The major findings of this report are 1) NAA and Cr concentrations were significantly reduced in the hippocampus of PTSD patients when compared with control subjects, implying that there are hippocampal abnormalities in PTSD; 2) however, there were no significant differences in hippocampal or ERC volumes between PTSD patients without recent history of alcohol abuse and control subjects. This contrasts to previous reports of hippocampal atrophy in PTSD, suggesting that alcohol abuse may have been at least in part responsible for these previous findings.
Changes in NAA have been widely attributed to changes in neuron number, density, or neuronal metabolism (Birken and Oldendorf 1989
). The finding of 23% to 24% reduction of hippocampal NAA in PTSD subjects of this study, in the absence of hippocampal volume loss, were surprising for two reasons. First, the magnitude of the NAA reduction is very similar to that, which we previously reported for patients with Alzheimer’s dementia (Schuff et al 1997
). Notwithstanding this similarity of NAA reductions, our PTSD patients showed no gross cognitive memory impairments. Second, hippocampal NAA reductions in Alzheimer’s disease were accompanied by substantial hippocampal volume losses in the range from 20% to 40% (Schuff et al 1997
). Reduced NAA of the anterior cingulate and no apparent atrophy on MRI was also reported from a 1
H MRS study of children with PTSD after sexual abuse (De Bellis et al 2000
). It is possible that neuron loss in PTSD is accompanied by sufficient glial proliferation that attenuates atrophy but does not affect NAA loss because there is no NAA in nonneuronal tissue (Birken and Oldendorf 1989
). Single photon emission computer tomography (SPECT) studies of PTSD (Sachinvala et al 2000
) showed increased blood perfusion in limbic areas, including the hippocampus, consistent with glial proliferation. We have observed reduced NAA with minimal hippocampal atrophy also in elderly patients with mild cognitive impairment, presumably due to gliosis in the early stages of neuronal degeneration (Schuff et al 1997
). Another explanation for NAA decrease in PTSD is impairment of neuronal processes, resulting in secondary NAA loss. Reversible NAA losses have been found in amyotrophic lateral sclerosis (Kalra et al 1998
), epilepsy after surgery (Hugg et al 1996
), in multiple sclerosis (De Stefano et al 1995
), and more recently in schizophrenic patients after treatment with antipsychotics (Bertolino et al 2001
; Heimberg et al 1998
). These changes have been attributed to reversible impairment of oxidative metabolism from which NAA production is dependent. Therefore, we cautiously interpret the finding of decreased hippocampal NAA in PTSD to reflect either neuron loss in the presence of gliosis and/or neuronal metabolic impairments. In this regard, NAA changes would be expected to be more sensitive to neuronal damage in PTSD than volume loss. The effect size in this study of hippocampal NAA changes was 1.2 (see ), which is markedly higher than the effect sizes in most (albeit not all) MRI studies of hippocampal volume losses in PTSD (see ).
Other MRI Studies of Hippocampus in PTSD
The resonance of Cr, detected by 1
H MRSI, reflects tissue composition of phosphocreatine (high energy phosphate reservoir) and free creatine. Acute ischemia, or other factors, which impair oxidative metabolism will reduce the ratio of phosphocreatine to creatine, but should not necessarily alter total creatine content. Creatine concentrations are usually higher in gray matter than in white matter (Schuff et al 2001
), presumably due to the higher metabolic rate of gray matter. Replacement of neurons in the hippocampus of PTSD by glial cells might explain the decrease of Cr in PTSD.
In contrast to substantial changes of NAA and Cr, we found no Cho changes in PTSD. The resonance of Cho, detected by 1
H MRSI, reflects primarily phosphocholine and glycerophosphocholine, which are both constituents of cell membranes. Cho increases have been reported in multiple sclerosis lesions (Bitsch et al 1999
) and in tumor cells (Wilken et al 2000
), presumably indicating membrane degradation and glial proliferation. On the other hand, an increase of Cho might not be expected in chronic illnesses like PTSD, unless there is continuing gliosis of sufficient magnitude following neuronal damage.
The second major finding of this study was no significant atrophy in the hippocampus and ERC of PTSD. Previous MRI findings of hippocampal atrophy in PTSD are summarized in . Bremner et al (1995)
found an 8% decrease of hippocampal volume in 26 Vietnam veterans with PTSD compared with 22 control subjects (matched for years of lifetime alcohol abuse and other factors). Furthermore, the decrease of hippocampal volume in PTSD was associated with deficits in short term verbal memory; however, only a midsection of the hippocampus was measured and volumes were not adjusted for head size that together, may have resulted in spurious findings. In another study of Vietnam veterans with PTSD, Gurvits et al (1996)
compared the hippocampal volumes of seven combat veterans with PTSD, seven combat veterans without a lifetime history of PTSD, and eight normal controls. The authors found a significant bilateral 22–26% reduction in hippocampal volume (adjusted for whole brain volume) of PTSD. Smaller hippocampal volumes were positively associated with greater combat exposure, greater PTSD severity, and greater impairment on neuropsychological measures; however, this study had a small sample size (including one PTSD subject with bipolar disorder) and groups were not matched for age. Furthermore, the findings differed in magnitude and laterality from the report by Bremner (Bremner et al 1995
). In a study of 17 adult victims of childhood sexual abuse, Bremner and colleagues (Bremner et al 1997
) found a 12% volume reduction in the left hippocampus (not in the right as in the study of Vietnam veterans) when compared with 17 control subjects matched for years of alcohol abuse; however, there was no matching for major depression and similar to their earlier report, only a midsection of the hippocampus was measured. In another study on 21 women with a history of child sexual abuse, Stein and colleagues (Stein et al 1997
) reported a significant 5% volume reduction in the left hippocampus when compared with 21 women without abuse history. In addition, hippocampal volume decrease correlated with dissociative symptom severity, but not with indices of explicit memory functioning; however, alcohol abuse, depression, and substance abuse were greater in the PTSD patients than the control group. Recently, Wikins et al (1996) found no difference in hippocampal volumes between 10 PTSD alcohol abusing patients and eight alcohol abusers without PTSD.
Despite the importance of these reports, there were some limitations: first, laterality was inconsistent across the studies, with changes being reported in the right, the left, and/or both hippocampi. Second, most studies included PTSD subjects with current alcohol dependence and/or depression. Alcoholism is common in PTSD (Fontanaet al 1990) and is associated with hippocampal atrophy (Laakso et al 2000
). Depression is also common in PTSD (Fontana et al 1990
), impairs memory performance, and has opposite effects on HPA axis function from PTSD (Axelson et al 1993a
). The relationship between depression and hippocampal size, however, is controversial. While some MRI studies (Nurnberger et al 1994
; Sheline et al 1996
) reported significantly reduced hippocampal volumes in major depression, other studies found no reduction (Axelson et al 1993b
; Vakili et al 2000
), although depression severity and treatment response correlated with hippocampal size (Vakili et al 2000
). In conclusion, there remain questions concerning the role of potential confounding variables in the previously reported MRI data in PTSD.
The current finding of no hippocampal volume difference between PTSD and controls strongly suggests that PTSD by itself is not associated with hippocampal atrophy. Given the means and SE of our measurements, we had the power to detect a 9% reduction of hippocampal volumes at .05 alpha, while previous MRI studies of PTSD reported significant hippocampal volume losses between 5% and 26%. This implies that previous reports may have been confounded by alcohol and/or depression. Whether there is an interaction between PTSD and alcoholism, and/or depression to accentuate hippocampal atrophy has not been determined.
Volumes of the ERC were also not significantly different between PTSD and controls. We had hypothesized that PTSD would be associated with reduced ERC volumes, because the ERC is part of the limbic-hippocampal complex with a high density of glucocorticoid receptors (Turner et al 1998
). The results show that, similar to the hippocampus, there is no association between ERC size and PTSD.
Possible mechanisms of hippocampal injury in PTSD
Elevated levels of glucocorticoids, the adrenal steroids that are secreted during stress, are known to affect specifically hippocampal neurons and/or glial cells by inhibiting glucose metabolism (Horner et al 1990
) and antioxidant enzyme activity (Sapolsky et al 1988
), besides several other processes. Furthermore, excessive exposure to glucocorticoids seems to affect the ability of hippocampal neurons to survive (Sapolsky et al 1990
) and in previous PTSD studies the evidence of this phenomenon was decreased hippocampal volume. The finding of decreased NAA and Cr in the absence of decreased volume of the hippocampus of PTSD is still consistent with metabolic impairment and/or loss of neurons. Furthermore, the results of this study add support to the view that the hippocampus may participate in the pathophysiology of PTSD, as a preexposure condition increasing vulnerability to PTSD, as a result of glucocorticoid bursts during acute traumatic stress or as a contributor to symptomatology. Damage to neurons in the hippocampus could begin during the exposure to the traumatic stressor(s), a view that is consistent with the large body of research about the acute effects of stress; however, MRI findings indicate that exposure alone does not impact the hippocampus (Gurvits et al 1996
). On the other hand, if the impact of acute stress on the hippocampus is repeatedly encountered, as a result of the characteristic symptoms of re-experiencing for example, a more parsimonious mechanism emerges that fits the existing data about both acute stress and PTSD. Alternatively, reduced NAA and Cr levels could be related to a premorbid condition of increased vulnerability of hippocampal neurons to insults, possibly predisposing the individual for the development of PTSD. Whether these interpretations are accurate can only be addressed in future prospective studies.
There are several limitations to this study. Firstly, we did not control for lifetime burden of depression that may have contributed to hippocampal atrophy. Secondly, a technical limitation is that the coarse spatial resolution of 1H MRSI sampled also some tissue outside the hippocampus that may have introduced spurious NAA variations. Furthermore, T1/T2 relaxations of the metabolite resonances were not measured due to prohibitively long acquisition times, prohibiting determination of absolute metabolite concentrations.
In conclusion, this study showed substantial NAA and Cr losses in the absence of volume losses in the hippocampal region of PTSD patients without alcohol abuse during the last five years, a finding that is consistent with the view that the hippocampus participates in the pathophysiology of PTSD. Further research will be necessary to determine the significance of these findings.