- Email: [email protected]
Hippocampal Volume and Mood Disorders After Traumatic Brain Injury
Hippocampal Volume and Mood Disorders After Traumatic Brain Injury Ricardo E. Jorge, Laura Acion, Sergio E. Starkstein, and Vincent Magnotta Background: Recent evidence from clinical studies and animal models of traumatic brain injury (TBI) suggest that neuronal and glial loss might progress after the initial insult in selectively vulnerable regions of the brain such as the hippocampus. There is also evidence that hippocampal dysfunction plays a role in the pathogenesis of mood disorders. We examined the relationship between hippocampal damage and mood disorders after TBI and the effect of hippocampal atrophy on the outcome of TBI patients. Methods: The study group consisted of 37 patients with closed head injury who were evaluated at baseline and at 3, 6, and 12 months after trauma. Psychiatric diagnosis was made with a structured clinical interview and DSM-IV criteria. Quantitative magnetic resonance imaging scans were obtained at 3-months follow-up. Results: Patients with moderate to severe head injury had significantly lower hippocampal volumes than patients with mild TBI. Patients who developed mood disorders had significantly lower hippocampal volumes than patients without mood disturbance. Furthermore, there was a significant interaction between mood disorders diagnosis and severity of TBI, by which patients with moderate to severe TBI who developed mood disorders had significantly smaller hippocampal volumes than patients with equivalent severe TBI who did not develop mood disturbance. Finally, reduced hippocampal volumes were associated with poor vocational outcome at 1-year follow-up. Conclusions: Our findings are consistent with a “double-hit” mechanism by which neural and glial elements already affected by trauma are further compromised by the functional changes associated with mood disorders (e.g., the neurotoxic effects of increased levels of cortisol or excitotoxic damage resulting from overactivation of glutaminergic pathways). Finally, patients with greater hippocampal damage were less likely to return to a productive life 1 year after trauma. Key Words: Glial loss, hippocampal, mood disorder, TBI
T
raumatic brain injury (TBI) is a leading cause of death and disability in the United States. Each year, more than 1.5 million Americans sustain a TBI. As a result of these injuries, an estimated 80,000 –90,000 patients will experience long-term disability (Thurman et al. 1999). Traumatic brain injury is characterized by pathological changes in diverse cortical areas, subcortical nuclei, and white matter (WM) tracts. The mechanisms and temporal course of cell damage after TBI has been the focus of experimental and clinical studies during the past 2 decades. For instance, Colicos et al. (1996), with a controlled cortical impact model of TBI, identified the presence of dystrophic neurons in the dentate gyrus and the CA1 and CA3 subfields of the hippocampus for up to 2 weeks after trauma. Smith et al. (1997) studied the temporal course of histopathological changes after parasagittal fluid-percussion (FP) brain injury in rats. Quantitative analysis demonstrated progressive neuronal loss in the cerebral cortex and hippocampus over 1 year after injury. Taken as a whole, findings from animal models of TBI suggest that cell death mechanisms might consist of a continuum between necrotic and apoptotic pathways and that traumatic brain damage includes chronic neurodegenerative changes (Povlishock and Katz 2005; Raghupathi et al. 2000). These changes have also been observed in WM tracts of TBI patients up to 1 year after injury (Williams et al. 2001). Furthermore, neuroradiological studies have also demonstrated progres-
From the Department of Psychiatry (REJ, LA); Department of Radiology (VM), University of Iowa, Iowa City, Iowa; and the Department of Psychiatry (SES), University of Western Australia, Perth, Australia. Address reprint requests to Ricardo E. Jorge, M.D., University of Iowa College of Medicine, Psychiatry Research/2-202 MEB, Iowa City, IA, 52242-1000; E-mail: [email protected]. Received April 20, 2006; revised July 17, 2006; accepted July 19, 2006.
0006-3223/07/$32.00 doi:10.1016/j.biopsych.2006.07.024
sive atrophic changes among TBI patients (Gale et al. 2005; MacKenzie et al. 2002; Shiozaki et al. 2001). The hippocampus seems to be selectively vulnerable to these posttraumatic changes, a fact that might be related to the particular neurobiological features of hippocampal neurons and the unique characteristics of the hippocampal circuit (DeKosky et al. 2004; Delorenzo et al. 2005; Kotapka et al. 1991, 1994; McCarthy 2003). Temporal lobe morphology is substantially altered in TBI, with disproportionate WM loss and hippocampal atrophy (Ariza et al. 2006; Bigler et al. 2002). The resulting functional changes in neuronal circuitry might constitute the neurological substrate of cognitive and behavioral deficits that are frequently seen after TBI (Arciniegas et al. 2001; Ariza et al. 2004, 2006; Bigler et al. 1997; Tomaiuolo et al. 2004). There is also evidence that hippocampal dysfunction is an important component of at least some forms of mood disorders (Brown et al. 1999; Evans et al. 2005; MacQueen et al. 2003; McEwen 2000; Sapolsky 2000; Sapolsky and Pulsinelli 1985). Several studies have found hippocampal volumes to be reduced in depressed patients relative to healthy subjects (Bremner et al. 2000; Campbell et al. 2004; Frodl et al. 2002, 2004; Mervaala et al. 2000; Steffens et al. 2000; Vythilingam et al. 2002). However, other studies have failed to find significant differences in hippocampal volumes between actively depressed patients and control subjects (Axelson et al. 1993; Vakili et al. 2000; Vythilingam et al. 2004). This variability is probably related to methodological differences in the assessment of hippocampal volumes as well as heterogeneity of the clinical samples with regard to age, previous medical and psychiatric history, comorbid substance abuse, and duration of illness (Campbell et al. 2004; Videbech and Ravnkilde 2004; Vythilingam et al. 2004). For instance, different studies reported negative correlations between hippocampal volume and illness duration (Bell-McGinty et al. 2002; Sheline et al. 1999, 2003). Finally, hippocampal changes have also been described among patients with bipolar disorder BIOL PSYCHIATRY 2007;62:332–338 © 2007 Society of Biological Psychiatry
R.E. Jorge et al. and might constitute a neuroanatomical risk factor for the development of this condition (Hajek et al. 2005). In the present study, we analyze the relationship between hippocampal damage and mood disturbance after TBI. We hypothesized that the occurrence of mood disorders during the first year after TBI would be associated with significant changes in hippocampal morphology and that reduced hippocampal volumes would be a significant risk factor for poor psychosocial outcome after TBI. In addition, we hypothesized that hippocampal atrophy would be associated with greater impairment in memory functions.
Methods and Materials Subjects The study group consisted of 37 patients with TBI, 18 – 65 years of age, admitted to the University of Iowa Hospitals and Clinics or the Iowa Methodist Medical Center in Des Moines, Iowa, who were evaluated approximately 3 months after TBI. These patients were selected from a larger series of TBI patients enrolled in a recent observational study (Jorge et al. 2004) on the basis of the availability of high-resolution magnetic resonance imaging (MRI) scans appropriate to perform hippocampal volumetric studies. There were no significant differences between the patients included in this study (n ⫽ 37) and the rest of the TBI patients from this series (n ⫽ 55) in demographic variables, severity of TBI, degree of functional or cognitive impairment, premorbid social functioning, frequency of psychiatric disorders, or frequency of alcohol or other substance abuse. Severity of Brain Injury Severity of TBI was assessed with the 24-hour Glasgow Coma Scale (GCS) (Teasdale and Jennett 1976) score. According to this measure, GCS scores between 13 and 15 defined mild head injury, GCS scores between 9 and 12 defined moderate head injury, and GCS scores between 3 and 8 define severe head injury. Patients with a GCS score in the 13-15 range but who underwent intracranial surgical procedures or presented with focal lesions greater than 15 cc, however, were considered to have suffered a moderate head injury (Levin 1992; Levin et al. 1987). The overall severity of the traumatic injury was assessed with the Abbreviated Injury Scale (AIS) (MacKenzie et al. 1985). Psychiatric Assessment All patients were assessed by a psychiatrist with two semistructured interviews: a modified version of the Present State Examination (PSE) (Wing et al. 1990) designed to elicit symptoms of mood and anxiety disorder, and the Structured Clinical Interview for DSM-IV diagnoses (SCID) (Spitzer et al. 1992; Williams et al. 1992). Severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale (HAM-D) (Hamilton 1960). Family history of psychiatric disorders was assessed for first-degree relatives with the family history method and research diagnostic criteria (Andreasen et al. 1977). The Mini-Mental State Examination (MMSE) (Folstein et al. 1975) was used as a global measure of cognitive functioning. Impairment in activities of daily living was assessed with the Functional Independence Measure (FIM). Neuroimaging A high-resolution research MRI scan was obtained 3 months after the traumatic episode with a 1.5 T GE Signa (Milwaukee, Wisconsin) scanner at the Radiology Department of the Univer-
BIOL PSYCHIATRY 2007;62:332–338 333 sity of Iowa. Performing research MRIs with a 3-month delay from the acute episode has been useful to demonstrate more consistent brain-behavioral relationships and minimizes the effect of patient attrition (Bigler 2003; Blatter et al. 1997; Levin 1992; Wilson et al. 1995). The MRI images were obtained with a standardized protocol consisting of four different image sets. The T1-weighted sequence (echo time [TE] ⫽ 5, repetition time [TR] ⫽ 24, flip angle ⫽ 40°, number of excitations [NEX] ⫽ 2.0, field of view [FOV] ⫽ 26.0, matrix ⫽ 256 ⫻ 192) has a coronal slice thickness ⫽ 1 mm. The T2-weighted sequence (TE ⫽ 104, TR ⫽ 3000, flip angle ⫽ 40°, NEX ⫽ 2.0, FOV ⫽ 24.0, matrix ⫽ 256 ⫻ 192.) has coronal slice thickness ⫽ 4.0 mm. The PD sequence (TE ⫽ 28, TR ⫽ 3000, NEX ⫽ 1.0, FOV ⫽ 26.0, matrix ⫽ 256 ⫻ 192.) has a coronal slice thickness of 3.0 mm. The FLAIR sequence (TE ⫽ 165, TR ⫽ 9002, TI ⫽ 2200, NEX ⫽ 1.0, FOV ⫽ 24.0, matrix ⫽2009256 ⫻ 192, flip angle ⫽ 90°) has slice thickness of 4.0 mm. The tools of a locally developed software package, BRAINS2, were employed to generate data from the four image sets. This software permits cross-modality image registration, automated tissue classification, automated regional identification, cortical surface generation, volume and surface measurement, threedimensional visualization of surfaces, and multi-planar telegraphing. The validity and reproducibility of morphometric analysis with the aforementioned software has been reported in previous studies (Andreasen et al. 1992, 1993, 1994, 1996; Cohen et al. 1992; Harris et al. 1999; Magnotta et al. 1999a, 1999b). In vivo volumetric measurement of the hippocampus was done with a method developed at the University of Iowa (Pantel et al. 2000). The method defines the hippocampal formation including the subiculum, Ammon’s horn (hippocampus proper), and the dentate gyrus with high reliability. The hippocampus was traced manually on a continuous tissue classified image. Boundary identification was based on the tissue classified image as well as the co-registered T1 and T2 images. The regions of interest were defined on the coronal plane. However, the tracing began with the generation of auxiliary guideline traces on the sagittal plane. Hippocampal volumes were normalized to total intracranial volume (TIV) to compensate for differences in head size. In addition, accounting for the fact that TBI might result in global brain atrophy, hippocampal volumes were also normalized to total brain volume (TBV) and statistical comparisons were performed with both TBV-normalized and TIV-normalized hippocampal volumes. Because there were no significant discrepancies between the results obtained with the alternative measures, we are reporting TIV-normalized volumes. Morphometric analysis was performed by a research assistant (LA) who was extensively trained and reliable in this technique (intraclass correlations of .92 and .86 for the left and right hippocampus, respectively) and who was blind to the psychiatric diagnosis and group assignment of the subjects. Neuropsychological Evaluation Subjects underwent neuropsychological assessment, evaluated by an experienced neuropsychologist at the time of the 3-month follow-up visit. Analyses included in this study focused on memory and frontal-executive functioning, as assessed by the after-eight tests: Rey Auditory Verbal Learning Test: delayed recall trial (Lezak 1983); Rey Complex Figure Test: delayed recall trial (Lezak 1983); Trail Making Test: A and B (Reitan 1971); Multilingual Aphasia Exam – Controlled Oral Word Association Test (COWAT) (Benton et al. 1994); Stroop Test: Color/Word trial (Golden 1978); Wisconsin Card Sorting Test: number of categowww.sobp.org/journal
334 BIOL PSYCHIATRY 2007;62:332–338
R.E. Jorge et al.
ries achieved, number of perseverative errors (Heaton et al. 1993). Return to Productive Activity We defined “return to productive activity” (RTPA) at 1-year follow-up as a dichotomous variable on the basis of the patients’ ability to return to work at a comparable pre-injury employment status, full-time school, or homemaking (Wagner et al. 2002). Specific vocational information was obtained from multiple sources, including a structured interview—the Social Functioning Examination (SFE)—that was administered to both patients and caregivers (Starr et al. 1983). Statistical Analysis Comparison of the groups was accomplished with simple 2 analyses when the expected frequencies were sufficiently large and with Fisher exact test when the 2 was not appropriate. Because some of our continuous measures were clearly nonnormally distributed, we chose Mann-Whitney tests for comparing the groups. To remain consistent, analysis of covariance (ANCOVA) was performed after rank transformation of the continuous variables. Logistic regression with a backward-stepwise procedure was used to define the predictive variables of vocational outcome.
Results Characteristics of the TBI Group The 37 TBI patients were predominantly men (51.3%), white (94.6%), relatively young (mean age ⫽ 36.3 years, SD ⫽ 14.3), and of lower socioeconomic status (60 % of them were from Hollingshead’s Classes IV and V). Of these 37 patients, 24 (65%) had moderate to severe head injuries, whereas the remaining 13 patients (35%) had had a mild TBI. Analysis of acute computed tomography (CT) and MRI scans showed that 20 of 37 patients (54 %) had diffuse patterns of TBI, whereas 17 patients (46%) had focal lesions in their initial radiological studies. Hippocampal Volumes and TBI Severity We compared hippocampal volumes among patients with mild TBI and patients with moderate to severe TBI with age as a covariate. Patients with moderate to severe head injury had significantly lower left [ANCOVA, F (3,36) ⫽ 7.0, p ⫽ .0009], right [ANCOVA, F (3,36) ⫽ 6.6, p ⫽ .0013], and total hippocampal volumes [ANCOVA, F (3,36) ⫽ 6.3, p ⬍ .0012] than patients with mild TBI. Hippocampal Volumes and Mood Disorders in Patients with TBI Mood disorders due to TBI with major depressed or mixed features were observed among 19 of 37 TBI patients (51.3%) Table 1. Background Characteristics Variable Age (mean, SD) Gender (% of women) SES (% of Classes IV–V) FIM Scores (mean, SD) MMSE Scores (mean, SD) SFE Scores (mean, SD)
Mood Disorders (n ⫽ 19)
No-Mood Disorders (n ⫽ 18)
33.6 (11.6) 47.4 64.7 64.3 (11.2) 27.3 (2.7) 202 (15)
36.8 (16.7) 55.6 55.6 63.5 (10.7) 27.6 (2.1) 240 (19)
SES, socioeconomic status; FIM, Functional Independence Measure; MMSE, Mini-Mental State Examination; SFE, Social Functioning Examination.
www.sobp.org/journal
Table 2. Severity of Traumatic Brain Injury and Neuroradiological Findings Variable GCS Score (mean, SD) Diffuse Injury (% of patients) Contusions (% of patients) Intracranial Hemorrhages (% of patients) Frontal Lesions (% of patients) Total Brain Volume (mean, SD) Left Frontal Grey Matter (% of TIV) (mean, SD)a Right Frontal Grey Matter (% of TIV) (mean, SD)
Mood Disorders (n ⫽ 19)
No-Mood Disorders (n ⫽ 18)
12.1 (2.4) 36.7 52.6
12.0 (2.3) 66.7 35.3
31.6 42.1 1305.7 (148.6)
22.2 27.8 1311.2 (131.9)
8.9 (.6)
9.4 (.6)
9.4 (.9)
9.7 (.6)
GCS, Glasgow Coma Scale; TIV, total intracranial volume. a Analysis of covariance, F ⫽ 7.8, p ⫽ .0087.
during the first 3 months after brain injury. We compared the group of TBI patients who developed mood disorders (MD, n ⫽ 19) with those patients who did not develop mood disorders during this 3-month period (no-MD, n ⫽ 18). There were no significant differences between the MD and the no-MD groups in demographic variables, degree of cognitive or activities of daily living (ADL) impairment as measured by MMSE and FIM scores, or pre-injury social functioning as measured by SFE scores (Table 1). Baseline Neurological and Neuroimaging Findings. There were no significant differences between the MD and the no-MD groups in severity of TBI as measured by the initial GCS scores. Analysis of acute CT and MRI scans demonstrated a higher frequency of focal and frontal lesions in the MD group. However, these differences did not reach statistical significance (Table 2). MRI Findings at 3-Month Follow-Up. There were no significant differences between the MD and the no-MD groups in total brain volume or the volume of identifiable lesions assessed at the 3-month MRI scan. There were no significant differences between the MD and the no-MD groups in total lobar volumes, including the left and right frontal lobes. However, patients who developed mood disorders had significantly reduced left frontal grey matter volumes than patients who did not develop mood disturbance [ANCOVA, F ⫽ 7.8, p ⫽ .0087] (Table 2). We also compared left and right hippocampal volumes between the MD and the no-MD groups, controlling for GCS scores: 1) For the left hippocampus, the ANCOVA model proved to be significant [F (3,36) ⫽ 3.4, p ⫽ .0335]. Analysis of individual variables demonstrated that patients with mood disorders have significant lower left hippocampal volumes than the no-MD group [F ⫽ 7.1, p ⫽ .0117]. In addition, there was a significant interaction between mood disorders diagnosis and severity of TBI [F ⫽ 6.2, p ⫽ .0179]. Post hoc contrasts revealed that patients with moderate to severe TBI who developed mood disorders had significantly smaller hippocampal volumes than patients with moderate to severe TBI who did not develop mood disorders [F ⫽ 4.6, p ⫽ .039]. 2) For the right hippocampus, the ANCOVA model proved to be significant [F (3,36) ⫽ 3.9, p ⫽ .0295]. Analysis of individual variables demonstrated that patients with mood disorders have significant lower right hippocampal volumes than the no-MD group [F ⫽ 9.2, p ⫽ .0047]. In addition, there was a significant interaction between mood
R.E. Jorge et al. disorders diagnosis and severity of TBI [F ⫽ 8.2, p ⫽ .0072]. Post hoc contrasts revealed that patients with moderate to severe TBI who developed mood disorders had significantly smaller hippocampal volumes than patients with moderate to severe TBI who did not develop mood disorders [F ⫽ 9.8, p ⬍ .0038]. Finally, after controlling for severity of TBI, there were no significant differences in left, right, or total hippocampal volumes between patients with a premorbid history of mood disorders and patients without such a history. In addition, there were no significant hippocampal volumetric differences between patients with and without alcohol use disorders. Hippocampal Volumes and Cognitive Functioning We collapsed our neuropsychological variables into two specific domains. The first domain gave us a global measure of memory functions and was defined as the average of the sum of Z scores from the following neuropsychological tests: RAVLT1 (Sum of Scores for Trials 1 to 5), RAVLT2 (delayed recall), RAVLT3 (recognition), and RCFT (immediate and delayed recall). The second domain was designed to provide a global estimate of executive functioning and consisted of the average of Z scores obtained in the following tests: Trails B, Stroop Interference Task, and number of perseverative errors observed during the Wisconsin Card Sorting Task (WCST). Cronbach ␣ coefficients were .69 and .80 for the executive and memory domains, respectively. Partial correlations of age, GCS scores, education, left and right hippocampus volumes, and memory and executive domain scores did not show a significant association between hippocampal volumes and cognitive domains assessed at the 3-month evaluation. Hippocampal Volume as a Predictor of Long-Term Outcome Considering the relationship between hippocampal atrophy and severity of TBI, we examined whether reduced hippocampal volumes assessed 3 months after trauma were associated with poor outcome at 1-year follow-up and, if so, what dimensions of outcome were specifically affected by hippocampus atrophy. Right, left, and total hippocampal volumes did not correlate with ADL functioning as measured by FIM scores at 1-year follow-up. In addition, hippocampal volumes were not significantly associated with cognitive functioning as measured by either MMSE scores or by patients’ performance in memory and executive functioning tests assessed at 1-year follow-up. We then examined the association between hippocampus volumes and RTPA at 1 year after TBI. A logistic regression model included age, initial GCS scores, presence of mood disorder and alcohol misuse, left frontal grey matter volume, and hippocampal volume as independent variables. The whole-model test was significant [-Log Likelihood 2 ⫽ 17.4, p ⫽ .0002]. Analysis of the individual variables showed that reduced hippocampal volumes [Wald-2 ⫽ 6.8, p ⫽ .0089] and the presence of mood disorders and alcohol misuse [Wald-2 ⫽ 6.2, p ⫽ .0126] were associated with a reduced probability of returning to productive activity.
Discussion In the present study, we examined the relationship between traumatic damage to the hippocampal formation and neurobehavioral outcome of TBI patients. Patients with moderate to severe head injury had significantly lower hippocampal volumes than patients with mild TBI. After adjusting for severity of TBI,
BIOL PSYCHIATRY 2007;62:332–338 335 patients who developed mood disorders had significantly smaller hippocampal volumes than patients who did not develop affective disturbance. In addition, there was a significant interaction between mood disorders diagnosis and severity of TBI, by which patients with moderate to severe TBI who developed mood disorders had significantly smaller hippocampal volumes than patients with equivalent severe TBI who did not develop mood disorders. We did not observe a significant association between hippocampal volume and performance in neuropsychological tasks assessing memory and executive functions. Finally, patients with reduced hippocampal volumes were less likely to return to productive activity at 1-year follow-up. Before examining the implications of these findings we need to mention the limitations of this study. Heterogeneity of clinical samples is an important confounder when analyzing the neuropsychiatric complications of TBI. We acknowledge, therefore, that our conclusions might not pertain to other groups of TBI patients. Although we have complete records of the psychiatric history of our patients, including substance misuse and affective disorders, we don’t have reliable information of the remote occurrence of physical or sexual abuse or quantitative measures of early life adversity that might affect morphometric findings of medial temporal structures. In addition, although there is consistent evidence of disruption of the hypothalamic–pituitary–adrenal (HPA) axis after brain damage, we did not obtain urinary, plasmatic, or salivary cortisol levels to be correlated with hippocampal volumes. Given these limitations, what are the most important implications of the aforementioned findings? The hippocampus is selectively vulnerable to the effect of TBI (Bigler et al. 2002; Grady et al. 2003; Rall et al. 2003; Tomaiuolo et al. 2004). Experimental studies have documented an excessive hippocampal release of glutamate (Biegon et al. 2004; Koura et al. 1998; Phillips and Reeves 2001) and acetylcholine (Dixon et al. 1995; Hayes et al. 1992; Sihver et al. 2001) and the activation of apoptotic cascades early in the course of traumatic injury (Nathoo et al. 2004; Raghupathi et al. 2000; Stone et al. 2002). Furthermore, apoptosis can be observed in subacute and chronic stages of TBI (Cernak et al. 2002; Eldadah and Faden 2000; Williams et al. 2001), and the initial glutamate and acetylcholine excess turns into chronic depletion of these neurotransmitters in hippocampus and forebrain structures (Biegon et al. 2004; Salmond et al. 2005). It is not surprising that more severe injuries are associated with greater hippocampal damage and that these pathological changes can be quantified with structural MRI techniques (Gold and Squire 2004). However, we need to explain why patients with more severe TBI who also developed mood disorders showed greater atrophic changes of the hippocampus. It is conceivable that more severe prefrontal, hippocampal, and hypothalamic damage would produce more profound changes in cognition, stress responses, and circadian rhythms that would ultimately lead to a greater vulnerability to develop mood disorders. However, we did not find a significant inverse correlation between hippocampal volume and the severity of mood symptoms. Our findings are more consistent with a “double-hit” mechanism by which neural and glial elements already affected by trauma are further compromised by the functional changes associated with mood disturbance. For instance, damaged hippocampal neurons might be more vulnerable to the neurotoxic effects of increased levels of cortisol or enhanced glutaminergic transmission that might be observed among depressed TBI patients. In turn, these pathological changes can further disrupt HPA axis responses, glutaminergic www.sobp.org/journal
336 BIOL PSYCHIATRY 2007;62:332–338 and GABAergic neurotransmission, contributing to chronic behavioral problems. The importance of multiple or combined insults in the pathogenesis of hippocampal atrophy has been recently emphasized among psychiatric populations (Vythilingam et al. 2004). We did not find significant correlations between hippocampal volumes and neuropsychological measures of memory and executive functioning. Although hippocampal and fornix atrophy has been previously associated with impaired memory function among TBI patients (Bigler et al. 2002; Tate and Bigler 2003), this association has not been consistently replicated (Serra-Grabulosa et al. 2005; Tomaiuolo et al. 2004). However, we must keep in mind that TBI is characterized by the presence of multiple lesions of the neural systems involved in complex cognitive tasks. Thus, significant correlations between neuropsychological performance and damage to individual brain structures are difficult to demonstrate. In our study, hippocampal atrophy assessed at 3 months after TBI was not associated with ADL or cognitive outcomes at 1-year follow-up. However, hippocampal volume reduction was associated with poor vocational outcome. Thus, patients with greater hippocampal damage were less likely to return to a productive life 1 year after trauma. Among TBI patients, vocational outcomes are related to several factors, such as severity of the initial injury and the age at the time of TBI (Cattelani et al. 2002; Cifu et al. 1997; Dikmen et al. 1994; Keyser-Marcus et al. 2002). Wagner et al. (2002) have shown that, rather than to the degree of impairment and disability, successful RTPA is significantly related to both home competency and social integration domains. In addition, we have previously shown that RTPA is negatively influenced by the occurrence of mood disorders and alcohol misuse during the year after TBI (Jorge et al. 2005). Interestingly, hippocampal atrophy remained a significant predictor of decreased productivity after controlling for the severity of injury and the occurrence of mood and alcohol use disorders. It is plausible that hippocampal dysfunction might also affect social cognition, reward processing, and decision making and that deficits in these areas might contribute to the detrimental effect of hippocampal damage on vocational outcome. Further studies should replicate the present findings with more sensitive imaging techniques such as magnetic resonance spectroscopy. In addition, it is important to examine whether preventing hippocampal damage early in the course of TBI would be associated with successful vocational recovery (Bigler 2002a, Tate 2000). This work was supported in part by the following National Institutes of Mental Health grants: MH-40355, MH-52879, and MH-53592. We thank R. Hansen for imaging analysis and T. Kopel and S. Rosazza for their precious support during this study. Andreasen N, Cizadlo T, Harris G, Swayze V 2nd, O’Leary DS, Cohen G, et al. (1993): Voxel processing techniques for the ante mortem study of neuroanatomy and neuropathology using magnetic resonance imaging. J Neuropsychiatry Clin Neurosci 5:121–130. Andreasen N, Cohen G, Harris G, Cizadlo T, Parkkinen J, Rezai K, Swayze VW 2nd (1992): Image processing for the study of brain structure and function: Problems and programs. J Neuropsychiatry Clin Neurosci 4:125–133. Andreasen NC, Endicott J, Spitzer RL, Winokur G (1977): The family history method using diagnostic criteria. Arch Gen Psychiatry 34:1229 –1235. Andreasen NC, Harris G, Cizadlo T, Arndt S, O’Leary DS, Swayze V, Flaum M (1994): Techniques for measuring sulcal/gyral patterns in the brain as visualized through magnetic resonance scanning: BRAINPLOT and BRAINMAP. Proc Natl Acad Sci USA 91:93–97.
www.sobp.org/journal
R.E. Jorge et al. Andreasen NC, Rajarethinam R, Cizadlo T, Arndt S, Swayze VW 2nd, Flashman LA, et al. (1996): Automatic atlas-based volume estimation of human brain regions from MR images. J Comput Assist Tomogr 20:98 –106. Arciniegas DB, Topkoff JL, Rojas DC, Sheeder J, Teale P, Young DA, et al. (2001): Reduced hippocampal volume in association with p50 nonsuppression following traumatic brain injury. J Neuropsychiatry Clin Neurosci 13:213–221. Ariza M, Junque C, Mataro M, Poca MA, Bargallo N, Olondo M, Sahuquillo J (2004): Neuropsychological correlates of basal ganglia and medial temporal lobe NAA/Cho reductions in traumatic brain injury. Arch Neurol 61:541–544. Ariza M, Serra-Grabulosa JM, Junque C, Ramirez B, Mataro M, Poca A, et al. (2006): Hippocampal head atrophy after traumatic brain injury. Neuropsychologia 44:1956 –1961. Axelson DA, Doraiswamy PM, McDonald WM, Boyko OB, Tupler LA, Patterson LJ, et al. (1993): Hypercortisolemia and hippocampal changes in depression. Psychiatry Res 47:163–173. Bell-McGinty S, Butters MA, Meltzer CC, Greer PJ, Reynolds CF 3rd, Becker JT (2002): Brain morphometric abnormalities in geriatric depression: Longterm neurobiological effects of illness duration. Am J Psychiatry 159: 1424 –1427. Benton AL, Hamsher K, Sivan AB (1994): Multilingual Aphasia Examination. Iowa City, Iowa: AJA Associates. Biegon A, Fry PA, Paden CM, Alexandrovich A, Tsenter J, Shohami E (2004): Dynamic changes in N-methyl-D-aspartate receptors after closed head injury in mice: Implications for treatment of neurological and cognitive deficits. Proc Natl Acad Sci U S A 101:5117–5122. Bigler ED (2003): Neurobiology and neuropathology underlie the neuropsychological deficits associated with traumatic brain injury. Arch Clin Neuropsychol 18:595– 621; discussion 623– 627. Bigler ED, Anderson CV, Blatter DD (2002a): Temporal lobe morphology in normal aging and traumatic brain injury. AJNR Am J Neuroradiol 23:255– 266. Bigler ED, Blatter DD, Anderson CV, et al. (1997): Hippocampal volume in normal aging and traumatic brain injury. AJNR Am J Neuroradiol 18: 11–23. Blatter DD, Bigler ED, Gale SD, Johnson SC, Anderson CV, Burnett BM, et al. (1997): MR-based brain and cerebrospinal fluid measurement after traumatic brain injury: Correlation with neuropsychological outcome. AJNR Am J Neuroradiol 18:1–10. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS (2000): Hippocampal volume reduction in major depression. Am J Psychiatry 157:115–158. Brown ES, Rush AJ, McEwen BS (1999): Hippocampal remodeling and damage by corticosteroids: Implications for mood disorders. Neuropsychopharmacology 21:474 – 484. Campbell S, Marriott M, Nahmias C, MacQueen GM (2004): Lower hippocampal volume in patients suffering from depression: A meta-analysis. Am J Psychiatry 161:598 – 607. Cattelani R, Tanzi F, Lombardi F, Mazzucchi A (2002): Competitive re-employment after severe traumatic brain injury: Clinical, cognitive and behavioural predictive variables. Brain Inj 16:51– 64. Cernak I, Chapman S, Hamlin G, Vink R (2002): Temporal characterisation of pro- and anti-apoptotic mechanisms following diffuse traumatic brain injury in rats. J Clin Neurosci 9:565. Cifu DX, Keyser-Marcus L, Lopez E, Wehman P, Kreutzer JS, Englander J, High W (1997): Acute predictors of successful return to work 1 year after traumatic brain injury: A multicenter analysis. Arch Phys Med Rehabil 78:125–131. Cohen G, Andreasen NC, Alliger R, Arndt S, Kuan J, Yuh WT, Ehrhardt J (1992): Segmentation techniques for the classification of brain tissue using magnetic resonance imaging. Psychiatry Res 45:33–51. Colicos MA, Dixon CE, Dash PK (1996): Delayed, selective neuronal death following experimental cortical impact injury in rats: Possible role in memory deficits. Brain Res 739:111–119. DeKosky ST, Taffe KM, Abrahamson EE, Dixon CE, Kochanek PM, Ikonomovic MD (2004): Time course analysis of hippocampal nerve growth factor and antioxidant enzyme activity following lateral controlled cortical impact brain injury in the rat. J Neurotrauma 21:491–500. Delorenzo RJ, Sun DA, Deshpande LS (2005): Cellular mechanisms underlying acquired epilepsy: The calcium hypothesis of the induction and maintenance of epilepsy. Pharmacol Ther 105:229 –266.
R.E. Jorge et al. Dikmen SS, Temkin NR, Machamer JE, Holubkov AL, Fraser RT, Winn HR (1994): Employment following traumatic head injuries. Arch Neurol 51: 177–186. Dixon CE, Liu SJ, Jenkins LW, Bhattachargee M, Whitson JS, Yang K, Hayes RL (1995): Time course of increased vulnerability of cholinergic neurotransmission following traumatic brain injury in the rat. Behav Brain Res 70: 125–131. Eldadah BA, Faden AI (2000): Caspase pathways, neuronal apoptosis, and CNS injury. J Neurotrauma 17:811– 829. Evans DL, Charney DS, Lewis L, Golden RN, Gorman JM, Krishnan KR, et al. (2005): Mood disorders in the medically ill: Scientific review and recommendations. Biol Psychiatry 58:175–189. Folstein MF, Folstein SE, McHugh PR (1975): Mini-Mental State: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189 –198. Frodl T, Meisenzahl EM, Zetzsche T, Born C, Groll C, Jager M, et al. (2002): Hippocampal changes in patients with a first episode of major depression. Am J Psychiatry 159:1112–1118. Frodl T, Meisenzahl EM, Zill P, Baghai T, Rujescu D, Leinsinger G, et al. (2004): Reduced hippocampal volumes associated with the long variant of the serotonin transporter polymorphism in major depression. Arch Gen Psychiatry 61:177–183. Gale SD, Baxter L, Roundy N, Johnson SC (2005): Traumatic brain injury and grey matter concentration: A preliminary voxel based morphometry study. J Neurol Neurosurg Psychiatry 76:984 –988. Gold JJ, Squire LR (2004): Quantifying medial temporal lobe damage in memory-impaired patients. Hippocampus 15:79 – 85. Golden CJ (1978): Stroop Color and Word Test. Chicago: Stoelting. Grady MS, Charleston JS, Maris D, Witgen BM, Lifshitz J (2003): Neuronal and glial cell number in the hippocampus after experimental traumatic brain injury: Analysis by stereological estimation. J Neurotrauma 20:929 –941. Hajek T, Carrey N, Alda M (2005): Neuroanatomical abnormalities as risk factors for bipolar disorder. Bipolar Disord 7:393– 403. Hamilton MA (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56 – 62. Harris G, Andreasen NC, Cizadlo T (1999): Improving tissue classification in MRI: A three-dimensional multispectral discriminant analysis method with automated training class selection. J Comput Assist Tomogr 23:144 – 154. Hayes RL, Jenkins LW, Lyeth BG (1992): Neurotransmitter-mediated mechanisms of traumatic brain injury: Acetylcholine and excitatory amino acids. J Neurotrauma 9(suppl 1):S173–S187. Heaton RK, Chelune GJ, Tailey JL (1993): The Wisconsin Card Sorting Test. Odessa, Florida: Psychological Assessment Resources. Jorge RE, Robinson RG, Moser D, Tateno A, Crespo-Facorro B, Arndt S (2004): Major depression following traumatic brain injury. Arch Gen Psychiatry 61:42–50. Jorge RE, Starkstein SE, Arndt S, Moser D, Crespo-Facorro B, Robinson RG (2005): Alcohol misuse and mood disorders following traumatic brain injury. Arch Gen Psychiatry 62:742–749. Keyser-Marcus LA, Bricout JC, Wehman P, Campbell LR, Cifu DX, Englander J, et al. (2002): Acute predictors of return to employment after traumatic brain injury: a longitudinal follow-up. Arch Phys Med Rehabil 83:635– 641. Kotapka MJ, Gennarelli TA, Graham DI, Adams JH, Thibault LE, Ross DT, Ford I (1991): Selective vulnerability of hippocampal neurons in accelerationinduced experimental head injury. J Neurotrauma 8:247–258. Kotapka MJ, Graham DI, Adams JH, Gennarelli TA (1994): Hippocampal pathology in fatal human head injury without high intracranial pressure. J Neurotrauma 11:317–324. Koura SS, Doppenberg EM, Marmarou A, Choi S, Young HF, Bullock R (1998): Relationship between excitatory amino acid release and outcome after severe human head injury. Acta Neurochir Suppl (Wien) 71:244 –246. Levin HS (1992): Neurobehavioral recovery. J Neurotrauma 9(suppl 1):S359 – S373. Levin HS, Amparo E, Eisenberg HM, Williams DH, High WM Jr., McArdle CB, Weiner RL (1987): Magnetic resonance imaging and computerized tomography in relation to the neurobehavioral sequelae of mild and moderate head injuries. J Neurosurg 66:706 –713. Lezak M (1983): Neuropsychological Assessment, 2nd ed. New York: Oxford University Press. MacKenzie EJ, Shapiro S, Eastham JN (1985): The Abbreviated Injury Scale and Injury Severity Score. Levels of inter- and intrarater reliability. Med Care 23:823– 835.
BIOL PSYCHIATRY 2007;62:332–338 337 MacKenzie JD, Siddiqi F, Babb JS, Bagley LJ, Mannon LJ, Sinson GP, Grossman RI (2002): Brain atrophy in mild or moderate traumatic brain injury: A longitudinal quantitative analysis. AJNR Am J Neuroradiol 23:1509 –1515. MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, et al. (2003): Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A 100:1387–1392. Magnotta V, Andreasen NC, Schultz SK, Harris G, Cizadlo T, Heckel D, et al. (1999a): Quantitative in vivo measurement of gynification in the human brain: Changes associated with aging. Cerebral Cortex 9:151–160. Magnotta V, Heckel D, Andreasen NC, Cizadlo T, Corson PW, Ehrhardt JC, Yuh WT (1999b): Measurement of brain structures by artificial neural networks: Two-dimensional and three-dimensional applications. Radiology 211:781–790. McCarthy MM (2003): Stretching the truth. Why hippocampal neurons are so vulnerable following traumatic brain injury. Exp Neurol 184:40 – 43. McEwen BS (2000): Allostasis and allostatic load: Implications for neuropsychopharmacology. Neuropsychopharmacology 22:108 –124. Mervaala E, Fohr J, Kononen M, Valkonen-Korhonen M, Vainio P, Partanen K, et al. (2000): Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med 30:117–125. Nathoo N, Narotam PK, Agrawal DK, Connolly CA, van Dellen JR, Barnett GH, Chetty R (2004): Influence of apoptosis on neurological outcome following traumatic cerebral contusion. J Neurosurg 101:233–240. Pantel J, O’Leary DS, Cretsinger K, Bockholt HJ, Keefe H, Magnotta VA, Andreasen NC (2000): A new method for the in vivo volumetric measurement of the human hippocampus with high neuroanatomical accuracy. Hippocampus 10:752–758. Phillips LL, Reeves TM (2001): Interactive pathology following traumatic brain injury modifies hippocampal plasticity. Restor Neurol Neurosci 19: 213–235. Povlishock JT, Katz DI (2005): Update of neuropathology and neurological recovery after traumatic brain injury. J Head Trauma Rehabil 20:76 –94. Raghupathi R, Graham DI, McIntosh TK (2000): Apoptosis after traumatic brain injury. J Neurotrauma 17:927–938. Rall JM, Matzilevich DA, Dash PK (2003): Comparative analysis of mRNA levels in the frontal cortex and the hippocampus in the basal state and in response to experimental brain injury. Neuropathol Appl Neurobiol 29: 118 –131. Reitan RM (1971): Trail making test results for normal and brain-damaged children. Percept Mot Skills 33:575–581. Salmond CH, Chatfield DA, Menon DK, Pickard JD, Sahakian BJ (2005): Cognitive sequelae of head injury: Involvement of basal forebrain and associated structures. Brain 128:189 –200. Sapolsky RM (2000): Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry 57:925–935. Sapolsky RM, Pulsinelli WA (1985): Glucocorticoids potentiate ischemic injury to neurons: Therapeutic implications. Science 229:1397–1400. Serra-Grabulosa JM, Junque C, Verger K, Salgado-Pineda P, Maneru C, Mercader JM (2005): Cerebral correlates of declarative memory dysfunctions in early traumatic brain injury. J Neurol Neurosurg Psychiatry 76:129 –131. Sheline YI, Gado MH, Kraemer HC (2003): Untreated depression and hippocampal volume loss. Am J Psychiatry 160:1516 –1518. Sheline YI, Sanghavi M, Mintun MA, Gado MH (1999): Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci 19:5034 –5043. Shiozaki T, Akai H, Taneda M, Hayakata T, Aoki M, Oda J, et al. (2001): Delayed hemispheric neuronal loss in severely head-injured patients. J Neurotrauma 18:665– 674. Sihver S, Marklund N, Hillered L, Langstrom B, Watanabe Y, Bergstrom M (2001): Changes in mACh, NMDA and GABA(A) receptor binding after lateral fluid-percussion injury: In vitro autoradiography of rat brain frozen sections. J Neurochem 78:417– 423. Smith DH, Chen XH, Pierce JE, Wolf JA, Trojanowski JQ, Graham DI, McIntosh TK (1997): Progressive atrophy and neuron death for one year following brain trauma in the rat. J Neurotrauma 14:715–727. Spitzer RL, Williams JB, Gibbon M, First MB (1992): The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description. Arch Gen Psychiatry 49:624 – 629. Starr LB, Robinson RG, Price TR (1983): The social functioning exam: An assessment of stroke patients. Soc Work Res Abstr 18:28 –33. Steffens DC, Byrum CE, McQuoid DR, Greenberg DL, Payne ME, Blitchington TF, et al. (2000): Hippocampal volume in geriatric depression. Biol Psychiatry 48:301–309.
www.sobp.org/journal
338 BIOL PSYCHIATRY 2007;62:332–338 Stone JR, Okonkwo DO, Singleton RH, Mutlu LK, Helm GA, Povlishock JT (2002): Caspase-3-mediated cleavage of amyloid precursor protein and formation of amyloid Beta peptide in traumatic axonal injury. J Neurotrauma 19:601– 614. Tate DF, Bigler ED (2000): Fornix and hippocampal atrophy in traumatic brain injury. Learn Mem 7:442– 446. Teasdale G, Jennett B (1976): Assessment and prognosis of coma after head injury. Acta Neurochir (Wien) 34:45–55. Thurman DJ, Alverson C, Dunn KA, Guerrero J, Sniezek JE (1999): Traumatic brain injury in the United States: A public health perspective. J Head Trauma Rehabil 14:602– 615. Tomaiuolo F, Carlesimo GA, Di Paola M, Petrides M, Fera F, Bonanni R, et al. (2004): Gross morphology and morphometric sequelae in the hippocampus, fornix, and corpus callosum of patients with severe nonmissile traumatic brain injury without macroscopically detectable lesions: A T1 weighted MRI study. J Neurol Neurosurg Psychiatry 75:1314 – 1322. Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF, Bonello-Cintron CM, Yurgelun-Todd DA (2000): Hippocampal volume in primary unipolar major depression: A magnetic resonance imaging study. Biol Psychiatry 47: 1087–1090. Videbech P, Ravnkilde B (2004): Hippocampal volume and depression: A meta-analysis of MRI studies. Am J Psychiatry 161:1957–1966.
www.sobp.org/journal
R.E. Jorge et al. Vythilingam M, Heim C, Newport J, Miller AH, Anderson E, Bronen R, et al. (2002): Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry 159:2072–2080. Vythilingam M, Vermetten E, Anderson GM, Luckenbaugh D, Anderson ER, Snow J, et al. (2004): Hippocampal volume, memory, and cortisol status in major depressive disorder: Effects of treatment. Biol Psychiatry 56:101– 112. Wagner AK, Hammond FM, Sasser HC, Wiercisiewski D (2002): Return to productive activity after traumatic brain injury: Relationship with measures of disability, handicap, and community integration. Arch Phys Med Rehabil 83:107–114. Williams JB, Gibbon M, First MB, Spitzer RL, Davies M, Borus J, et al. (1992): The Structured Clinical Interview for DSM-III-R (SCID). II. Multisite testretest reliability. Arch Gen Psychiatry 49:630 – 636. Williams S, Raghupathi R, MacKinnon MA, McIntosh TK, Saatman KE, Graham DI (2001): In situ DNA fragmentation occurs in white matter up to 12 months after head injury in man. Acta Neuropathol (Berl) 102:581–590. Wilson JT, Hadley DM, Wiedmann KD, Teasdale GM (1995): Neuropsychological consequences of two patterns of brain damage shown by MRI in survivors of severe head injury. J Neurol Neurosurg Psychiatry 59:328 –331. Wing JK, Babor T, Brugha T, Burke J, Cooper JE, Giel R, et al. (1990): SCAN. Schedules for Clinical Assessment in Neuropsychiatry. Arch Gen Psychiatry 47:589 –593.
T
raumatic brain injury (TBI) is a leading cause of death and disability in the United States. Each year, more than 1.5 million Americans sustain a TBI. As a result of these injuries, an estimated 80,000 –90,000 patients will experience long-term disability (Thurman et al. 1999). Traumatic brain injury is characterized by pathological changes in diverse cortical areas, subcortical nuclei, and white matter (WM) tracts. The mechanisms and temporal course of cell damage after TBI has been the focus of experimental and clinical studies during the past 2 decades. For instance, Colicos et al. (1996), with a controlled cortical impact model of TBI, identified the presence of dystrophic neurons in the dentate gyrus and the CA1 and CA3 subfields of the hippocampus for up to 2 weeks after trauma. Smith et al. (1997) studied the temporal course of histopathological changes after parasagittal fluid-percussion (FP) brain injury in rats. Quantitative analysis demonstrated progressive neuronal loss in the cerebral cortex and hippocampus over 1 year after injury. Taken as a whole, findings from animal models of TBI suggest that cell death mechanisms might consist of a continuum between necrotic and apoptotic pathways and that traumatic brain damage includes chronic neurodegenerative changes (Povlishock and Katz 2005; Raghupathi et al. 2000). These changes have also been observed in WM tracts of TBI patients up to 1 year after injury (Williams et al. 2001). Furthermore, neuroradiological studies have also demonstrated progres-
From the Department of Psychiatry (REJ, LA); Department of Radiology (VM), University of Iowa, Iowa City, Iowa; and the Department of Psychiatry (SES), University of Western Australia, Perth, Australia. Address reprint requests to Ricardo E. Jorge, M.D., University of Iowa College of Medicine, Psychiatry Research/2-202 MEB, Iowa City, IA, 52242-1000; E-mail: [email protected]. Received April 20, 2006; revised July 17, 2006; accepted July 19, 2006.
0006-3223/07/$32.00 doi:10.1016/j.biopsych.2006.07.024
sive atrophic changes among TBI patients (Gale et al. 2005; MacKenzie et al. 2002; Shiozaki et al. 2001). The hippocampus seems to be selectively vulnerable to these posttraumatic changes, a fact that might be related to the particular neurobiological features of hippocampal neurons and the unique characteristics of the hippocampal circuit (DeKosky et al. 2004; Delorenzo et al. 2005; Kotapka et al. 1991, 1994; McCarthy 2003). Temporal lobe morphology is substantially altered in TBI, with disproportionate WM loss and hippocampal atrophy (Ariza et al. 2006; Bigler et al. 2002). The resulting functional changes in neuronal circuitry might constitute the neurological substrate of cognitive and behavioral deficits that are frequently seen after TBI (Arciniegas et al. 2001; Ariza et al. 2004, 2006; Bigler et al. 1997; Tomaiuolo et al. 2004). There is also evidence that hippocampal dysfunction is an important component of at least some forms of mood disorders (Brown et al. 1999; Evans et al. 2005; MacQueen et al. 2003; McEwen 2000; Sapolsky 2000; Sapolsky and Pulsinelli 1985). Several studies have found hippocampal volumes to be reduced in depressed patients relative to healthy subjects (Bremner et al. 2000; Campbell et al. 2004; Frodl et al. 2002, 2004; Mervaala et al. 2000; Steffens et al. 2000; Vythilingam et al. 2002). However, other studies have failed to find significant differences in hippocampal volumes between actively depressed patients and control subjects (Axelson et al. 1993; Vakili et al. 2000; Vythilingam et al. 2004). This variability is probably related to methodological differences in the assessment of hippocampal volumes as well as heterogeneity of the clinical samples with regard to age, previous medical and psychiatric history, comorbid substance abuse, and duration of illness (Campbell et al. 2004; Videbech and Ravnkilde 2004; Vythilingam et al. 2004). For instance, different studies reported negative correlations between hippocampal volume and illness duration (Bell-McGinty et al. 2002; Sheline et al. 1999, 2003). Finally, hippocampal changes have also been described among patients with bipolar disorder BIOL PSYCHIATRY 2007;62:332–338 © 2007 Society of Biological Psychiatry
R.E. Jorge et al. and might constitute a neuroanatomical risk factor for the development of this condition (Hajek et al. 2005). In the present study, we analyze the relationship between hippocampal damage and mood disturbance after TBI. We hypothesized that the occurrence of mood disorders during the first year after TBI would be associated with significant changes in hippocampal morphology and that reduced hippocampal volumes would be a significant risk factor for poor psychosocial outcome after TBI. In addition, we hypothesized that hippocampal atrophy would be associated with greater impairment in memory functions.
Methods and Materials Subjects The study group consisted of 37 patients with TBI, 18 – 65 years of age, admitted to the University of Iowa Hospitals and Clinics or the Iowa Methodist Medical Center in Des Moines, Iowa, who were evaluated approximately 3 months after TBI. These patients were selected from a larger series of TBI patients enrolled in a recent observational study (Jorge et al. 2004) on the basis of the availability of high-resolution magnetic resonance imaging (MRI) scans appropriate to perform hippocampal volumetric studies. There were no significant differences between the patients included in this study (n ⫽ 37) and the rest of the TBI patients from this series (n ⫽ 55) in demographic variables, severity of TBI, degree of functional or cognitive impairment, premorbid social functioning, frequency of psychiatric disorders, or frequency of alcohol or other substance abuse. Severity of Brain Injury Severity of TBI was assessed with the 24-hour Glasgow Coma Scale (GCS) (Teasdale and Jennett 1976) score. According to this measure, GCS scores between 13 and 15 defined mild head injury, GCS scores between 9 and 12 defined moderate head injury, and GCS scores between 3 and 8 define severe head injury. Patients with a GCS score in the 13-15 range but who underwent intracranial surgical procedures or presented with focal lesions greater than 15 cc, however, were considered to have suffered a moderate head injury (Levin 1992; Levin et al. 1987). The overall severity of the traumatic injury was assessed with the Abbreviated Injury Scale (AIS) (MacKenzie et al. 1985). Psychiatric Assessment All patients were assessed by a psychiatrist with two semistructured interviews: a modified version of the Present State Examination (PSE) (Wing et al. 1990) designed to elicit symptoms of mood and anxiety disorder, and the Structured Clinical Interview for DSM-IV diagnoses (SCID) (Spitzer et al. 1992; Williams et al. 1992). Severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale (HAM-D) (Hamilton 1960). Family history of psychiatric disorders was assessed for first-degree relatives with the family history method and research diagnostic criteria (Andreasen et al. 1977). The Mini-Mental State Examination (MMSE) (Folstein et al. 1975) was used as a global measure of cognitive functioning. Impairment in activities of daily living was assessed with the Functional Independence Measure (FIM). Neuroimaging A high-resolution research MRI scan was obtained 3 months after the traumatic episode with a 1.5 T GE Signa (Milwaukee, Wisconsin) scanner at the Radiology Department of the Univer-
BIOL PSYCHIATRY 2007;62:332–338 333 sity of Iowa. Performing research MRIs with a 3-month delay from the acute episode has been useful to demonstrate more consistent brain-behavioral relationships and minimizes the effect of patient attrition (Bigler 2003; Blatter et al. 1997; Levin 1992; Wilson et al. 1995). The MRI images were obtained with a standardized protocol consisting of four different image sets. The T1-weighted sequence (echo time [TE] ⫽ 5, repetition time [TR] ⫽ 24, flip angle ⫽ 40°, number of excitations [NEX] ⫽ 2.0, field of view [FOV] ⫽ 26.0, matrix ⫽ 256 ⫻ 192) has a coronal slice thickness ⫽ 1 mm. The T2-weighted sequence (TE ⫽ 104, TR ⫽ 3000, flip angle ⫽ 40°, NEX ⫽ 2.0, FOV ⫽ 24.0, matrix ⫽ 256 ⫻ 192.) has coronal slice thickness ⫽ 4.0 mm. The PD sequence (TE ⫽ 28, TR ⫽ 3000, NEX ⫽ 1.0, FOV ⫽ 26.0, matrix ⫽ 256 ⫻ 192.) has a coronal slice thickness of 3.0 mm. The FLAIR sequence (TE ⫽ 165, TR ⫽ 9002, TI ⫽ 2200, NEX ⫽ 1.0, FOV ⫽ 24.0, matrix ⫽2009256 ⫻ 192, flip angle ⫽ 90°) has slice thickness of 4.0 mm. The tools of a locally developed software package, BRAINS2, were employed to generate data from the four image sets. This software permits cross-modality image registration, automated tissue classification, automated regional identification, cortical surface generation, volume and surface measurement, threedimensional visualization of surfaces, and multi-planar telegraphing. The validity and reproducibility of morphometric analysis with the aforementioned software has been reported in previous studies (Andreasen et al. 1992, 1993, 1994, 1996; Cohen et al. 1992; Harris et al. 1999; Magnotta et al. 1999a, 1999b). In vivo volumetric measurement of the hippocampus was done with a method developed at the University of Iowa (Pantel et al. 2000). The method defines the hippocampal formation including the subiculum, Ammon’s horn (hippocampus proper), and the dentate gyrus with high reliability. The hippocampus was traced manually on a continuous tissue classified image. Boundary identification was based on the tissue classified image as well as the co-registered T1 and T2 images. The regions of interest were defined on the coronal plane. However, the tracing began with the generation of auxiliary guideline traces on the sagittal plane. Hippocampal volumes were normalized to total intracranial volume (TIV) to compensate for differences in head size. In addition, accounting for the fact that TBI might result in global brain atrophy, hippocampal volumes were also normalized to total brain volume (TBV) and statistical comparisons were performed with both TBV-normalized and TIV-normalized hippocampal volumes. Because there were no significant discrepancies between the results obtained with the alternative measures, we are reporting TIV-normalized volumes. Morphometric analysis was performed by a research assistant (LA) who was extensively trained and reliable in this technique (intraclass correlations of .92 and .86 for the left and right hippocampus, respectively) and who was blind to the psychiatric diagnosis and group assignment of the subjects. Neuropsychological Evaluation Subjects underwent neuropsychological assessment, evaluated by an experienced neuropsychologist at the time of the 3-month follow-up visit. Analyses included in this study focused on memory and frontal-executive functioning, as assessed by the after-eight tests: Rey Auditory Verbal Learning Test: delayed recall trial (Lezak 1983); Rey Complex Figure Test: delayed recall trial (Lezak 1983); Trail Making Test: A and B (Reitan 1971); Multilingual Aphasia Exam – Controlled Oral Word Association Test (COWAT) (Benton et al. 1994); Stroop Test: Color/Word trial (Golden 1978); Wisconsin Card Sorting Test: number of categowww.sobp.org/journal
334 BIOL PSYCHIATRY 2007;62:332–338
R.E. Jorge et al.
ries achieved, number of perseverative errors (Heaton et al. 1993). Return to Productive Activity We defined “return to productive activity” (RTPA) at 1-year follow-up as a dichotomous variable on the basis of the patients’ ability to return to work at a comparable pre-injury employment status, full-time school, or homemaking (Wagner et al. 2002). Specific vocational information was obtained from multiple sources, including a structured interview—the Social Functioning Examination (SFE)—that was administered to both patients and caregivers (Starr et al. 1983). Statistical Analysis Comparison of the groups was accomplished with simple 2 analyses when the expected frequencies were sufficiently large and with Fisher exact test when the 2 was not appropriate. Because some of our continuous measures were clearly nonnormally distributed, we chose Mann-Whitney tests for comparing the groups. To remain consistent, analysis of covariance (ANCOVA) was performed after rank transformation of the continuous variables. Logistic regression with a backward-stepwise procedure was used to define the predictive variables of vocational outcome.
Results Characteristics of the TBI Group The 37 TBI patients were predominantly men (51.3%), white (94.6%), relatively young (mean age ⫽ 36.3 years, SD ⫽ 14.3), and of lower socioeconomic status (60 % of them were from Hollingshead’s Classes IV and V). Of these 37 patients, 24 (65%) had moderate to severe head injuries, whereas the remaining 13 patients (35%) had had a mild TBI. Analysis of acute computed tomography (CT) and MRI scans showed that 20 of 37 patients (54 %) had diffuse patterns of TBI, whereas 17 patients (46%) had focal lesions in their initial radiological studies. Hippocampal Volumes and TBI Severity We compared hippocampal volumes among patients with mild TBI and patients with moderate to severe TBI with age as a covariate. Patients with moderate to severe head injury had significantly lower left [ANCOVA, F (3,36) ⫽ 7.0, p ⫽ .0009], right [ANCOVA, F (3,36) ⫽ 6.6, p ⫽ .0013], and total hippocampal volumes [ANCOVA, F (3,36) ⫽ 6.3, p ⬍ .0012] than patients with mild TBI. Hippocampal Volumes and Mood Disorders in Patients with TBI Mood disorders due to TBI with major depressed or mixed features were observed among 19 of 37 TBI patients (51.3%) Table 1. Background Characteristics Variable Age (mean, SD) Gender (% of women) SES (% of Classes IV–V) FIM Scores (mean, SD) MMSE Scores (mean, SD) SFE Scores (mean, SD)
Mood Disorders (n ⫽ 19)
No-Mood Disorders (n ⫽ 18)
33.6 (11.6) 47.4 64.7 64.3 (11.2) 27.3 (2.7) 202 (15)
36.8 (16.7) 55.6 55.6 63.5 (10.7) 27.6 (2.1) 240 (19)
SES, socioeconomic status; FIM, Functional Independence Measure; MMSE, Mini-Mental State Examination; SFE, Social Functioning Examination.
www.sobp.org/journal
Table 2. Severity of Traumatic Brain Injury and Neuroradiological Findings Variable GCS Score (mean, SD) Diffuse Injury (% of patients) Contusions (% of patients) Intracranial Hemorrhages (% of patients) Frontal Lesions (% of patients) Total Brain Volume (mean, SD) Left Frontal Grey Matter (% of TIV) (mean, SD)a Right Frontal Grey Matter (% of TIV) (mean, SD)
Mood Disorders (n ⫽ 19)
No-Mood Disorders (n ⫽ 18)
12.1 (2.4) 36.7 52.6
12.0 (2.3) 66.7 35.3
31.6 42.1 1305.7 (148.6)
22.2 27.8 1311.2 (131.9)
8.9 (.6)
9.4 (.6)
9.4 (.9)
9.7 (.6)
GCS, Glasgow Coma Scale; TIV, total intracranial volume. a Analysis of covariance, F ⫽ 7.8, p ⫽ .0087.
during the first 3 months after brain injury. We compared the group of TBI patients who developed mood disorders (MD, n ⫽ 19) with those patients who did not develop mood disorders during this 3-month period (no-MD, n ⫽ 18). There were no significant differences between the MD and the no-MD groups in demographic variables, degree of cognitive or activities of daily living (ADL) impairment as measured by MMSE and FIM scores, or pre-injury social functioning as measured by SFE scores (Table 1). Baseline Neurological and Neuroimaging Findings. There were no significant differences between the MD and the no-MD groups in severity of TBI as measured by the initial GCS scores. Analysis of acute CT and MRI scans demonstrated a higher frequency of focal and frontal lesions in the MD group. However, these differences did not reach statistical significance (Table 2). MRI Findings at 3-Month Follow-Up. There were no significant differences between the MD and the no-MD groups in total brain volume or the volume of identifiable lesions assessed at the 3-month MRI scan. There were no significant differences between the MD and the no-MD groups in total lobar volumes, including the left and right frontal lobes. However, patients who developed mood disorders had significantly reduced left frontal grey matter volumes than patients who did not develop mood disturbance [ANCOVA, F ⫽ 7.8, p ⫽ .0087] (Table 2). We also compared left and right hippocampal volumes between the MD and the no-MD groups, controlling for GCS scores: 1) For the left hippocampus, the ANCOVA model proved to be significant [F (3,36) ⫽ 3.4, p ⫽ .0335]. Analysis of individual variables demonstrated that patients with mood disorders have significant lower left hippocampal volumes than the no-MD group [F ⫽ 7.1, p ⫽ .0117]. In addition, there was a significant interaction between mood disorders diagnosis and severity of TBI [F ⫽ 6.2, p ⫽ .0179]. Post hoc contrasts revealed that patients with moderate to severe TBI who developed mood disorders had significantly smaller hippocampal volumes than patients with moderate to severe TBI who did not develop mood disorders [F ⫽ 4.6, p ⫽ .039]. 2) For the right hippocampus, the ANCOVA model proved to be significant [F (3,36) ⫽ 3.9, p ⫽ .0295]. Analysis of individual variables demonstrated that patients with mood disorders have significant lower right hippocampal volumes than the no-MD group [F ⫽ 9.2, p ⫽ .0047]. In addition, there was a significant interaction between mood
R.E. Jorge et al. disorders diagnosis and severity of TBI [F ⫽ 8.2, p ⫽ .0072]. Post hoc contrasts revealed that patients with moderate to severe TBI who developed mood disorders had significantly smaller hippocampal volumes than patients with moderate to severe TBI who did not develop mood disorders [F ⫽ 9.8, p ⬍ .0038]. Finally, after controlling for severity of TBI, there were no significant differences in left, right, or total hippocampal volumes between patients with a premorbid history of mood disorders and patients without such a history. In addition, there were no significant hippocampal volumetric differences between patients with and without alcohol use disorders. Hippocampal Volumes and Cognitive Functioning We collapsed our neuropsychological variables into two specific domains. The first domain gave us a global measure of memory functions and was defined as the average of the sum of Z scores from the following neuropsychological tests: RAVLT1 (Sum of Scores for Trials 1 to 5), RAVLT2 (delayed recall), RAVLT3 (recognition), and RCFT (immediate and delayed recall). The second domain was designed to provide a global estimate of executive functioning and consisted of the average of Z scores obtained in the following tests: Trails B, Stroop Interference Task, and number of perseverative errors observed during the Wisconsin Card Sorting Task (WCST). Cronbach ␣ coefficients were .69 and .80 for the executive and memory domains, respectively. Partial correlations of age, GCS scores, education, left and right hippocampus volumes, and memory and executive domain scores did not show a significant association between hippocampal volumes and cognitive domains assessed at the 3-month evaluation. Hippocampal Volume as a Predictor of Long-Term Outcome Considering the relationship between hippocampal atrophy and severity of TBI, we examined whether reduced hippocampal volumes assessed 3 months after trauma were associated with poor outcome at 1-year follow-up and, if so, what dimensions of outcome were specifically affected by hippocampus atrophy. Right, left, and total hippocampal volumes did not correlate with ADL functioning as measured by FIM scores at 1-year follow-up. In addition, hippocampal volumes were not significantly associated with cognitive functioning as measured by either MMSE scores or by patients’ performance in memory and executive functioning tests assessed at 1-year follow-up. We then examined the association between hippocampus volumes and RTPA at 1 year after TBI. A logistic regression model included age, initial GCS scores, presence of mood disorder and alcohol misuse, left frontal grey matter volume, and hippocampal volume as independent variables. The whole-model test was significant [-Log Likelihood 2 ⫽ 17.4, p ⫽ .0002]. Analysis of the individual variables showed that reduced hippocampal volumes [Wald-2 ⫽ 6.8, p ⫽ .0089] and the presence of mood disorders and alcohol misuse [Wald-2 ⫽ 6.2, p ⫽ .0126] were associated with a reduced probability of returning to productive activity.
Discussion In the present study, we examined the relationship between traumatic damage to the hippocampal formation and neurobehavioral outcome of TBI patients. Patients with moderate to severe head injury had significantly lower hippocampal volumes than patients with mild TBI. After adjusting for severity of TBI,
BIOL PSYCHIATRY 2007;62:332–338 335 patients who developed mood disorders had significantly smaller hippocampal volumes than patients who did not develop affective disturbance. In addition, there was a significant interaction between mood disorders diagnosis and severity of TBI, by which patients with moderate to severe TBI who developed mood disorders had significantly smaller hippocampal volumes than patients with equivalent severe TBI who did not develop mood disorders. We did not observe a significant association between hippocampal volume and performance in neuropsychological tasks assessing memory and executive functions. Finally, patients with reduced hippocampal volumes were less likely to return to productive activity at 1-year follow-up. Before examining the implications of these findings we need to mention the limitations of this study. Heterogeneity of clinical samples is an important confounder when analyzing the neuropsychiatric complications of TBI. We acknowledge, therefore, that our conclusions might not pertain to other groups of TBI patients. Although we have complete records of the psychiatric history of our patients, including substance misuse and affective disorders, we don’t have reliable information of the remote occurrence of physical or sexual abuse or quantitative measures of early life adversity that might affect morphometric findings of medial temporal structures. In addition, although there is consistent evidence of disruption of the hypothalamic–pituitary–adrenal (HPA) axis after brain damage, we did not obtain urinary, plasmatic, or salivary cortisol levels to be correlated with hippocampal volumes. Given these limitations, what are the most important implications of the aforementioned findings? The hippocampus is selectively vulnerable to the effect of TBI (Bigler et al. 2002; Grady et al. 2003; Rall et al. 2003; Tomaiuolo et al. 2004). Experimental studies have documented an excessive hippocampal release of glutamate (Biegon et al. 2004; Koura et al. 1998; Phillips and Reeves 2001) and acetylcholine (Dixon et al. 1995; Hayes et al. 1992; Sihver et al. 2001) and the activation of apoptotic cascades early in the course of traumatic injury (Nathoo et al. 2004; Raghupathi et al. 2000; Stone et al. 2002). Furthermore, apoptosis can be observed in subacute and chronic stages of TBI (Cernak et al. 2002; Eldadah and Faden 2000; Williams et al. 2001), and the initial glutamate and acetylcholine excess turns into chronic depletion of these neurotransmitters in hippocampus and forebrain structures (Biegon et al. 2004; Salmond et al. 2005). It is not surprising that more severe injuries are associated with greater hippocampal damage and that these pathological changes can be quantified with structural MRI techniques (Gold and Squire 2004). However, we need to explain why patients with more severe TBI who also developed mood disorders showed greater atrophic changes of the hippocampus. It is conceivable that more severe prefrontal, hippocampal, and hypothalamic damage would produce more profound changes in cognition, stress responses, and circadian rhythms that would ultimately lead to a greater vulnerability to develop mood disorders. However, we did not find a significant inverse correlation between hippocampal volume and the severity of mood symptoms. Our findings are more consistent with a “double-hit” mechanism by which neural and glial elements already affected by trauma are further compromised by the functional changes associated with mood disturbance. For instance, damaged hippocampal neurons might be more vulnerable to the neurotoxic effects of increased levels of cortisol or enhanced glutaminergic transmission that might be observed among depressed TBI patients. In turn, these pathological changes can further disrupt HPA axis responses, glutaminergic www.sobp.org/journal
336 BIOL PSYCHIATRY 2007;62:332–338 and GABAergic neurotransmission, contributing to chronic behavioral problems. The importance of multiple or combined insults in the pathogenesis of hippocampal atrophy has been recently emphasized among psychiatric populations (Vythilingam et al. 2004). We did not find significant correlations between hippocampal volumes and neuropsychological measures of memory and executive functioning. Although hippocampal and fornix atrophy has been previously associated with impaired memory function among TBI patients (Bigler et al. 2002; Tate and Bigler 2003), this association has not been consistently replicated (Serra-Grabulosa et al. 2005; Tomaiuolo et al. 2004). However, we must keep in mind that TBI is characterized by the presence of multiple lesions of the neural systems involved in complex cognitive tasks. Thus, significant correlations between neuropsychological performance and damage to individual brain structures are difficult to demonstrate. In our study, hippocampal atrophy assessed at 3 months after TBI was not associated with ADL or cognitive outcomes at 1-year follow-up. However, hippocampal volume reduction was associated with poor vocational outcome. Thus, patients with greater hippocampal damage were less likely to return to a productive life 1 year after trauma. Among TBI patients, vocational outcomes are related to several factors, such as severity of the initial injury and the age at the time of TBI (Cattelani et al. 2002; Cifu et al. 1997; Dikmen et al. 1994; Keyser-Marcus et al. 2002). Wagner et al. (2002) have shown that, rather than to the degree of impairment and disability, successful RTPA is significantly related to both home competency and social integration domains. In addition, we have previously shown that RTPA is negatively influenced by the occurrence of mood disorders and alcohol misuse during the year after TBI (Jorge et al. 2005). Interestingly, hippocampal atrophy remained a significant predictor of decreased productivity after controlling for the severity of injury and the occurrence of mood and alcohol use disorders. It is plausible that hippocampal dysfunction might also affect social cognition, reward processing, and decision making and that deficits in these areas might contribute to the detrimental effect of hippocampal damage on vocational outcome. Further studies should replicate the present findings with more sensitive imaging techniques such as magnetic resonance spectroscopy. In addition, it is important to examine whether preventing hippocampal damage early in the course of TBI would be associated with successful vocational recovery (Bigler 2002a, Tate 2000). This work was supported in part by the following National Institutes of Mental Health grants: MH-40355, MH-52879, and MH-53592. We thank R. Hansen for imaging analysis and T. Kopel and S. Rosazza for their precious support during this study. Andreasen N, Cizadlo T, Harris G, Swayze V 2nd, O’Leary DS, Cohen G, et al. (1993): Voxel processing techniques for the ante mortem study of neuroanatomy and neuropathology using magnetic resonance imaging. J Neuropsychiatry Clin Neurosci 5:121–130. Andreasen N, Cohen G, Harris G, Cizadlo T, Parkkinen J, Rezai K, Swayze VW 2nd (1992): Image processing for the study of brain structure and function: Problems and programs. J Neuropsychiatry Clin Neurosci 4:125–133. Andreasen NC, Endicott J, Spitzer RL, Winokur G (1977): The family history method using diagnostic criteria. Arch Gen Psychiatry 34:1229 –1235. Andreasen NC, Harris G, Cizadlo T, Arndt S, O’Leary DS, Swayze V, Flaum M (1994): Techniques for measuring sulcal/gyral patterns in the brain as visualized through magnetic resonance scanning: BRAINPLOT and BRAINMAP. Proc Natl Acad Sci USA 91:93–97.
www.sobp.org/journal
R.E. Jorge et al. Andreasen NC, Rajarethinam R, Cizadlo T, Arndt S, Swayze VW 2nd, Flashman LA, et al. (1996): Automatic atlas-based volume estimation of human brain regions from MR images. J Comput Assist Tomogr 20:98 –106. Arciniegas DB, Topkoff JL, Rojas DC, Sheeder J, Teale P, Young DA, et al. (2001): Reduced hippocampal volume in association with p50 nonsuppression following traumatic brain injury. J Neuropsychiatry Clin Neurosci 13:213–221. Ariza M, Junque C, Mataro M, Poca MA, Bargallo N, Olondo M, Sahuquillo J (2004): Neuropsychological correlates of basal ganglia and medial temporal lobe NAA/Cho reductions in traumatic brain injury. Arch Neurol 61:541–544. Ariza M, Serra-Grabulosa JM, Junque C, Ramirez B, Mataro M, Poca A, et al. (2006): Hippocampal head atrophy after traumatic brain injury. Neuropsychologia 44:1956 –1961. Axelson DA, Doraiswamy PM, McDonald WM, Boyko OB, Tupler LA, Patterson LJ, et al. (1993): Hypercortisolemia and hippocampal changes in depression. Psychiatry Res 47:163–173. Bell-McGinty S, Butters MA, Meltzer CC, Greer PJ, Reynolds CF 3rd, Becker JT (2002): Brain morphometric abnormalities in geriatric depression: Longterm neurobiological effects of illness duration. Am J Psychiatry 159: 1424 –1427. Benton AL, Hamsher K, Sivan AB (1994): Multilingual Aphasia Examination. Iowa City, Iowa: AJA Associates. Biegon A, Fry PA, Paden CM, Alexandrovich A, Tsenter J, Shohami E (2004): Dynamic changes in N-methyl-D-aspartate receptors after closed head injury in mice: Implications for treatment of neurological and cognitive deficits. Proc Natl Acad Sci U S A 101:5117–5122. Bigler ED (2003): Neurobiology and neuropathology underlie the neuropsychological deficits associated with traumatic brain injury. Arch Clin Neuropsychol 18:595– 621; discussion 623– 627. Bigler ED, Anderson CV, Blatter DD (2002a): Temporal lobe morphology in normal aging and traumatic brain injury. AJNR Am J Neuroradiol 23:255– 266. Bigler ED, Blatter DD, Anderson CV, et al. (1997): Hippocampal volume in normal aging and traumatic brain injury. AJNR Am J Neuroradiol 18: 11–23. Blatter DD, Bigler ED, Gale SD, Johnson SC, Anderson CV, Burnett BM, et al. (1997): MR-based brain and cerebrospinal fluid measurement after traumatic brain injury: Correlation with neuropsychological outcome. AJNR Am J Neuroradiol 18:1–10. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS (2000): Hippocampal volume reduction in major depression. Am J Psychiatry 157:115–158. Brown ES, Rush AJ, McEwen BS (1999): Hippocampal remodeling and damage by corticosteroids: Implications for mood disorders. Neuropsychopharmacology 21:474 – 484. Campbell S, Marriott M, Nahmias C, MacQueen GM (2004): Lower hippocampal volume in patients suffering from depression: A meta-analysis. Am J Psychiatry 161:598 – 607. Cattelani R, Tanzi F, Lombardi F, Mazzucchi A (2002): Competitive re-employment after severe traumatic brain injury: Clinical, cognitive and behavioural predictive variables. Brain Inj 16:51– 64. Cernak I, Chapman S, Hamlin G, Vink R (2002): Temporal characterisation of pro- and anti-apoptotic mechanisms following diffuse traumatic brain injury in rats. J Clin Neurosci 9:565. Cifu DX, Keyser-Marcus L, Lopez E, Wehman P, Kreutzer JS, Englander J, High W (1997): Acute predictors of successful return to work 1 year after traumatic brain injury: A multicenter analysis. Arch Phys Med Rehabil 78:125–131. Cohen G, Andreasen NC, Alliger R, Arndt S, Kuan J, Yuh WT, Ehrhardt J (1992): Segmentation techniques for the classification of brain tissue using magnetic resonance imaging. Psychiatry Res 45:33–51. Colicos MA, Dixon CE, Dash PK (1996): Delayed, selective neuronal death following experimental cortical impact injury in rats: Possible role in memory deficits. Brain Res 739:111–119. DeKosky ST, Taffe KM, Abrahamson EE, Dixon CE, Kochanek PM, Ikonomovic MD (2004): Time course analysis of hippocampal nerve growth factor and antioxidant enzyme activity following lateral controlled cortical impact brain injury in the rat. J Neurotrauma 21:491–500. Delorenzo RJ, Sun DA, Deshpande LS (2005): Cellular mechanisms underlying acquired epilepsy: The calcium hypothesis of the induction and maintenance of epilepsy. Pharmacol Ther 105:229 –266.
R.E. Jorge et al. Dikmen SS, Temkin NR, Machamer JE, Holubkov AL, Fraser RT, Winn HR (1994): Employment following traumatic head injuries. Arch Neurol 51: 177–186. Dixon CE, Liu SJ, Jenkins LW, Bhattachargee M, Whitson JS, Yang K, Hayes RL (1995): Time course of increased vulnerability of cholinergic neurotransmission following traumatic brain injury in the rat. Behav Brain Res 70: 125–131. Eldadah BA, Faden AI (2000): Caspase pathways, neuronal apoptosis, and CNS injury. J Neurotrauma 17:811– 829. Evans DL, Charney DS, Lewis L, Golden RN, Gorman JM, Krishnan KR, et al. (2005): Mood disorders in the medically ill: Scientific review and recommendations. Biol Psychiatry 58:175–189. Folstein MF, Folstein SE, McHugh PR (1975): Mini-Mental State: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189 –198. Frodl T, Meisenzahl EM, Zetzsche T, Born C, Groll C, Jager M, et al. (2002): Hippocampal changes in patients with a first episode of major depression. Am J Psychiatry 159:1112–1118. Frodl T, Meisenzahl EM, Zill P, Baghai T, Rujescu D, Leinsinger G, et al. (2004): Reduced hippocampal volumes associated with the long variant of the serotonin transporter polymorphism in major depression. Arch Gen Psychiatry 61:177–183. Gale SD, Baxter L, Roundy N, Johnson SC (2005): Traumatic brain injury and grey matter concentration: A preliminary voxel based morphometry study. J Neurol Neurosurg Psychiatry 76:984 –988. Gold JJ, Squire LR (2004): Quantifying medial temporal lobe damage in memory-impaired patients. Hippocampus 15:79 – 85. Golden CJ (1978): Stroop Color and Word Test. Chicago: Stoelting. Grady MS, Charleston JS, Maris D, Witgen BM, Lifshitz J (2003): Neuronal and glial cell number in the hippocampus after experimental traumatic brain injury: Analysis by stereological estimation. J Neurotrauma 20:929 –941. Hajek T, Carrey N, Alda M (2005): Neuroanatomical abnormalities as risk factors for bipolar disorder. Bipolar Disord 7:393– 403. Hamilton MA (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56 – 62. Harris G, Andreasen NC, Cizadlo T (1999): Improving tissue classification in MRI: A three-dimensional multispectral discriminant analysis method with automated training class selection. J Comput Assist Tomogr 23:144 – 154. Hayes RL, Jenkins LW, Lyeth BG (1992): Neurotransmitter-mediated mechanisms of traumatic brain injury: Acetylcholine and excitatory amino acids. J Neurotrauma 9(suppl 1):S173–S187. Heaton RK, Chelune GJ, Tailey JL (1993): The Wisconsin Card Sorting Test. Odessa, Florida: Psychological Assessment Resources. Jorge RE, Robinson RG, Moser D, Tateno A, Crespo-Facorro B, Arndt S (2004): Major depression following traumatic brain injury. Arch Gen Psychiatry 61:42–50. Jorge RE, Starkstein SE, Arndt S, Moser D, Crespo-Facorro B, Robinson RG (2005): Alcohol misuse and mood disorders following traumatic brain injury. Arch Gen Psychiatry 62:742–749. Keyser-Marcus LA, Bricout JC, Wehman P, Campbell LR, Cifu DX, Englander J, et al. (2002): Acute predictors of return to employment after traumatic brain injury: a longitudinal follow-up. Arch Phys Med Rehabil 83:635– 641. Kotapka MJ, Gennarelli TA, Graham DI, Adams JH, Thibault LE, Ross DT, Ford I (1991): Selective vulnerability of hippocampal neurons in accelerationinduced experimental head injury. J Neurotrauma 8:247–258. Kotapka MJ, Graham DI, Adams JH, Gennarelli TA (1994): Hippocampal pathology in fatal human head injury without high intracranial pressure. J Neurotrauma 11:317–324. Koura SS, Doppenberg EM, Marmarou A, Choi S, Young HF, Bullock R (1998): Relationship between excitatory amino acid release and outcome after severe human head injury. Acta Neurochir Suppl (Wien) 71:244 –246. Levin HS (1992): Neurobehavioral recovery. J Neurotrauma 9(suppl 1):S359 – S373. Levin HS, Amparo E, Eisenberg HM, Williams DH, High WM Jr., McArdle CB, Weiner RL (1987): Magnetic resonance imaging and computerized tomography in relation to the neurobehavioral sequelae of mild and moderate head injuries. J Neurosurg 66:706 –713. Lezak M (1983): Neuropsychological Assessment, 2nd ed. New York: Oxford University Press. MacKenzie EJ, Shapiro S, Eastham JN (1985): The Abbreviated Injury Scale and Injury Severity Score. Levels of inter- and intrarater reliability. Med Care 23:823– 835.
BIOL PSYCHIATRY 2007;62:332–338 337 MacKenzie JD, Siddiqi F, Babb JS, Bagley LJ, Mannon LJ, Sinson GP, Grossman RI (2002): Brain atrophy in mild or moderate traumatic brain injury: A longitudinal quantitative analysis. AJNR Am J Neuroradiol 23:1509 –1515. MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, et al. (2003): Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A 100:1387–1392. Magnotta V, Andreasen NC, Schultz SK, Harris G, Cizadlo T, Heckel D, et al. (1999a): Quantitative in vivo measurement of gynification in the human brain: Changes associated with aging. Cerebral Cortex 9:151–160. Magnotta V, Heckel D, Andreasen NC, Cizadlo T, Corson PW, Ehrhardt JC, Yuh WT (1999b): Measurement of brain structures by artificial neural networks: Two-dimensional and three-dimensional applications. Radiology 211:781–790. McCarthy MM (2003): Stretching the truth. Why hippocampal neurons are so vulnerable following traumatic brain injury. Exp Neurol 184:40 – 43. McEwen BS (2000): Allostasis and allostatic load: Implications for neuropsychopharmacology. Neuropsychopharmacology 22:108 –124. Mervaala E, Fohr J, Kononen M, Valkonen-Korhonen M, Vainio P, Partanen K, et al. (2000): Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med 30:117–125. Nathoo N, Narotam PK, Agrawal DK, Connolly CA, van Dellen JR, Barnett GH, Chetty R (2004): Influence of apoptosis on neurological outcome following traumatic cerebral contusion. J Neurosurg 101:233–240. Pantel J, O’Leary DS, Cretsinger K, Bockholt HJ, Keefe H, Magnotta VA, Andreasen NC (2000): A new method for the in vivo volumetric measurement of the human hippocampus with high neuroanatomical accuracy. Hippocampus 10:752–758. Phillips LL, Reeves TM (2001): Interactive pathology following traumatic brain injury modifies hippocampal plasticity. Restor Neurol Neurosci 19: 213–235. Povlishock JT, Katz DI (2005): Update of neuropathology and neurological recovery after traumatic brain injury. J Head Trauma Rehabil 20:76 –94. Raghupathi R, Graham DI, McIntosh TK (2000): Apoptosis after traumatic brain injury. J Neurotrauma 17:927–938. Rall JM, Matzilevich DA, Dash PK (2003): Comparative analysis of mRNA levels in the frontal cortex and the hippocampus in the basal state and in response to experimental brain injury. Neuropathol Appl Neurobiol 29: 118 –131. Reitan RM (1971): Trail making test results for normal and brain-damaged children. Percept Mot Skills 33:575–581. Salmond CH, Chatfield DA, Menon DK, Pickard JD, Sahakian BJ (2005): Cognitive sequelae of head injury: Involvement of basal forebrain and associated structures. Brain 128:189 –200. Sapolsky RM (2000): Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry 57:925–935. Sapolsky RM, Pulsinelli WA (1985): Glucocorticoids potentiate ischemic injury to neurons: Therapeutic implications. Science 229:1397–1400. Serra-Grabulosa JM, Junque C, Verger K, Salgado-Pineda P, Maneru C, Mercader JM (2005): Cerebral correlates of declarative memory dysfunctions in early traumatic brain injury. J Neurol Neurosurg Psychiatry 76:129 –131. Sheline YI, Gado MH, Kraemer HC (2003): Untreated depression and hippocampal volume loss. Am J Psychiatry 160:1516 –1518. Sheline YI, Sanghavi M, Mintun MA, Gado MH (1999): Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci 19:5034 –5043. Shiozaki T, Akai H, Taneda M, Hayakata T, Aoki M, Oda J, et al. (2001): Delayed hemispheric neuronal loss in severely head-injured patients. J Neurotrauma 18:665– 674. Sihver S, Marklund N, Hillered L, Langstrom B, Watanabe Y, Bergstrom M (2001): Changes in mACh, NMDA and GABA(A) receptor binding after lateral fluid-percussion injury: In vitro autoradiography of rat brain frozen sections. J Neurochem 78:417– 423. Smith DH, Chen XH, Pierce JE, Wolf JA, Trojanowski JQ, Graham DI, McIntosh TK (1997): Progressive atrophy and neuron death for one year following brain trauma in the rat. J Neurotrauma 14:715–727. Spitzer RL, Williams JB, Gibbon M, First MB (1992): The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description. Arch Gen Psychiatry 49:624 – 629. Starr LB, Robinson RG, Price TR (1983): The social functioning exam: An assessment of stroke patients. Soc Work Res Abstr 18:28 –33. Steffens DC, Byrum CE, McQuoid DR, Greenberg DL, Payne ME, Blitchington TF, et al. (2000): Hippocampal volume in geriatric depression. Biol Psychiatry 48:301–309.
www.sobp.org/journal
338 BIOL PSYCHIATRY 2007;62:332–338 Stone JR, Okonkwo DO, Singleton RH, Mutlu LK, Helm GA, Povlishock JT (2002): Caspase-3-mediated cleavage of amyloid precursor protein and formation of amyloid Beta peptide in traumatic axonal injury. J Neurotrauma 19:601– 614. Tate DF, Bigler ED (2000): Fornix and hippocampal atrophy in traumatic brain injury. Learn Mem 7:442– 446. Teasdale G, Jennett B (1976): Assessment and prognosis of coma after head injury. Acta Neurochir (Wien) 34:45–55. Thurman DJ, Alverson C, Dunn KA, Guerrero J, Sniezek JE (1999): Traumatic brain injury in the United States: A public health perspective. J Head Trauma Rehabil 14:602– 615. Tomaiuolo F, Carlesimo GA, Di Paola M, Petrides M, Fera F, Bonanni R, et al. (2004): Gross morphology and morphometric sequelae in the hippocampus, fornix, and corpus callosum of patients with severe nonmissile traumatic brain injury without macroscopically detectable lesions: A T1 weighted MRI study. J Neurol Neurosurg Psychiatry 75:1314 – 1322. Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF, Bonello-Cintron CM, Yurgelun-Todd DA (2000): Hippocampal volume in primary unipolar major depression: A magnetic resonance imaging study. Biol Psychiatry 47: 1087–1090. Videbech P, Ravnkilde B (2004): Hippocampal volume and depression: A meta-analysis of MRI studies. Am J Psychiatry 161:1957–1966.
www.sobp.org/journal
R.E. Jorge et al. Vythilingam M, Heim C, Newport J, Miller AH, Anderson E, Bronen R, et al. (2002): Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry 159:2072–2080. Vythilingam M, Vermetten E, Anderson GM, Luckenbaugh D, Anderson ER, Snow J, et al. (2004): Hippocampal volume, memory, and cortisol status in major depressive disorder: Effects of treatment. Biol Psychiatry 56:101– 112. Wagner AK, Hammond FM, Sasser HC, Wiercisiewski D (2002): Return to productive activity after traumatic brain injury: Relationship with measures of disability, handicap, and community integration. Arch Phys Med Rehabil 83:107–114. Williams JB, Gibbon M, First MB, Spitzer RL, Davies M, Borus J, et al. (1992): The Structured Clinical Interview for DSM-III-R (SCID). II. Multisite testretest reliability. Arch Gen Psychiatry 49:630 – 636. Williams S, Raghupathi R, MacKinnon MA, McIntosh TK, Saatman KE, Graham DI (2001): In situ DNA fragmentation occurs in white matter up to 12 months after head injury in man. Acta Neuropathol (Berl) 102:581–590. Wilson JT, Hadley DM, Wiedmann KD, Teasdale GM (1995): Neuropsychological consequences of two patterns of brain damage shown by MRI in survivors of severe head injury. J Neurol Neurosurg Psychiatry 59:328 –331. Wing JK, Babor T, Brugha T, Burke J, Cooper JE, Giel R, et al. (1990): SCAN. Schedules for Clinical Assessment in Neuropsychiatry. Arch Gen Psychiatry 47:589 –593.