC and medial parietal activation is often present but not clearly related to encoding success. Future studies need to clarify the roles of incidental/intentional and successful/failed

encoding of verbally/visually presented material as the networks that underpin them may overlap but are not identical. At present there appears to be a lack of appropriate studies designed to reveal the neural correlates of impaired performance on standard clinical verbal episodic memory tests. The verbal episodic memory paradigm that we employed bares much closer resemblance to clinical measures and our data will therefore be informative of the neural correlations of clinically observed amnesia (§3.9.3). The following section deals with attention and the interaction between episodic memory and attention.

1.5 Attention

Attention is crucial for everyday functioning and the ability to direct attention to information sources relevant to survival helps to compensate for the limited capacity of human cognition. Attention underpins almost all other cognitive processing;

consequently, attentional deficits can have widespread effects on behaviour.

Attentional is impaired early in the course of AD but appears intact in AMCI.

However, clinical observation in AD and the cholinergic hypothesis (§1.1.2) suggest that attentional deficits may be present in AMCI. We studied the neural correlates of selective and divided attention in AMCI, and in this section, attention is introduced and the available findings from behavioural and functional neuroimaging studies are discussed to inform the interpretation of the results.

1.5.1 Theoretical Background

Attention refers to the capacity to direct consciousness towards specific internal or external stimuli. It can be sustained (maintained over a period of time), selective (ignoring non-task relevant stimuli) and divided. Divided attention refers to the capacity to simultaneously attend to multiple stimuli that may come from one (within-modal) or more (across-(within-modal) sensory inputs. Attention is typically studied using tasks during which subjects are required to monitor a series of stimuli and to react to the presentation of predetermined target stimuli. Pressing a button usually registers a participant’s reaction and the time recorded is known as the reaction time (RT).

Target stimuli can be presented at regular or varying frequency and in isolation or together with other distractor stimuli. Sustained attention is typically studied on tasks where target stimuli are presented with regular frequency and in isolation. Selective attention is studied on tasks where target stimuli are presented together with distractor

stimuli. A measure of accuracy is usually calculated and this can vary from the basic percentage of correct responses to more sophisticated measures that take into account incorrect responses on non-targets (false recognition). We will look into the details of measuring accuracy in the methods section (§3.9.1.3).

The increased cognitive effort required during divided attention results in a dual-task decrement, evident as slower RT and/or decreased accuracy (Posner, 1978).

An example of such a divided attention task involves serial visual search of a series of images and responses to predetermined target images, and simultaneous serial auditory search of words or tones with responses to target stimuli.

Recent functional neuroimaging studies have identified three attention related neural networks, each responsible for a different attentional function (Fan et al., 2005;

Posner, 2004; Posner et al., 2000; Wang and Fan, 2007). These functions include alerting, orienting and executive control. Understanding each of these functions and the network that underpins them will inform the discussion of our functional

neuroimaging results and we will look at them in turn.

Alerting achieves and maintains a heightened state of arousal in preparation for a tasks, it is underpinned by a network which includes thalamic nuclei, frontal and parietal cortices. Orienting selectively focuses attention on single or multiple items among distracters, it relies on a network that includes the parietal lobes, frontal eye fields, superior colliculi, and thalamus (pulvinar). Executive control monitors and resolves conflicts in planning and decision-making, it contributes to error detection, and it inhibits automatic execution of habitual actions; it relies on a network that includes the PFC, anterior cingulate, supplementary motor area and basal ganglia.

Varying contributions from these functions seem to underpin the attentional capacities referred to earlier (selective, divided, sustained) so whereas divided attention may

make heavy demands on all three capacities, selective attention will require less orienting and executive control. We next look at the findings from studies of attention in AMCI.