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Although electroconvulsive therapy (ECT) is a widely used and effective treatment for refractory depression, the neural underpinnings of its therapeutic effects remain poorly understood. To address this issue, here, we focused on a core cognitive deficit associated with depression, which tends to be reliably ameliorated through ECT, specifically, the ability to learn visuospatial information. Thus, we pursued three goals. First, we tested whether ECT can "normalize" the functional brain organization patterns associated with visuospatial memory and whether such corrections would predict post-ECT improvements in learning visuospatial information. Second, we investigated whether, among healthy individuals, stronger expression of the neural pattern, susceptible to adjustments through ECT, would predict reduced incidence of depression-relevant cognition and affect. Third, we sought to quantify the heritability of the ECT-correctable neural profile. Thus, in a task fMRI study with a clinical and a healthy comparison sample, we characterized two functional connectome patterns: one that typifies trait depression (i.e., differentiates patients from healthy individuals) and another that is susceptible to "normalization" through ECT. Both before and after ECT, greater expression of the trait depression neural profile was associated with more frequent repetitive thinking about past personal events (affective persistence), a hallmark of depressogenic cognition. Complementarily, post-treatment, stronger expression of the ECT-corrected neural profile was linked to improvements in visuospatial learning, a mental ability which is markedly impaired in depression. Subsequently, using data from the Human Connectome Project (HCP) (N = 333), we demonstrated that the functional brain organization of healthy participants with greater levels of subclinical depression and higher incidence of its associated cognitive deficits (affective persistence, impaired learning) shows greater similarity

The hippocampus (HC) interacts with distributed brain regions to support memory and shows significant volume reductions in aging, but little is known about age effects on hippocampal whole-brain structural covariance. It is also unclear whether the anterior and posterior HC show similar or distinct patterns of whole-brain covariance and to what extent these are related to memory functions organized along the hippocampal longitudinal axis. Using the multivariate approach partial least squares, we assessed structural whole-brain covariance of the HC in addition to regional volume, in young, middle-aged and older adults (n = 221), and assessed associations with episodic and spatial memory. Based on findings of sex differences in both memory and brain aging, we further considered sex as a potential modulating factor of age effects. There were two main covariance patterns: one capturing common anterior and posterior covariance, and one differentiating the two regions by capturing anterior-specific covariance only. These patterns were differentially related to associative memory while unrelated to measures of single-item memory and spatial memory. Although patterns were qualitatively comparable across age groups, participants' expression of both patterns decreased with age, independently of sex. The results suggest that the organization of hippocampal structural whole-brain covariance remains stable across age, but that the integrity of these networks decreases as the brain undergoes age-related alterations.

Knowledge concerning the normal aging of cerebral white matter will improve our understanding of abnormal changes in neurodegenerative diseases. The microstructural basis of white matter maturation and aging can be investigated using diffusion tensor imaging (DTI). Generally, diffusion anisotropy increases during childhood and adolescence followed by a decline in middle age. However, this process is subject to spatial variations between tracts. The aim of this study was to investigate to what extent age-related variations also occur within tracts. DTI parameters were compared between segments of two white matter tracts, the cingulate bundle (CB) and the inferior fronto-occipital fasciculus (IFO), in 257 healthy individuals between 13 and 84years of age. Segments of the CB and the IFO were extracted and parameters for each segment were averaged across the hemispheres. The data was analysed as a function of age. Results show that age-related changes differ both between and within individual tracts. Different age trajectories were observed in all segments of the analysed tracts for all DTI parameters. In conclusion, aging does not affect white matter tracts uniformly but is regionally specific; both between and within white matter tracts.

Studying memory in infants can be challenging, as they cannot express their subjective recollection verbally. In this study we use a novel method with which we can assess episodic recognition memory through pupillometry, using identical procedures and stimuli for infants and adults. In three experiments of 4- and 7-month-old infants, and adults we show that the adult pupillary response is larger to previously seen than to never seen items (old/new effect). Pupil dilations index subjective memory experience in adults, producing distinct pupil dilations to items judged as remembered, familiar, and new, regardless of actual previous exposure (Experiment 1). Seven-month-old infants demonstrate a clear pupillary old/new effect, very similar to that of adults (Experiment 2), whereas 4-month-olds do not demonstrate such an effect (Experiment 3). Our findings suggest that the mnemonic mechanisms that serve infants' and adults' episodic recognition memory are more similar than previously asserted: they are not fully developed at 4 months of age but that there is contiguity in human episodic memory development from 7 months of age.

fMRI studies have identified distinct resting-state functional connectivity (RSFC) networks associated with the anterior and posterior hippocampus. However, the functional relevance of these two networks is still largely unknown. Hippocampal lesion studies and task-related fMRI point to a role for the anterior hippocampus in non-spatial episodic memory and the posterior hippocampus in spatial memory. We used Relevance Vector Regression (RVR), a machine-learning method that enables predictions of continuous outcome measures from multivariate patterns of brain imaging data, to test the hypothesis that patterns of whole-brain RSFC associated with the anterior hippocampus predict episodic memory performance, while patterns of whole-brain RSFC associated with the posterior hippocampus predict spatial memory performance. Magnetic resonance imaging (MRI) and memory assessment took place at two separate occasions. The anterior and posterior RSFC largely corresponded with previous findings, and showed no effect of laterality. Supporting the hypothesis, RVR produced accurate predictions of episodic performance from anterior, but not posterior, RSFC, and accurate predictions of spatial performance from posterior, but not anterior, RSFC. In contrast, a univariate approach could not predict performance from resting-state connectivity. This supports a functional dissociation between the anterior and posterior hippocampus, and indicates a multivariate relationship between intrinsic functional networks and cognitive performance within specific domains, that is relatively stable over time.

The anterior hippocampus has been implicated in associative memory, and along with hippocampal volume, this type of memory declines with age. However, few cross-sectional studies include middle-aged samples, making it unclear at what point these age-related changes occur. In addition, although men and women have been shown to differ in associative memory and rates of age-related hippocampal atrophy, sex-differences in aging are rarely studied. To address these issues, we assessed memory for word-pairs, hippocampal volume and activation during encoding and retrieval, across middle-aged (n=39) and older (n=44) participants, specifically in relation to sex. Older adults showed significantly poorer associative memory compared to middle-aged adults, paralleled by smaller anterior hippocampi and less activation during successful retrieval. The age-by-sex interaction observed in memory performance was also mirrored in the volume and activation of the hippocampus, indicating more pronounced age-effects in men as compared to women. These results indicate a specific role of the anterior hippocampus in verbal associative memory and suggest they both decline between middle-age and older age.

Apolipoprotein E (APOE) ε4 has been associated with smaller hippocampal volumes in healthy aging, while findings in young adults are inconclusive. Previous studies have mostly used univariate methods, and without considering potential anterior/posterior differences. Here, we used a multivariate method, partial least squares, and assessed whole-brain structural covariance of the anterior (aHC) and posterior (pHC) hippocampus in young adults (n = 97) as a function of APOE ε4 status and sex. Two significant patterns emerged: 1) specific structural covariance of the aHC with frontal regions, temporal and occipital areas in APOE ε4 women, whereas the volume of both the aHC and pHC in all other groups co-varied with frontal, parietal and cerebellar areas; and 2) opposite structural covariance of the pHC in ε4 carriers compared to the aHC in non-carriers, with the pHC of ε4 carriers covarying with parietal and frontal areas, and the aHC of ε4 non-carriers covarying with motor areas and the middle frontal gyrus. APOE ε4 has in young adults been associated with better episodic and spatial memory, functions involving the aHC and pHC, respectively. We found no associations between structural covariance and performance, suggesting that other factors underlie the performance differences seen between carriers and non-carriers. Our findings indicate that APOE ε4 carriers and non-carriers differ in hippocampal organization and that there are differences as a function of sex and hippocampal segment. They stress the need to consider the hippocampus as a heterogeneous structure, and highlight the benefits of multivariate methods in assessing group differences in the brain.

The apolipoprotein E (APOE) ϵ4 allele is known to be a major genetic risk factor for Alzheimer's disease (AD). It has been linked to especially episodic memory decline and hippocampal atrophy in both healthy and demented elderly populations. In young adults, ϵ4 carriers have shown better performance in episodic memory compared to non-carriers. Spatial memory, however, has not been thoroughly assessed in relation to APOE in spite of its dependence on the hippocampus. In this study, we assessed the effect of APOE genotype on a variety of spatial and episodic memory tasks as well as hippocampal volume assessed through manual tracing in a sample of young adults (N=123). We also assessed whether potential effects were modulated by sex. The presence of one or more ϵ4 alleles had positive effects on spatial function and memory and object location memory, but no effect on word recognition. Men were superior to women in spatial function and memory but there were no sex differences in the other tasks. In spite of APOE ϵ4 carriers having superior performance in several memory tasks, no difference was found as a function of APOE genotype in hippocampal volume. To our knowledge, this study is the first to show that APOE ϵ4 has a positive effect on spatial ability in young adults.

While there is ample evidence that the hippocampus is functionally heterogeneous along its longitudinal axis, there is still no consensus regarding its exact organization. Whereas spatial memory tasks frequently engage the posterior hippocampus, the regions engaged during episodic memory are more varying and may depend on the specific nature of the stimuli. Here, we investigate the effect of stimulus content on the location of hippocampal recruitment during episodic memory encoding and retrieval of pictorial and verbal material with a meta-analysis approach, using activation likelihood estimation and restricting the analysis to the hippocampus. Verbal material was associated with left-lateralized anterior activation, compared to pictorial material that recruited a more posterior aspect of the hippocampus, primarily within the right hemisphere. This effect held for encoding of both single items and item-item associations but was less clear during retrieval. The findings lend further support to a functional subdivision of the hippocampus along its longitudinal axis and indicate that the content of episodic memories is one factor that determines the location of hippocampal recruitment.

We investigated the individual and combined effects of enactment and testing on memory for action phrases to address whether both study techniques commonly promote item-specific processing. Participants (N = 112) were divided into four groups (n = 28). They either exclusively studied 36 action phrases (e.g., "lift the glass") or both studied and cued-recalled them in four trials. During study trials participants encoded the action phrases either by motorically performing them, or by reading them aloud, and they took final verb-cued recall tests over 18-min and 1-week retention intervals. A testing effect was demonstrated for action phrases, however, only when they were verbally encoded, and not when they were enacted. Similarly, enactive (relative to verbal) encoding reduced the rate of forgetting, but only when the action phrases were exclusively studied, and not when they were also tested. These less-than-additive effects of enactment and testing on the rate of forgetting, as well as on long-term retention, support the notion that both study techniques effectively promote item-specific processing that can only be marginally increased further by combining them.

Sex differences in episodic and spatial memory are frequently observed, suggesting that there may be sex-related structural differences in the hippocampus (HC). Earlier findings are inconsistent, possibly due to a known variability along the hippocampal longitudinal axis. Here, we assessed potential sex differences in hippocampal volume and structural covariance with the rest of the brain in young men and women (N=76), considering the anterior (aHC) and posterior (pHC) hippocampus separately. Women exhibited a larger pHC than men adjusted for brain size. Using partial least squares, we identified two significant patterns of structural covariance of the aHC and pHC. The first included brain areas that covaried positively and negatively in volume with both the aHC and pHC in men, but showed greater covariance with the aHC than pHC in women. The second pattern revealed distinct structural covariance of the aHC and pHC that showed a clear difference between men and women: in men the pHC showed reliable structural covariance with the medial and lateral parietal lobes and the prefrontal cortex, whereas in women the aHC showed reliable structural covariance with the anterior temporal lobe bilaterally. This pattern converges with resting state functional connectivity of the aHC and pHC and suggests that these hippocampal sections interact with different brain regions, consistent with a division of labor with regards to episodic and spatial memory. Our findings lend support to a division of the HC into an anterior and posterior part and identify sex as a potential moderating factor when investigating hippocampal structure and connectivity.

Poster presented at the Cognitive Neuroscience Society Annual Meeting, Boston, USA

Gender differences in spatial memory favoring men are frequently reported, and the involvement of the hippocampus in these functions is well-established. However, little is known of whether this behavioral gender difference is mirrored in a gender difference in hippocampal function. Here we assessed hippocampal activity, using functional MRI, while 24 men and women moved through three-dimensional virtual mazes (navigation phase) of varying length, and at the end-point estimated the direction of the starting-point (pointing phase). Men were indeed more accurate than women at estimating direction, and this was especially true in longer mazes. Both genders activated the posterior hippocampus throughout the whole task. During the navigation phase, men showed a larger activation in the right hippocampus than women, while in the pointing phase, women showed a larger activation in the left hippocampus than men. Right-lateralized activation during the navigation phase was associated with greater task performance, and may reflect a spatial strategy that is beneficial in this task. Left-sided activation during the pointing phase might reflect a less efficient post hoc verbal recapitulation of the route. This study is the first to identify neural correlates of the commonly observed male advantage in recalling one's original position, and points to hippocampal lateralization as a possible explanation for this behavioral gender difference.

The hippocampus is crucial for episodic autobiographical memory retrieval. Functional neuroimaging evidence suggests that it is similarly engaged in recent and remote retrieval when memories are matched on vividness and personal importance. Far fewer studies have investigated the nature of hippocampal-neocortical coactivation in relation to memory remoteness. The purpose of this study was to examine hippocampal activity and functional connectivity as a function of memory age. Unlike most studies of autobiographical memory, we included autobiographical memories formed in the days and weeks before scanning, in addition to truly remote memories on the order of months and years. Like previous studies, we found that the hippocampus was active bilaterally regardless of memory age, with anterior activity increasing up to 1 yr and then decreasing, and with posterior activity being less sensitive to memory age. More importantly, hippocampal functional connectivity varied with memory age. Retrieving recent memories (=1 yr) showed a late coactivation of the hippocampus and areas of the autobiographical memory network, whereas retrieving remote memories (10 yrs) showed an early negative coactivation of the hippocampus and left inferior frontal gyrus followed by a positive coactivation with anterior cingulate. This finding may reflect that the hippocampus is more strongly integrated with the autobiographical memory network for recent than for remote memories, and that more effort is required to recover remote memories.

The aging, non-demented brain undergoes several physiological changes, some of which may and some of which may not affect cognitive function. The goal of the present study was to examine the effects of subcortical and periventricular white matter hyperintensities (WMHs), and cortical and subcortical atrophy on cognitive function (episodic and semantic memory, attention, and perceptual, cognitive, and motor speed). This was done within a European collaborative study, CASCADE (Cardiovascular Determinants of Dementia), in which Magnetic Resonance Imaging (MRI) was performed on community-dwelling individuals. The study includes 1,254 persons from eight European study centers, ranging between 64 and 76 years of age (M 69.4 + 3.3; 55% men). When demographics (age, education, and sex), study center, and concurrent brain changes had been adjusted for, periventricular WHMS predicted lower performance in motor speed and Stroop (errors). The findings are consistent with findings from lesion and functional neuroimaging studies.

This paper presents the cognitive test battery used in the CASCADE Study (Cardiovascular Determinants of Dementia) for examining the consequences of cerebral white matter lesions and atrophy. The test battery includes nine different tasks assessing memory, executive function, and global cognitive function. Three episodic memory tasks were used in combinations to assess the role of attention and speed on encoding. Estimates of short- and long-term memory capacity were also derived from these three memory tasks. Semantic memory production / frontal lobe functions were assessed by means of a word fluency test. The Letter Digit Substitution test and the Stroop test were used to assess speed of processing and attention. Motor speed was measured with the Purdue Pegboard test, and global cognitive function was assessed by the Mini Mental State Examination. Overall performance data for the whole CASCADE sample and for each of eight study centers are presented for each test. Possible reasons for performance differences among study centers are discussed.

Härtill 4 uppsatser.

Functional connectivity across large-scale brain networks alters in older age and changes are often associated with memory decline. Studies assessing hippocampal resting-state functional connectivity (rsFC), however, rarely consider the anterior and posterior hippocampus separately, although evidence suggests they are part of two distinct networks differentially supporting memory. While only a limited number of studies have considered age effects on axis-related hippocampal connectivity, findings suggest that rsFC of the two regions display differential effects of age. Reports on the link between such effects and memory are however inconclusive, and previous findings mainly concern episodic memory, ignoring spatial memory also dependent on the hippocampus. Here, we therefore assessed age effects on axis-related hippocampal rsFC, accounting for associations with both episodic and spatial memory in young, middle-aged and older adults (n=194). The anterior and posterior hippocampus showed different age-related decreases in connectivity assessed across middle and older age, but common to the regions was a decreased coupling with the medial orbitofrontal cortex. Only connectivity between the posterior hippocampus and the lingual gyrus increased as a function of age, displaying negative associations with episodic memory. In contrast, the region’s connectivity with the insula, decreasing with age, was positively related to spatial memory. Consistent with previous reports, our findings indicate that hippocampal rsFC vary with age in an axis-dependent manner, and further add to the knowledge on this differentiation’s relevance to memory by showing that age-related rsFC of the anterior and posterior hippocampus is differentially associated with episodic and spatial memory.