Neuroanatomical Correlates of Depression in Post Traumatic Brain Injury: Preliminary Results of a Pilot Study

Participants were recruited by advertisements in local newspapers. Subjects 18 years of age or older, with closed head injury, date of TBI between 3 and 60 months prior to the evaluations, no history of diagnosable mood disorder prior to TBI, Mini-Mental State Examination (MMSE) score >18, stable medical history prior to injury, and sufficient cognitive capacity to provide consent were included. The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-1) was administered to all participants. TBI-depressed patients (cases) were required to meet DSM-IV criteria for a major depressive episode after TBI (296.83; major depressive-like episode) and to have never met the criteria prior to TBI. Nondepressed TBI subjects (comparison subjects) were required to have never met criteria for major depressive episode (296.83).

These results suggest a possible role for frontal cortex, temporal lobe, and basal ganglia pathology in post-TBI depression, as well as reduced left occipital volume. This may be due to the known association of frontal and occipital lesions post-TBI, likely due to the contrecoup lesions common in motor vehicle accidents. 14

Post-TBI depression subjects had reduced N -acetylaspartate/creatine ratio (statistical trend) and reduced choline/creatine ratio (statistically significant) in the right basal ganglia. N -acetylaspartate is generally believed to be an indicator of neuronal and axonal integrity. 9 It is reduced following TBI, reflecting diffuse axonal injury or metabolic dysfunction. 9 Choline-containing compounds are involved in cell membrane metabolism; increased choline levels suggest cell membrane breakdown or cell proliferation. 9 Reduced choline in post-TBI patients may suggest absence of cell membrane inflammation, cell membrane repair, or glial cell proliferation. The creatine peak contains both creatine and phosphocreatine, which are involved in cellular energy metabolism. Increased creatine might suggest increased neuronal cell repair or neuronal cell proliferation. It is decreased in conditions associated with cell death. 9 Thus, our observations of reduced N -acetylaspartate/creatine and choline/creatine are suggestive of decreased neuronal health and viability in the basal ganglia.

The cognitive testing is consistent with frontotemporal pathology. Depressed subjects (cases) had slowed psychomotor processing speed and poorer executive functioning (Trail Making test, part B) than comparison subjects, both domains thought to be subsumed by frontal cortex. This is more likely due to brain pathology than major depression itself, since the effect of major depression on set-shifting paradigms (including Trail Making test, part B) is inconsistent at best. 15 Also some studies have noted poor performance on tests of mental flexibility in dysphoric nondepressed patients suggesting that mental inflexibility may be related to the symptom of depressed mood rather than the syndrome of major depression. 16, 17 TBI is associated with neuronal loss and reduced white matter integrity which can result in dysfunction of neuronal networks and poor performance in cognitive functioning for a prolonged period. 18, 19 Another explanation, however, could be the increased age in the depressed group. Older age is also associated with increased neuronal loss and reduced white matter integrity, which can reduce cognitive reserve. 20 Immediate recall on the first three trials of the Brief Visuospatial Memory Test can be conceptualized as a test of visual learning likely mediated by the frontal lobes, while delayed recall assesses visual memory mediated primarily by the temporal lobes (although frontal lobe functioning is considered important for retrieval of information that has been adequately encoded and consolidated by mesial temporal lobe structures). Depressed subjects performed worse than comparison subjects on the delayed recall tests of both verbal and visual memory and had reduced right and left gray matter temporal lobe volumes (statistical trend). This is consistent with other studies 21, 22 that have implicated temporal lobe abnormalities in the pathophysiology of major depression.

An interesting finding, however, was the better performance by the depressed group on the WCST categories. This is probably secondary to the increased severity of brain injury in the comparison group.

In summary, preliminary findings from this pilot study suggest that post-TBI depression is associated with temporal lobe pathology (with concurrent cognitive and MRI findings) but not as clearly with frontal lobe pathology. The finding of basal ganglia pathology on MRSI suggests that MRSI might be complementary to MRI and display different patterns of sensitivity to brain pathology.

This is the first report of proton MRSI findings in TBI subjects with and without new-onset major depression following TBI. Also, this is the first study to replicate the lesion location findings in TBI depression published by Jorge et al. 7, 8 Limitations include a small sample size, discordance in age and severity of TBI for cases and comparison subjects, limited coverage of temporal lobes, and lack of control for use of psychotropic medications.

The preliminary results of our pilot study suggest a possible role of frontotemporal lobes and basal ganglia pathology in depression after TBI.

These results also highlight the usefulness of volumetric MRI and MRSI in determining patterns of brain injury associated with post-TBI depression. Future research should focus on the use of these techniques for both disease detection and response to treatment.

This study was supported by National Center for Research Resources (NCRR/NIH) Grant # MO1RR00052. The abstract was presented at the 2008 annual neuropsychiatry conference, Savannah, GA.

Dr. Rao has a grant from Forest to conduct a clinical trial in post-TBI depression and a grant from Pfizer to conduct a clinical trial in poststroke anxiety.

The authors wish to acknowledge Drs. Barbara A. Holshouser and Karen A. Tong, Department of Radiology, Section of Neuroradiology, Loma Linda University School of Medicine, California, for their invaluable assistance during the preparation of this manuscript.