Hippocampal Volumes in Patients With Chronic Combat-Related Posttraumatic Stress Disorder: A Systematic Review
Abstract
Methods
![](/cms/10.1176/appi.neuropsych.12010003/asset/images/large/12f1.jpeg)
Review Process
Results
Brain Area | (N) Positive Studiesa (p≤0.05) | (+) Total QS | (+) Mean QS | (N) Negative Studies (p>0.05) | (−) Total QS | (−) Mean QS |
---|---|---|---|---|---|---|
Hippocampus | (9) Bremner et al;18 Gilbertson et al;9 Gurvits et al;22 Hedges et al;23 Kasai et al;25 Pavić et al;30 Vythilingam et al;33 Wang et al;34 Woodward et al36 | 30 | 3.33 | (3) Hedges et al;24 Neylan et al;29 Schuff et al32 | 6 | 2.00 |
Mean/total hippocampus | (6) Gilbertson et al;9 Gurvits et al;22 Hedges et al;23 Vythilingam et al;33 Wang et al;34 Woodward et al36 | 20 | 3.33 | (4) Bremner et al;18 Hedges et al;24 Neylan et al;29 Pavić et al30 | 12 | 3.00 |
L hippocampus | (3) Gurvits et al;22 Hedges et al;23 Vythilingam et al33 | 9 | 3.00 | (6) Bremner et al;18 Gilbertson et al;9 Hedges et al;24 Kasai et al;25 Neylan et al;29 Pavić et al30 | 20 | 3.33 |
R hippocampus | (6) Bremner et al;18 Gilbertson et al;9 Hedges et al;23 Kasai et al;25 Pavić et al;30 Vythilingam et al33 | 20 | 3.33 | (4) Gurvits et al;22 Hedges et al;24 Neylan et al;29 Schuff et al32 | 9 | 2.25 |
Frontal lobe cortex | (2) Geuze et al;20 Woodward et al38 | 7 | 3.50 | (1) Hedges et al24 | 2 | 2.00 |
Temporal lobe cortex | (2) Geuze et al;20 Woodward et al38 | 7 | 3.50 | (3) Bremner et al;18 Hedges et al;24 Vythilingam et al33 | 9 | 3.00 |
Parietal lobe cortex | (0) | NA | NA | (1) Woodward et al38 | 4 | 4.00 |
Occipital lobe cortex | (0) | NA | NA | (1) Woodward et al38 | 4 | 4.00 |
Paralimbic cortex | (3) Kasai et al;25 Woodward et al;35 Woodward et al38 | 12 | 4.00 | (1) Hedges et al24 | 2 | 2.00 |
ACC | (3) Kasai et al;25 Woodward et al;35 Woodward et al38 | 12 | 4.00 | (0) | NA | NA |
Non-ACC | (2) Kasai et al;25 Woodward et al38 | 8 | 4.00 | (1) Hedges et al24 | 2 | 2.00 |
Amygdala | (1) Pavliša et al31 | 3 | 3.00 | (3) Gilbertson et al;9 Gurvits et al;22 Hedges et al24 | 9 | 3.00 |
Cerebellum | (1) Levitt et al26 | 4 | 4.00 | (0) | NA | NA |
White matter | (2) Canive et al;19 Hedges et al24 | 4 | 2.00 | (1) Hedges et al23 | 2 | 2.00 |
Septum pellucidum | (2) May et al;27 Myslobodsky et al28 | 6 | 3.00 | (0) | NA | NA |
QS | Study | WBA or ROI β (T) / Slice Thickness (mm) | Subject Groups | Description | N M/F | Mean Age (SD) | Brain Area(s) | Main Findings |
---|---|---|---|---|---|---|---|---|
4 | Gilbertson et al21 | ROI 1.5 T / 1.5 mm | Cohort | Vietnam veterans with severe combat-related PTSD (CAPS >65) | 12 12/0 | 53.1 | Total hippocampus | ↓ volume in PTSD+ twin pair vs. PTSD− twin pair (p=0.004); volume difference within twin pairs: NS |
PTSD+ veterans | (3.3) | |||||||
Control 1 | Twin siblings of PTSD+ veterans | 12 | 53.1 | |||||
Twins of PTSD+ | 12/0 | (3.3) | ||||||
Control 2 | Vietnam combat veterans without PTSD | 23 | 51.8 | R hippocampus | ↓ volume in PTSD+ twin pair vs. PTSD− twin pair (p=0.003); volume difference within twin pairs: NS | |||
PTSD− veterans | 23/0 | (2.3) | ||||||
Control 3 | Twin siblings of PTSD− veterans | 23 | 51.8 | |||||
Twins of PTSD− | 23/0 | (2.3) | ||||||
4 | Vythilingam et al33 | ROI 1.5 T / 1.5 mm | Cohort | Gulf War veterans with combat-related PTSD | 14 | 35 | Mean hippocampal head | ↓ volume in cohort versus civilian control (p<0.04); difference between cohort and reservist or combat controls: NS |
8/6 | (9) | |||||||
Control 1 | Gulf War combat veterans without PTSD | 23 | 35 | Left hippocampal head | ↓ volume in cohort vs. civilian control (p<0.04); difference between cohort and reservist or combat controls: NS | |||
Vietnam | 15/8 | (7) | ||||||
Control 2 | Non-deployed reservists without PTSD | 22 | 39 | Right hippocampal head | ↓ volume in cohort vs. civilian control (p<0.04); difference between cohort and reservist or combat controls: NS | |||
Reservist | 9/13 | (7) | ||||||
Control 3 | Healthy civilians without PTSD | 29 | 34 | |||||
Civilian | 9/20 | (10) | ||||||
4 | Woodward et al36 | ROI 1.5 T / 1.5–1.7 mm | Cohort 1 | Vietnam veterans with combat-related PTSD | 38 | 53.5 | Hippocampus | 9% smaller in PTSD+/Alcohol+ subgroup vs. PTSD−/ Alcohol+ subgroup (p=0.002); inversely correlated with Combat Exposure Scale score in Vietnam cohort vs. Vietnam control (p<0.03). |
Vietnam | 38/0 | (2.6) | ||||||
Cohort 2 | Gulf War veterans with combat-related PTSD | 13 | 37.0 | |||||
Gulf War | 13/0 | (5.7) | ||||||
Control 1 | Vietnam veterans without PTSD | 25 | 56.0 | |||||
Vietnam | 25/0 | (3.5) | ||||||
Control 2 | Gulf War veterans without PTSD | 23 | 36.7 | |||||
Gulf War | 19/4 | (3.9) | ||||||
3 | Bremner et al18 | ROI 1.5 T / 3 mm | Cohort | Vietnam veterans with combat-related PTSD | 26 | 46.0 | R hippocampus | 8.0% smaller in cohort vs. control (p=0.03) |
26/0 | (1.8) | |||||||
Control | Civilians without PTSD; matched for age, sex, race, handedness, height, weight, education, socioeconomic level, and years of Alcohol abuse | 22 | 44.5 | |||||
22/0 | (7.3) | |||||||
3 | Gurvits et al22 | ROI 1.5 T / 1.5 mm | Cohort | Vietnam veterans with combat-related PTSD | 7 | 44.4 | Total hippocampus | Volume correlated with ↑ CAPS score (p=0.001) and ↑ M-PTSD score (p=0.03), both measures of PTSD severity |
7/0 | (1.7) | |||||||
Control 1 | Vietnam combat veterans without PTSD | 7 | 47.6 | L hippocampus | ↓ volume in cohort vs. veteran and civilian control (p<0.001); finding significant after controlling for months of Alcohol abuse and Combat Exposure Scale score (p=0.02) | |||
Veteran | 7/0 | (2.9) | ||||||
Control 2 | Civilians without PTSD | 8 | 38.1 | R hippocampus | ↓ volume in cohort vs. veteran and civilian controls (p<0.001); finding NS after controlling for months of Alcohol abuse and Combat Exposure Scale score | |||
Civilian | 8/0 | (10.0) | ||||||
3 | Pavić et al30 | ROI 2.0 T / 1.1 mm | Cohort | Croatian War veterans with combat-related PTSD; 9 years post-traumatic event | 15 | 41.0 | R hippocampus | ↓ volume in cohort vs. control (p<0.05) |
15/0 | (5.37) | |||||||
Control | Civilian controls; matched for age, sex, handedness, education, and socioeconomic level | 15 | ||||||
15/0 | ||||||||
3 | Wang et al34 | ROI 4.0 T / 1 mm | Cohort | Veterans with combat-related PTSD | 17 | 41 | Total hippocampus | ↓ volume in cohort vs. control (p=0.05); PTSD diagnosis explains 31% of variance; age explains 56% of variance |
17/0 | (12) | |||||||
Control | Veterans without PTSD; matched for age | 19 | 38 | CA3 / dentate gyrus | 11.4% (1.5% SD) smaller in cohort vs. control (p=0.02) | |||
19/0 | (15) | |||||||
2 | Hedges et al23 | ROI 1.5 T / 1 mm | Cohort | Vietnam veterans with combat-related PTSD | 4 | 54.5 | L hippocampus | ↓ volume in cohort vs. control (p=0.029) |
4/0 | (6.02) | |||||||
Control | Civilians without PTSD; matched for age and total intracranial volume | 4 | 54.3 | R hippocampus | ↓ volume in cohort vs. control (p=0.029) | |||
4/0 | (7.09) |
QS | Study | WBA or ROI β (T) / Slice Thickness (mm) | Subject Groups | Description | N M/F | Mean Age (SD) | Brain Areas(s) | Main Finding(s) |
---|---|---|---|---|---|---|---|---|
4 | Kasai et al25 | ROI 1.5 T / 1.5 mm | Cohort | Vietnam veterans with severe combat-related PTSD | 18 | 52.8 | Pregenual ACC | ↓ gray-matter density in PTSD+ veterans vs. PTSD- veterans (p=0.004); ↓ gray-matter density in PTSD+ veterans vs. all controls (p=0.02); significant correlation with symptom cluster B (re-experiencing; p=0.008) |
PTSD+ veterans | 18/0 | (3.4) | ||||||
Control 1 | Twin siblings of PTSD+ veterans | 18 | 52.8 | |||||
Twins of PTSD+ | 18/0 | (3.4) | ||||||
Control 2 | Vietnam combat veterans w/o PTSD | 23 | 51.8 | |||||
PTSD− veterans | 23/0 | (2.3) | ||||||
Control 3 | Twin siblings of PTSD− veterans | 23 | 51.8 | |||||
Twins of PTSD− | 23/0 | (2.3) | ||||||
4 | Woodward et al35 | ROI 1.5 T / 1.5–1.7 mm | Cohort 1 | Vietnam veterans with combat-related PTSD | 38 | 53.5 | ACC | ↓ volume in both cohorts vs. both controls (p=0.001); still significant in Alcohol− subgroups (p=0.012); volume inversely correlated with total CAPS score (p<0.001) and total M-PTSD score (p<0.001) |
Vietnam | 38/0 | (2.6) | ||||||
Cohort 2 | Gulf War veterans with combat-related PTSD | 13 | 37.0 | |||||
Gulf War | 10/3 | (5.7) | ||||||
Control 1 | Vietnam veterans without PTSD | 25 | 56.0 | |||||
Vietnam | 25/0 | (3.5) | ||||||
Control 2 | Gulf War veterans without PTSD | 23 | 36.7 | |||||
Gulf War | 19/4 | (3.9) | ||||||
4 | Woodward et al38 (All results adjusted for stature and cerebral white-matter volume.) | WBA 1.5 T / 1.5–1.7 mm | Cohort 1 | Alcohol+ veterans with combat-related PTSD | 24 | 50.3 | Parahippocampal gyrus | ↓ volume associated with PTSD (p<0.001) |
Alcohol+ | NR | (2.6) | ||||||
Cohort 2 | Alcohol− veterans with combat-related PTSD | 26 | 48.3 | |||||
Alcohol− | NR | (9.0) | ||||||
Control 1 | Alcohol+ combat veterans without PTSD | 19 | 47.1 | Rostral (pregenual) ACC | ↓ volume associated with PTSD (p<0.03) | |||
Alcohol+ | NR | (11.1) | ||||||
Control 2 | Alcohol− combat veterans without PTSD | 28 | 45.9 | Caudal (dorsal) ACC | ↓ volume associated with PTSD (p<0.01) | |||
Alcohol− | NR | (9.5) | ||||||
3 | Pavliša et al31 | ROI 2.0 T / 1.1 mm | Cohort | Croatian War veterans with combat-related PTSD | 11 | 40.0 | Amygdala | R smaller than L in cohort (p=0.031); ↓ R-to-L ratio in cohort versus Szabo control (p<0.0001); ↓ R-to-L ratio in cohort versus Bower control (p=0.0005) |
11/0 | (5.44) | |||||||
Control 1 | Healthy, alcohol-free civilian comparison group from Szabo et al., matched for sex and handedness | 9 | 27 | |||||
Szabo | 9/0 | (NR) | ||||||
Control 2 | Healthy, alcohol-free civilian comparison group without past head injury, medical or psychiatric history, from Bower et al., matched for sex and handedness | 31 | NR | |||||
Bower | 31/0 |
QS | Study | WBA or ROI β (T) / Slice Thickness (mm) | Subject Groups | Description | N M/F | Mean Age (SD) | Brain Area(s) | Main Finding(s) |
---|---|---|---|---|---|---|---|---|
4 | Woodward et al38 (All results adjusted for stature and cerebral white-matter volume.) | WBA 1.5 T / 1.5–1.7 mm | Cohort 1Alcohol+ | Alcohol+ veterans with combat-related PTSD | 24NR | 50.3(2.6) | Total cortexParcellated cortex | PTSD associated with ↓ volume (p<0.001), ↓ thickness (p=0.03) |
↓ volume associated with PTSD (p<0.001) | ||||||||
Cohort 2 | Alcohol−veterans with combat-related PTSD | 26 | 48.3 | Superior and transverse temporal cortex | ↓ volume associated with PTSD (p<0.001), ↓ thickness (p=0.04), ↓ area (p=0.003) | |||
Alcohol− | NR | (9.0) | ||||||
Control 1 | Alcohol+combat veterans without PTSD | 19 | 47.1 | Lateral division of orbital frontal cortex | ↓ volume associated with PTSD (p=0.001) | |||
Alcohol+ | NR | (11.1) | ||||||
Control 2 | Alcohol−combat veterans without PTSD | 28 | 45.9 | Pars orbitalis of inferior frontal gyrus | ↓ volume associated with PTSD (p=0.002) | |||
Alcohol− | NR | (9.5) | ||||||
4 | Kasai et al25 | ROI 1.5 T / 1.5 mm | Cohort | Vietnam veterans with severe combat-related PTSD | 18 | 52.8 | R midinsula | ↓ gray-matter density in PTSD+ veterans vs. PTSD− veterans (p=0.001); significant correlation with symptom cluster B (re-experiencing; p=0.006) |
PTSD+ veterans | 18/0 | (3.4) | ||||||
Control 1 | Twin siblings of PTSD+ veterans | 18 | 52.8 | L anterior insula | ↓ gray-matter density in PTSD+ veterans vs. PTSD− veterans (p=0.005); significant correlation with symptom cluster B (re-experiencing; p=0.013) | |||
Twins of PTSD+ veterans | 18/0 | (3.4) | ||||||
Control 2 | Vietnam combat veterans w/o PTSD | 23 | 51.8 | |||||
PTSD− veterans | 23/0 | (2.3) | ||||||
Control 3 | Twin siblings of PTSD- veterans | 23 | 51.8 | |||||
Twins of PTSD+ veterans | 23/0 | (2.3) | ||||||
3 | Geuze et al20 | ROI 1.5 T / 1.2 mm | Cohort | Dutch veterans with combat-related PTSD | 2525/0 | 35.08(4.44) | L superior frontal gyrus | ↓ cortical thickness in cohort vs. control (p=0.001) |
L middle frontal gyrus | ↓ cortical thickness in cohort vs. control (p=0.004) | |||||||
L inferior temporal gyrus | ↓ cortical thickness in cohort vs. control (p=0.012) | |||||||
Control | Dutch combat veterans without PTSD; matched for age, sex, time since trauma, year, and country of development. | 2525/0 | 34.01(5.61) | L superior temporal gyrus | ↓ cortical thickness in cohort versus control (p=0.032) | |||
R superior frontal gyrus | ↓ cortical thickness in cohort vs. control (p=0.018) | |||||||
R middle frontal gyrus | ↓ cortical thickness in cohort vs. control (p=0.026) | |||||||
2 | Canive et al19 | WBA NR | Cohort | Veterans with combat-related PTSD | 42 | NR | Cortex | ↑ incidence of cortical atrophy in cohort vs. control (p value NR) |
42/0 | ||||||||
Control | Civilians without PTSD, matched for average age (±5 years) | 20 | NR | |||||
20/0 |
QS | Study | WBA or ROI β (T) / Slice Thickness (mm) | Subject Groups | Description | N M/F | Mean Age (SD) | Brain Area(s) | Main Finding(s) |
---|---|---|---|---|---|---|---|---|
4 | Levitt et al26 | ROI 1.5 T / 1.5 mm | Cohort | Vietnam veterans with severe combat-related PTSD | 18 | 52.5 | Anterior superior cerebellar vermis | Volume correlated between twins (p<0.0001); volume difference in PTSD+ veterans and their twins vs. PTSD− veterans and their twins: NS |
PTSD+ veterans | 18/0 | (3.2) | ||||||
Control 1 | Twin siblings of PTSD+ veterans | 20 | 52.8 | Posterior superior cerebellar vermis | Volume correlated between twins (p=0.003); volume difference in PTSD+ veterans and their twins vs. PTSD− veterans and their twins: NS | |||
Twins of PTSD+ | 20/0 | (3.2) | ||||||
Control 2 | Vietnam combat veterans without PTSD | 22 | 51.7 | Inferior posterior cerebellar vermis | Volume correlated between twins (p=0.001); volume difference in PTSD+ veterans and their twins vs. PTSD− veterans and their twins: NS | |||
PTSD− veterans | 22/0 | (2.3) | ||||||
Control 3 | Twin siblings of PTSD− veterans | 23 | 51.8 | Total cerebellar vermis | Volume correlated between twins (p<0.001); volume difference in PTSD+ veterans and their twins vs. PTSD− veterans and their twins: NS | |||
Twins of PTSD− | 23/0 | (2.3) | ||||||
4 | Woodward et al37 | ROI 1.5 T / 1.5–1.7 mm | Cohort 1 | Vietnam veterans with combat-related PTSD | 38 | 53.5 | Sulcal CSF | ↓ volume in Vietnam cohort vs. Vietnam control, Alcohol− only (p<0.01); ↓ volume in Gulf War cohort vs. Gulf War control, no Alcohol interaction (p<0.01); ↓ volume in both cohorts vs. both controls, no Alcohol interaction (p<0.01) |
Vietnam | 38/0 | (2.6) | ||||||
Cohort 2 | Gulf War veterans with combat-related PTSD | 13 | 37.0 | |||||
Gulf War | 10/3 | (5.7) | ||||||
Control 1 | Vietnam veterans without PTSD | 25 | 56.0 | Total cranium | ↓ volume in Vietnam cohort vs. Vietnam control, no Alcohol interaction (p<0.01); ↓ volume in Gulf War cohort vs. Gulf War control (p<0.01), with ↓ volume in Gulf War Alcohol+ versus Gulf War Alcohol− (p<0.01); in all subjects; ↓ volume associated with PTSD+ (p<0.001), Alcohol+ (p<0.05), Gulf War veterans (p<0.001) | |||
Vietnam | 25/0 | (3.5) | ||||||
Control 2 | Gulf War veterans without PTSD | 23 | 36.7 | |||||
Gulf War | 19/4 | (3.9) | ||||||
3 | May et al27 | ROI 1.5 T / 1.5 mm | Cohort | Vietnam veterans with severe combat-related PTSD | 20 | 52.3 | Septum pellucidum | Presence of cavum septum pellucidum significantly correlated between twins (p=0.01); correlation based on PTSD diagnosis: NS; correlation based on PTSD diagnosis × combat exposure: NS |
PTSD+ veterans | 20/0 | (3.3) | ||||||
Control 1 | Twin siblings of PTSD+ veterans | 23 | 52.7 | |||||
Twins of PTSD+ | 23/0 | (3.2) | ||||||
Control 2 | Vietnam combat veterans without PTSD | 23 | 51.8 | |||||
PTSD− veterans | 23/0 | (2.3) | ||||||
Control 3 | Twin siblings of PTSD− veterans | 24 | 51.8 | |||||
Twins of PTSD− | 24/0 | (2.3) | ||||||
3 | Myslobodsky et al28 | WBA 0.5 T / 4.7 mm | Cohort | Veterans with combat-related PTSD | 10 | 33 | Septum pellucidum | Presence of cavum septum pellucidum more frequent in cohort versus normal control (p=0.04); 0/10 combat controls with cavum septum pellucidum (p value NR). |
NR | (7.3) | |||||||
Control 1 | Normal controls without PTSD, matched for age (subgroup of 10 veterans with combat experience) | 21 | 31 | |||||
Normal | NR | (6.7) | ||||||
Control 2 | Patients with post-concussion syndrome (PCS) | 7 | Range | |||||
PCS | NR | 20–35 | ||||||
2 | Canive et al19 | WBA NR | Cohort | Veterans with combat-related PTSD | 42 | NR | White matter | ↑ incidence of white-matter lesions in cohort versus control (p value NR) |
42/0 | ||||||||
Control | Civilians without PTSD; matched for age (±5 years) | 20 | NR | |||||
20/0 | ||||||||
2 | Hedges et al24 | ROI 1.5 T / 1.2 mm | Cohort | Vietnam veterans with combat-related PTSD | 6 | 55.5 | R temporal lobe white matter | ↓ volume in cohort vs. control (p=0.0164) |
6/0 | (1.87) | |||||||
Control | Vietnam veterans without combat-related PTSD | 5 | 55.0 | |||||
5/0 | (2.55) |
Hippocampal Differences (see Table 2)
Paralimbic Differences (See Table 3)
Cortical and Frontal/Temporal Lobe Differences (See Table 4)
Other Regional Differences (See Table 5)
Longitudinal Study
Discussion
Future Research
Conclusions
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