Sinéad L. Mullally

Aerobic exercise improves hippocampal function and increases BDNF in the serum of young adult males.

Physical activity has been reported to improve cognitive function in humans and rodents, possibly via a brain-derived neurotrophic factor (BDNF)-regulated mechanism. In this study of human subjects, we have assessed the effects of acute and chronic exercise on performance of a face-name matching task, which recruits the hippocampus and associated structures of the medial temporal lobe, and the Stroop word-colour task, which does not, and have assessed circulating concentrations of BDNF and IGF-1 in parallel. The results show that a short period of high-intensity cycling results in enhancements in performance of the face-name matching, but not the Stroop, task. These changes in cognitive function were paralleled by increased concentration of BDNF, but not IGF-1, in the serum of exercising subjects. 3 weeks of cycling training had no effect on cardiovascular fitness, as assessed by VO2 scores, cognitive function, or serum BDNF concentration. Increases in fitness, cognitive function and serum BDNF response to acute exercise were observed following 5 weeks of aerobic training. These data indicate that both acute and chronic exercise improve medial temporal lobe function concomitant with increased concentrations of BDNF in the serum, suggesting a possible functional role for this neurotrophic factor in exercise-induced cognitive enhancement in humans.

The Hippocampus: A Manifesto for Change

We currently lack a unified and mechanistic account of how the hippocampus supports a range of disparate cognitive functions that includes episodic memory, imagining the future, and spatial navigation. Here, we argue that in order to leverage this long-standing issue, traditional notions regarding the architecture of memory should be eschewed. Instead, we invoke the idea that scenes are central to hippocampal information processing. This view is motivated by mounting evidence that the hippocampus is constantly constructing spatially coherent scenes, automatically anticipating and synthesizing representations of the world beyond the immediate sensorium. By characterizing the precise relationship between scenes and the hippocampus, we believe a theoretically enriched understanding of its fundamental role and its breakdown in pathology can emerge.

A New Role for the Parahippocampal Cortex in Representing Space

The debate surrounding the function of the human posterior parahippocampal cortex (PHC) is currently dominated by two competing theories. The spatial layout hypothesis proposes that PHC processes information about the shape of space embodied in layout-defining scene features. The contextual association hypothesis rejects this notion, proposing instead that PHC responds to highly contextualized, but not necessarily spatial, stimuli. Here we present a novel concept that suggests PHC is primarily concerned with any representation that depicts three-dimensional local space, be it scenes or even single objects. Specifically, we identified space-defining (SD) and space-ambiguous (SA) single objects, where SD objects consistently evoke a strong sense of the surrounding space while SA objects do not, in the absence of any background, spatial layout, or context. We found that participants could easily identify and distinguish between SD and SA objects. This distinction was subsequently affirmed at a neural level, where visualizing or viewing single SD objects compared with SA objects engaged PHC, despite these single SD objects offering no information about the shape or layout of the space. Moreover, this PHC response was robust and not accounted for by other factors, including contextual associations. Instead, it was linked to intrinsic object properties, specifically a combination of perceived object size and portability. By showing that PHC is responsive to the awareness of surrounding local space suggests its role in scene processing is basic and fundamental, such that it is not dependent on complex scene properties such as geometric structure, scene schema, or contextual associations.

Retrosplenial Cortex Codes for Permanent Landmarks

Landmarks are critical components of our internal representation of the environment, yet their specific properties are rarely studied, and little is known about how they are processed in the brain. Here we characterised a large set of landmarks along a range of features that included size, visual salience, navigational utility, and permanence. When human participants viewed images of these single landmarks during functional magnetic resonance imaging (fMRI), parahippocampal cortex (PHC) and retrosplenial cortex (RSC) were both engaged by landmark features, but in different ways. PHC responded to a range of landmark attributes, while RSC was engaged by only the most permanent landmarks. Furthermore, when participants were divided into good and poor navigators, the latter were significantly less reliable at identifying the most permanent landmarks, and had reduced responses in RSC and anterodorsal thalamus when viewing such landmarks. The RSC has been widely implicated in navigation but its precise role remains uncertain. Our findings suggest that a primary function of the RSC may be to process the most stable features in an environment, and this could be a prerequisite for successful navigation.

Evidence for a Specific Defect in Hippocampal Memory in Overt and Subclinical Hypothyroidism

CONTEXT Declarative memory largely depends upon normal functioning temporal lobes (hippocampal complex) and prefrontal cortex. Animal studies suggest abnormal hippocampal function in hypothyroidism. OBJECTIVE The aim of the study was to assess declarative memory in overt and subclinical (SCH) hypothyroid patients before and after l-T(4) (LT4) replacement and in matched normal subjects. DESIGN AND SETTING A prospective, open-labeled interventional study was conducted at a teaching hospital. PARTICIPANTS AND INTERVENTION Hypothyroid (n = 21) and SCH (n = 17) patients underwent neuropsychological tests at baseline and 3 and 6 months after LT4 replacement. Normal subjects were studied at the same time-points. MAIN OUTCOME Tests of spatial, verbal, associative, and working memory; attention; and response inhibition and the Hospital Anxiety and Depression Scale were administered. RESULTS Baseline deficits in spatial, associative, and verbal memory, which rely upon the integrity of the hippocampal and frontal areas, were identified in patients with overt hypothyroidism. Spatial and verbal memory were impaired in SCH patients (P < 0.05). TSH levels correlated negatively (P < 0.05) with these deficits. After LT4 replacement, verbal memory normalized. Spatial memory normalized in the SCH group but remained impaired in the hypothyroid group. Associative memory deficits persisted in the overt hypothyroid group. Hospital Anxiety and Depression Scale scores did not correlate with cognitive function. Measures of attention and response inhibition did not differ from control subjects. CONCLUSION Cognitive impairment occurs in SCH and more markedly in overt hypothyroidism. These impairments appear predominantly mnemonic in nature, suggesting that the etiology is not indicative of general cognitive slowing. We propose that these deficits may reflect an underlying disruption of normal hippocampal function and/or connectivity.

Memory, Imagination, and Predicting the Future: A Common Brain Mechanism?

On the face of it, memory, imagination, and prediction seem to be distinct cognitive functions. However, metacognitive, cognitive, neuropsychological, and neuroimaging evidence is emerging that they are not, suggesting intimate links in their underlying processes. Here, we explore these empirical findings and the evolving theoretical frameworks that seek to explain how a common neural system supports our recollection of times past, imagination, and our attempts to predict the future.

Scene Construction in Amnesia: An fMRI Study

In recent years, there has been substantial interest in how the human hippocampus not only supports recollection of past experiences, but also the construction of fictitious and future events, and the leverage this might offer for understanding the operating mechanisms of the hippocampus. Evidence that patients with bilateral hippocampal damage and amnesia cannot construct novel or future scenes/events has been influential in driving this line of research forward. There are, however, some patients with hippocampal damage and amnesia who retain the ability to construct novel scenes. This dissociation may indicate that the hippocampus is not required for scene construction, or alternatively, there could be residual function in remnant hippocampal tissue sufficient to support the basic construction of scenes. Resolving this controversy is central to current theoretical debates about the hippocampus. To investigate, we used fMRI and a scene construction task to test patient P01, who has dense amnesia, ∼50% bilateral hippocampal volume loss, and intact scene construction. We found that scene construction in P01 was associated with increased activity in a set of brain areas, including medial temporal, retrosplenial, and posterior parietal cortices, that overlapped considerably with the regions engaged in control participants performing the same task. Most notably, the remnant of P01s right hippocampus exhibited increased activity during scene construction. This suggests that the intact scene construction observed in some hippocampal-damaged amnesic patients may be supported by residual function in their lesioned hippocampus, in accordance with theoretical frameworks that ascribe a vital role to the hippocampus in scene construction.

Constructing, Perceiving, and Maintaining Scenes: Hippocampal Activity and Connectivity

In recent years, evidence has accumulated to suggest the hippocampus plays a role beyond memory. A strong hippocampal response to scenes has been noted, and patients with bilateral hippocampal damage cannot vividly recall scenes from their past or construct scenes in their imagination. There is debate about whether the hippocampus is involved in the online processing of scenes independent of memory. Here, we investigated the hippocampal response to visually perceiving scenes, constructing scenes in the imagination, and maintaining scenes in working memory. We found extensive hippocampal activation for perceiving scenes, and a circumscribed area of anterior medial hippocampus common to perception and construction. There was significantly less hippocampal activity for maintaining scenes in working memory. We also explored the functional connectivity of the anterior medial hippocampus and found significantly stronger connectivity with a distributed set of brain areas during scene construction compared with scene perception. These results increase our knowledge of the hippocampus by identifying a subregion commonly engaged by scenes, whether perceived or constructed, by separating scene construction from working memory, and by revealing the functional network underlying scene construction, offering new insights into why patients with hippocampal lesions cannot construct scenes.

Learning to remember: the early ontogeny of episodic memory.

Highlights • We review literature on the ontogeny of episodic memory in the first postnatal year.• We discuss several extant points of contention.• One of which involves the status of hippocampal function.• We highlight the potential usefulness of MRI in progressing points of debate.

The hippocampus extrapolates beyond the view in scenes: An fMRI study of boundary extension

Boundary extension (BE) is a pervasive phenomenon whereby people remember seeing more of a scene than was present in the physical input, because they extrapolate beyond the borders of the original stimulus. This automatic embedding of a scene into a wider context supports our experience of a continuous and coherent world, and is therefore highly adaptive. BE, whilst occurring rapidly, is nevertheless thought to comprise two stages. The first involves the active extrapolation of the scene beyond its physical boundaries, and is constructive in nature. The second phase occurs at retrieval, where the initial extrapolation beyond the original scene borders is revealed by a subsequent memory error. The brain regions associated with the initial, and crucial, extrapolation of a scene beyond the view have never been investigated. Here, using functional MRI (fMRI) and a classic BE paradigm, we found that this extrapolation of scenes occurred rapidly around the time a scene was first viewed, and was associated with engagement of the hippocampus (HC) and parahippocampal cortex (PHC). Using connectivity analyses we determined that the HC in particular seemed to drive the BE effect, exerting top–down influence on PHC and indeed as far back down the processing stream as early visual cortex (VC). These cortical regions subsequently displayed activity profiles that tracked the trial-by-trial subjective perception of the scenes, rather than physical reality, thereby reflecting the behavioural expression of the BE error. Together our results show that the HC is involved in the active extrapolation of scenes beyond their physical borders. This information is then automatically and rapidly channelled through the scene processing hierarchy as far back as early VC. This suggests that the anticipation and construction of scenes is a pervasive and important aspect of our online perception, with the HC playing a central role.