Functional segmentation of the hippocampus in the healthy human brain and in Alzheimer's disease
Highlights
► Human hippocampus can be divided into 3 regions, based on functional connectivity. ► Hippocampal functional connectivity changes in Alzheimer's disease. ► Changes in the functional connectivity correlates with the episodic memory.
Introduction
Studies in animals show that the hippocampus can be anatomically and functionally segmented into distinct subregions along its ventrodorsal axis in rat which is equivalent to the anterio-posterior axis in primates (Fanselow and Dong, 2010). Human studies suggest an anterior–posterior subdivision of cognitive functional domains in the hippocampus (Dong et al., 2009, Greicius et al., 2003a, Maguire et al., 1997, Moser and Moser, 1998).
Anatomical studies using anterograde or retrograde neural tracing have demonstrated that the hippocampus has direct connections with the anterior and ventromedial nuclei of the thalamus in both rodents and primates (Amaral and Cowan, 1980, Parvizi et al., 2006, van Groen et al., 1999). We previously demonstrated similar connections in human brain using probabilistic diffusion tensor tractography (Zarei et al., 2010). The connection of the hippocampus with PFC via the parahippocampus and entorhinal cortex in monkey has been also reported using invasive neural tracing techniques (Carmichael and Price, 1995, Insausti et al., 1987, Lavenex et al., 2002, Morris et al., 1999, Suzuki and Amaral, 1994). The posterior cingulate cortex (Lavenex et al., 2002, Morris et al., 1999, Parvizi et al., 2006, Suzuki and Amaral, 1994, van Groen et al., 1999) and posterior parietal cortex (Lavenex et al., 2002, Mesulam et al., 1977) also are connected with hippocampus via parahippocampal gyrus and entorhinal cortex.
FMRI studies have identified several so-called resting state networks (RSNs), defined as brain regions displaying high temporal correlations in spontaneous changes of the BOLD signal of the unstimulated, resting brain (Beckmann et al., 2005, Damoiseaux et al., 2009, Fox et al., 2005, Raichle, 2010). One well-known network is known as the “default mode network” (DMN) (Biswal et al., 1995, Cordes et al., 2001) which includes the PCC, precuneus and anterior cingulate, medial prefrontal and lateral parietal cortices as well as the hippocampus and thalamus (Greicius et al., 2009). The DMN is characterized by correlated BOLD signal reductions during the performance of cognitive tasks relative to the resting state (Greicius et al., 2003b, Greicius et al., 2004, Raichle et al., 2001).
A resting state functional connectivity study revealing two separate brain networks correlated with distinct subregions within the medial temporal region suggested that connectivity might be able to be used to functionally parcellate the hippocampus (Kahn et al., 2008). These authors showed that activity in the body of hippocampus and posterior parahippocampal gyrus correlated with the activity in lateral parietal cortex, posterior cingulate, retrosplenial cortex, and ventral medial prefrontal cortex, while resting BOLD signal in the anterior hippocampus and the perirhinal/entorhinal cortices correlated with the lateral temporal cortex extending into the temporal pole. Functional parcellation of the human thalamus (Zhang et al., 2008) and cerebellum (O'Reilly et al., 2009) has been possible using these methods.
Such work may be relevant to relating structural, functional and behavioral pathologies in AD. Several studies have shown changes of functional connectivity between structures that are part of the DMN in earlier stages of AD (Greicius et al., 2004, Sorg et al., 2007, Wang et al., 2006, Zhang et al., 2009). For example, reduced functional connectivity between the right hippocampus and medial PFC, ventral anterior cingulate cortex and PCC, as well as an increase of functional connectivity between the left hippocampus and the right lateral PFC were reported (Stein et al., 2000, Wang et al., 2006).
In this study we tested: 1) if the human hippocampus can be segmented into distinct subregions based on relative patterns of functional connectivity in the “resting state”; 2) if connectivity pattern of the hippocampal subregions changes in AD; and, 3) if the magnitude of change in regional functional connectivity of the hippocampus can be related with cognitive impairment in AD.
Section snippets
Subjects
MR images were obtained from two groups of right-handed subjects: 22 old healthy subjects without memory complaints (age 70.7 ± 6.0, range 60 to 81 years; MMSE 28.7 ± 1.4; 13 females), and 16 patients with mild Alzheimer's disease (AD) (age 69.5 ± 6.9 years, range 59 to 79 years; MMSE 22.9 ± 3.2; 8 females). Patients were recruited at the Alzheimer Center of the VU University Medical Center, Amsterdam, the Netherlands. Diagnostic criteria of AD were that of NINCDS-ADRDA (McKhann et al., 1984), with MMSE
Results
Demographic and neuropsychological data of patients and control groups have previously been reported (Damoiseaux et al., 2009). Both groups had similar demographic characteristics in terms of age, gender and educational level. As expected, AD subjects performed significantly worse in neuropsychological tests than the control group (see Table 1).
Discussion
In this study, we have shown that the hippocampus can be functionally divided into three distinguishable subregions (head, body and tail) according to the dominant functional connectivity in resting state fMRI data with large grey matter ROIs defined anatomically to include the PFC, PCC and thalamus, respectively. To the best of our knowledge this is the first report of anatomical segmentation of the hippocampus based on functional connectivities to other brain regions in humans in vivo.
A
Conclusions
We conclude that the human hippocampus consists of three functionally distinct regions in which resting state activity is correlated with activities in the thalamus, the prefrontal cortex and posterior cingulate cortex. Relative changes in the coordinated activities across this system, characterized by increased functional connectivity between the PFC and the hippocampus, and decreased functional connectivity between the PCC and the hippocampus, is seen in early AD. These changes correlated
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