My Hippocampus Is Bigger Than Yours!by James W. Jefferson, M.D.
Just exactly what is a hippocampus and what does it have to do with geriatric dementia and depression? According to the ancient Greeks, a hippocampus was a sea horse with the head and forequarters of a horse, and a tail and hindquarters of a fish or dolphin (Hippos
is Greek for horse and kampos
is Greek for a sea monster). Neptune, the Roman God of the sea, was said to have used a hippocampus for his mount.
Rather predictably, the name became the genus specification for those small marine fish known as sea horses (the short-snouted sea horse has the distinction of being classified as Hippocampus hippocampus). Neuroanatomists must have seen a resemblance to the sea horse when they identified a horseshoe-shaped structure in the temporal lobe of the brain. So as not to appear unprofessional, they named this structure the hippocampus rather than the sea horse.
The hippocampus (or hippocampi since there are two of them) appears to have important functions related to both memory and mood. According to one source (www.neurophys.wisc.edu), components of the hippocampus include the following: entorhinal cortex, presubiculum, subiculum, prosubiculum, dentate gyrus, and areas known as CA1, CA2, CA3 and CA4.
Since any further description of hippocampal anatomy is more likely to induce sleep than interest, I will now focus on function. The hippocampus plays a central role in spatial orientation with damage resulting in impaired ability to navigate in familiar areas. A positron emission tomography study of London cab drivers, for instance, found that the right hippocampus was activated when subjects were asked to recall complex routes to destinations, but not when recalling information about famous landmarks (Maguire et al., 1997). Consequently, when you hop into a cab at a major airport, it may be prudent to assure yourself that the driver has a functional hippocampus.
There is a decrease in hippocampal volume during the course of normal aging, but in patients with Alzheimer's dementia, the atrophy is more extreme. This may account for these individuals' well-known propensity for getting lost. In addition to the part it plays in spatial orientation, the hippocampus plays an important role in memory encoding and retrieving. Magnetic resonance imaging (MRI) studies have found bilateral reduction in hippocampal volume to be a sensitive predictor of early Alzheimer's dementia.
Hippocampal atrophy has also been observed in Cushing's syndrome, depression and posttraumatic stress disorder. Recently, Sapolsky (2000) provided an elegant discussion of hippocampal atrophy in these three conditions and the role that glucocorticoids may play in their etiology. Of particular interest was the apparent reversibility of atrophy in two studies of Cushing's syndrome following successful treatment of the condition. Consistent with this finding was a study using postmortem human brain tissue that demonstrated the ability of hippocampal neurons to regenerate (Eriksson et al., 1998).
Neurogenesis in an adult brain, particularly in the dentate gyrus of the hippocampus, is an encouraging observation of unclear clinical significance. Since glucocorticoids and stress appear to inhibit such cell growth and since environmental enrichment (Sapolsky, 2000) may promote it, it may be wise to pursue a stress-free yet intellectually and emotionally gratifying life (may the largest hippocampus win).
When it comes to depression, the role of glucocorticoids in causing hippocampal volume reduction is less clear, since hypercortisolism is not a consistent finding in depression. Sapolsky (2000) reviewed three volumetric MRI studies of patients with severe, chronic or recurrent depression that found evidence of hippocampal atrophy. Unfortunately, the one study that correlated extent of atrophy with duration of remission from depression found no indication of improvement over time. To be fair, these studies involved relatively small samples (n=10, n=24, n=16). Other studies have not found hippocampal volume changes associated with severe depression, possibly because they used less sensitive MRI equipment (Sapolsky, 2000).
Recently, a cross-sectional study of 66 depressed geriatric patients (compared to 18 nondepressed geriatric controls) found that the depressed group had smaller right (p=0.014) and left (p=0.073) hippocampal volumes (after accounting for the effects of total brain volume, age and gender) (Steffens et al., 2000). The authors concluded that these findings "suggest a role for hippocampal dysfunction in depression, particularly in late-age onset depression."
They also quite rightly pointed out limitations of the study: timing of entry vis-à-vis acuteness of depression, its cross-sectional nature, MRI sensitivity or lack thereof, the use of post-hoc analysis, substantial hippocampal volume overlap between controls and patients, and findings that were sometimes only non-specific trends.
One such trend was a negative correlation between age of onset and hippocampal volume. Since late-onset depression may well be a risk factor for Alzheimer's dementia, it is possible that this finding may be an indication of preclinical dementia rather than of depression itself (patients with clinically obvious dementia were excluded from the study). As the authors acknowledged, longitudinal studies with clinical correlations will be necessary to further unravel the role played by the hippocampus in depression and dementia.
There is also the cause and effect relationship between anatomy and clinical disorder that would need to be unraveled. For example, does hippocampal atrophy cause or predispose to depression, or does depression cause or predispose to hippocampal atrophy?
Pending the arrival of more conclusive data, clinicians are advised to focus their efforts on identifying and treating depression in the elderly. Not only is major depressive disorder a very common condition, but subsyndromal depression is also quite prevalent (and treatable).
For instance, a recent randomized, placebo-controlled study of minor depression or dysthymia in 415 elderly primary care patients found paroxetine (Paxil) to be more effective than placebo (Williams et al., 2000). A problem-solving type of behaviorally oriented psychotherapy designed for use in primary care (Problem-Solving Treatment-Primary Care [PST-PC]) was no more effective overall than placebo, although it was particularly beneficial at one of the four study sites.
We have a long way to go before we know if hippocampal dysfunction plays a definite causal role in geriatric depression or dementia. Until then, it seems wise to do whatever we can to minimize the risk of hippocampal atrophy (in ourselves and our patients), and at the same time continue to focus on providing accurate diagnosis and the best possible treatment of these conditions.
Dr. Jefferson is distinguished senior scientist at the Madison Institute of Medicine and clinical professor of psychiatry at the University of Wisconsin Medical School.