Heidi M. Bonnici

Increased Prefrontal Gyrification in a Large High-Risk Cohort Characterizes Those Who Develop Schizophrenia and Reflects Abnormal Prefrontal Development

BACKGROUND In our cohort considered at high risk (HR) of developing schizophrenia, we previously found a significant difference in extent of right prefrontal cortical folding between those who subsequently developed schizophrenia and a matched group who remained well. This study aimed to determine if this preexisting difference distinguished 17 individuals who developed schizophrenia from the 128 HR individuals in the cohort who remained well and to explore possible underlying differences in cortical composition. METHODS Prefrontal cortical folding was measured by an automated version of the Gyrification Index (A-GI), a ratio reflecting extent of folding. Multivariate logistic regression assessed the probability that prefrontal A-GI predicts diagnostic outcome and subsequently assessed the effect on A-GI of regional cerebrospinal fluid and gray and white matter. RESULTS High-risk individuals who subsequently developed schizophrenia were distinguished from the remaining cohort by increased right prefrontal cortex (PFC) A-GI. Mean right PFC gray matter volume also differed between groups, but white matter volume did not. Correlations of age with gray and white matter further distinguished groups and a linear regression analysis showed a significant interaction between age and diagnosis on mean volume of right PFC white matter. CONCLUSIONS Increased A-GI appears to indicate abnormal right prefrontal development in those who develop schizophrenia.

Pre-frontal lobe gyrification index in schizophrenia, mental retardation and comorbid groups:an automated study

In this paper, we describe the application of an automated method of calculating Gyrification Index (GI) - the Automated GI (A-GI) - to a total of 95 age-matched and sex-matched patients with mental retardation, schizophrenia, comorbid mental retardation and schizophrenia and controls. The results given by the A-GI program show that subjects with mental retardation possessed the lowest GI values in the pre-frontal lobes, with comorbid and schizophrenia groups being midway between this and the controls. The results showed no significant difference in pre-frontal gyrification between the schizophrenia and the comorbid groups. Although the four groups showed a similar pattern of (spatial) differences in terms of pre-frontal lobe volume, this did not solely account for the differences in A-GI. A significant negative correlation between GI and age was also observed across all four groups. These findings suggest that people with schizophrenia have reduced pre-frontal cortical folding regardless of whether or not they have low IQ. Previous studies in the same cohort have suggested that individuals comorbid for schizophrenia and mental retardation may in fact suffer from severe schizophrenia which has led to their low IQ. The pattern of differences observed in the current study supports this view.

Decoding Information in the Human Hippocampus: A User's Guide.

Multi-voxel pattern analysis (MVPA), or ‘decoding’, of fMRI activity has gained popularity in the neuroimaging community in recent years. MVPA differs from standard fMRI analyses by focusing on whether information relating to specific stimuli is encoded in patterns of activity across multiple voxels. If a stimulus can be predicted, or decoded, solely from the pattern of fMRI activity, it must mean there is information about that stimulus represented in the brain region where the pattern across voxels was identified. This ability to examine the representation of information relating to specific stimuli (e.g., memories) in particular brain areas makes MVPA an especially suitable method for investigating memory representations in brain structures such as the hippocampus. This approach could open up new opportunities to examine hippocampal representations in terms of their content, and how they might change over time, with aging, and pathology. Here we consider published MVPA studies that specifically focused on the hippocampus, and use them to illustrate the kinds of novel questions that can be addressed using MVPA. We then discuss some of the conceptual and methodological challenges that can arise when implementing MVPA in this context. Overall, we hope to highlight the potential utility of MVPA, when appropriately deployed, and provide some initial guidance to those considering MVPA as a means to investigate the hippocampus.

Representations of Recent and Remote Autobiographical Memories in Hippocampal Subfields

The hippocampus has long been implicated in supporting autobiographical memories, but little is known about how they are instantiated in hippocampal subfields. Using high‐resolution functional magnetic resonance imaging (fMRI) combined with multivoxel pattern analysis we found that it was possible to detect representations of specific autobiographical memories in individual hippocampal subfields. Moreover, while subfields in the anterior hippocampus contained information about both recent (2 weeks old) and remote (10 years old) autobiographical memories, posterior CA3 and DG only contained information about the remote memories. Thus, the hippocampal subfields are differentially involved in the representation of recent and remote autobiographical memories during vivid recall.

CA3 size predicts the precision of memory recall

Significance How does the brain allow us to recall numerous life experiences despite there often being a high degree of similarity between memories? This is a key question in neuroscience. Moreover, there is also keen interest in understanding why some people are able to recall memories with greater clarity than other people. In this study, we identified a specific brain region, CA3, an area within a structure called the hippocampus, and a mechanism within it that helps to explain individual differences in recollection. These findings have relevance for all of us in elucidating memory muddles in general, in aging, and possibly also in conditions such as dementia, where confusion about the past is often evident. There is enduring interest in why some of us have clearer memories than others, given the substantial individual variation that exists in retrieval ability and the precision with which we can differentiate past experiences. Here we report novel evidence showing that variation in the size of human hippocampal subfield CA3 predicted the amount of neural interference between episodic memories within CA3, which in turn predicted how much retrieval confusion occurred between past memories. This effect was not apparent in other hippocampal subfields. This shows that subtle individual differences in subjective mnemonic experience can be accurately gauged from measurable variations in the anatomy and neural coding of hippocampal region CA3. Moreover, this mechanism may be relevant for understanding memory muddles in aging and pathological states.

Obesity and insulin resistance are associated with reduced activity in core memory regions of the brain

ABSTRACT Increasing research in animals and humans suggests that obesity may be associated with learning and memory deficits, and in particular with reductions in episodic memory. Rodent models have implicated the hippocampus in obesity‐related memory impairments, but the neural mechanisms underlying episodic memory deficits in obese humans remain undetermined. In the present study, lean and obese human participants were scanned using fMRI while completing a What‐Where‐When episodic memory test (the “Treasure‐Hunt Task”) that assessed the ability to remember integrated item, spatial, and temporal details of previously encoded complex events. In lean participants, the Treasure‐Hunt task elicited significant activity in regions of the brain known to be important for recollecting episodic memories, such as the hippocampus, angular gyrus, and dorsolateral prefrontal cortex. Both obesity and insulin resistance were associated with significantly reduced functional activity throughout the core recollection network. These findings indicate that obesity is associated with reduced functional activity in core brain areas supporting episodic memory and that insulin resistance may be a key player in this association. HIGHLIGHTSObesity associated with reduced activity in core recollection network during episodic memory.Insulin resistance associated with reduced activity in core recollection network during episodic memory.Insulin resistance, but not obesity, associated with poorer memory performance.

Assessing hippocampal functional reserve in temporal lobe epilepsy: A multi-voxel pattern analysis of fMRI data

Summary Assessing the functional reserve of key memory structures in the medial temporal lobes (MTL) of pre-surgical patients with intractable temporal lobe epilepsy (TLE) remains a challenge. Conventional functional MRI (fMRI) memory paradigms have yet to fully convince of their ability to confidently assess the risk of a post-surgical amnesia. An alternative fMRI analysis method, multi-voxel pattern analysis (MVPA), focuses on the patterns of activity across voxels in specific brain regions that are associated with individual memory traces. This method makes it possible to investigate whether the hippocampus and related structures contralateral to any proposed surgery are capable of laying down and representing specific memories. Here we used MVPA-fMRI to assess the functional integrity of the hippocampi and MTL in patients with long-standing medically refractory TLE associated with unilateral hippocampal sclerosis (HS). Patients were exposed to movie clips of everyday events prior to scanning, which they subsequently recalled during high-resolution fMRI. MTL structures were delineated and pattern classifiers were trained to learn the patterns of brain activity across voxels associated with each memory. Predictable patterns of activity across voxels associated with specific memories could be detected in MTL structures, including the hippocampus, on the side contralateral to the HS, indicating their functional viability. By contrast, no discernible memory representations were apparent in the sclerotic hippocampus, but adjacent MTL regions contained detectable information about the memories. These findings suggest that MVPA in fMRI memory studies of TLE can indicate hippocampal functional reserve and may be useful to predict the effects of hippocampal resection in individual patients.

Representations of specific acoustic patterns in the auditory cortex and hippocampus

Previous behavioural studies have shown that repeated presentation of a randomly chosen acoustic pattern leads to the unsupervised learning of some of its specific acoustic features. The objective of our study was to determine the neural substrate for the representation of freshly learnt acoustic patterns. Subjects first performed a behavioural task that resulted in the incidental learning of three different noise-like acoustic patterns. During subsequent high-resolution functional magnetic resonance imaging scanning, subjects were then exposed again to these three learnt patterns and to others that had not been learned. Multi-voxel pattern analysis was used to test if the learnt acoustic patterns could be ‘decoded’ from the patterns of activity in the auditory cortex and medial temporal lobe. We found that activity in planum temporale and the hippocampus reliably distinguished between the learnt acoustic patterns. Our results demonstrate that these structures are involved in the neural representation of specific acoustic patterns after they have been learnt.

Two years later - Revisiting autobiographical memory representations in vmPFC and hippocampus

ABSTRACT A long‐standing question in memory neuroscience concerns how and where autobiographical memories of personal experiences are represented in the brain. In a previous high resolution multivoxel pattern analysis fMRI study, we examined two week old (recent) and ten year old (remote) autobiographical memories (Bonnici et al., 2012, J. Neurosci. 32:16982–16991). We found that remote memories were particularly well represented in ventromedial prefrontal cortex (vmPFC) compared to recent memories. Moreover, while both types of memory were represented within anterior and posterior hippocampus, remote memories were more easily distinguished in the posterior portion. These findings suggested that a change of some kind had occurred between two weeks and ten years in terms of where autobiographical memories were represented in the brain. In order to examine this further, here participants from the original study returned two years later and recalled the memories again. We found that there was no difference in the detectability of memory representations within vmPFC for the now 2 year old and 12 year old memories, and this was also the case for the posterior hippocampus. Direct comparison of the two week old memories (original study) with themselves two years later (present study) confirmed that their representation within vmPFC had become more evident. Overall, this within‐subjects longitudinal fMRI study extends our understanding of autobiographical memory representations by allowing us to narrow the window within which their consolidation is likely to occur. We conclude that after a memory is initially encoded, its representation within vmPFC has stablised by, at most, two years later. HighlightsWe studied patterns of fMRI activity associated with autobiographical memories.We focussed in particular on vmPFC and posterior hippocampus.These brain regions preferentially supported remote autobiographical memories.Our longitudinal study showed this effect was apparent two years after encoding.A memory was supported by different neural populations in the hippocampus as it aged.

Goal-directed mechanisms that constrain retrieval predict subsequent memory for new “foil” information

To remember a previous event, it is often helpful to use goal-directed control processes to constrain what comes to mind during retrieval. Behavioral studies have demonstrated that incidental learning of new “foil” words in a recognition test is superior if the participant is trying to remember studied items that were semantically encoded compared to items that were non-semantically encoded. Here, we applied subsequent memory analysis to fMRI data to understand the neural mechanisms underlying the “foil effect”. Participants encoded information during deep semantic and shallow non-semantic tasks and were tested in a subsequent blocked memory task to examine how orienting retrieval towards different types of information influences the incidental encoding of new words presented as foils during the memory test phase. To assess memory for foils, participants performed a further surprise old/new recognition test involving foil words that were encountered during the previous memory test blocks as well as completely new words. Subsequent memory effects, distinguishing successful versus unsuccessful incidental encoding of foils, were observed in regions that included the left inferior frontal gyrus and posterior parietal cortex. The left inferior frontal gyrus exhibited disproportionately larger subsequent memory effects for semantic than non-semantic foils, and significant overlap in activity during semantic, but not non-semantic, initial encoding and foil encoding. The results suggest that orienting retrieval towards different types of foils involves re-implementing the neurocognitive processes that were involved during initial encoding.