## Protocol Section
### Identification Module
**NCT ID:** NCT01805479

**Brief Title:** Exercise Training in Depressed Traumatic Brain Injury Survivors

**Official Title:** Exercise Training in Depressed Traumatic Brain Injury Survivors

#### Organization Study ID Info
**ID:** PT107574
#### Organization
**Class:** OTHER
**Full Name:** Virginia Commonwealth University
#### Secondary ID Infos
**ID:** 7K23HD067553
**Link:** https://reporter.nih.gov/quickSearch/7K23HD067553
**Type:** NIH
### Status Module
#### Completion Date
**Date:** 2014-06

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2015-12-21

**Type:** ESTIMATED

**Last Update Submit Date:** 2015-12-18

**Overall Status:** WITHDRAWN

#### Primary Completion Date
**Date:** 2014-06

**Type:** ACTUAL

#### Start Date
**Date:** 2013-02

**Status Verified Date:** 2015-12

#### Study First Post Date
**Date:** 2013-03-06
**Type:** ESTIMATED
**Study First Submit Date:** 2013-03-01
**Study First Submit QC Date:** 2013-03-04
**Why Stopped:** Unable to enroll participants. Sponsor requested study closure.
### Sponsor Collaborators Module

#### Collaborators

**Class:** NIH

**Name:** Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

#### Lead Sponsor

**Class:** OTHER

**Name:** Virginia Commonwealth University

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** The purpose of this study is to determine the feasibility of successfully delivering moderate intensity aerobic exercise training to depressed traumatic brain injury subjects between one and three years after injury.

**Detailed Description:** Traumatic brain injury (TBI) alters the lives of many civilians and those involved in armed conflicts. Sequelae of TBI includes depression in up to 30% of cases. Appearance of depression after TBI impairs recovery and results in sub-optimal re-integration into society. Treatment of post TBI depression relies on oral medications, whose efficacy and side effect profile is sub-optimal. Exercise training is effective in spontaneous depression as a stand alone treatment and in conjunction with oral medications, and this may represent an alternative treatment option in the TBI population. Further, the pathophysiology of depression after TBI has yet to be examined with the full scientific rigor required. This project proposes to use exercise training of moderate intensity as a treatment for depression after TBI, while measuring biological markers as a way to investigate efficacy and provide insight into the pathophysiology.

### Conditions Module

**Conditions:**

- Depression

- Traumatic Brain Injury

**Keywords:**

- exercise

- depression

- traumatic brain injury

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** SINGLE

**Who Masked:**

- PARTICIPANT

#### Enrollment Info

**Type:** ACTUAL

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** This group will use a stretching and flexibility program designed to utilize minimal levels of aerobic capacity. It was chosen in place of a education-based control group due to the high level of personal interaction that is found in the active arm.

**Intervention Names:**

- Other: stretching and flexibility program

**Label:** stretching-flexibility

**Type:** PLACEBO_COMPARATOR

#### Arm Group 2

**Description:** aerobic activity targeting 60% peak heart rate for 12 weeks is the active group.

**Intervention Names:**

- Other: aerobic exercise

**Label:** aerobic exercise group

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- aerobic exercise group

**Description:** the active arm will be asked to perform 60% of maximum heart rate

**Name:** aerobic exercise

**Type:** OTHER

#### Intervention 2

**Arm Group Labels:**

- stretching-flexibility

**Description:** stretching and flexibility program for the Placebo Comparator Arm

**Name:** stretching and flexibility program

**Type:** OTHER

### Outcomes Module

#### Primary Outcomes

**Description:** The primary aim is to measure the rate of completion of the exercise protocol.

**Measure:** completion of exercise protocol

**Time Frame:** 12 weeks

#### Secondary Outcomes

**Description:** cognitive testing battery will be performed to examine the impact of exercise on cognition in depressed traumatic brain injury subjects. Administered to both arms.

**Measure:** neuropsychological testing

**Time Frame:** pre and post intervention, week zero and week 13

**Description:** depression symptom inventories will be performed to examine the impact of exercise on cognition in depressed traumatic brain injury subjects. Administered to both arms.

**Measure:** mood assessment

**Time Frame:** week 0, week 13, and weekly during 12 week intervention

**Description:** Columbia-Suicide Severity Rating Scale was developed to meet the need for tracking changes in a person's suicidal thinking and behavior over time, and to determine who is most at risk. Administered to both arms.

**Measure:** Columbia-Suicide Severity Rating Scale

**Time Frame:** week 0, week 13, and weekly during 12 week intervention

**Description:** MRI will be done before and after exercise protocol on a subset of subjects. Selection of these subjects will be done by randomization, starting once the MRI is available for use. The purpose is to examine the brain for exercise influenced volumetric changes. Administered to a subset of both arms of the study.

**Measure:** magnetic resonance imaging

**Time Frame:** week 0, week 13

**Description:** brain-derived neurotrophic factor, vascular endothelial growth factor, insulin-like growth factor-1. The listed neurotrophic factors have been linked to depression and have been shown to be influenced by exercise. The impact of depression and exercise in the context of traumatic brain injury is unknown. Administered to both study arms.

**Measure:** biochemical assays

**Time Frame:** week 0, week 13

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* CT brain with subdural hematoma, subarachnoid hemorrhage, and/or cortical contusion
* Glasgow outcome scale extended of 4 to 8
* speaks English
* Beck Depression Inventory -II score between 14 and 28
* sedentary life style
* one to three years after traumatic brain injury

Exclusion Criteria:

* prior history of brain process (example, stroke, brain tumor)
* aphasia
* psychosis, mania, bipolar disorder, schizophrenia
* pregnancy
* inability to exercise via cycles or treadmill

**Maximum Age:** 65 Years

**Minimum Age:** 14 Years

**Sex:** ALL

**Standard Ages:**

- CHILD

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Richmond

**Country:** United States

**Facility:** Virginia Commonwealth University

**State:** Virginia

**Zip:** 23298-0568

#### Overall Officials

**Official 1:**

**Affiliation:** Virginia Commonwealth University

**Name:** Anne Hudak, MD

**Role:** PRINCIPAL_INVESTIGATOR

### References Module

#### References

**Citation:** Dunn AL, Trivedi MH, Kampert JB, Clark CG, Chambliss HO. The DOSE study: a clinical trial to examine efficacy and dose response of exercise as treatment for depression. Control Clin Trials. 2002 Oct;23(5):584-603. doi: 10.1016/s0197-2456(02)00226-x.

**PMID:** 12392873

**Citation:** Dunn AL, Trivedi MH, Kampert JB, Clark CG, Chambliss HO. Exercise treatment for depression: efficacy and dose response. Am J Prev Med. 2005 Jan;28(1):1-8. doi: 10.1016/j.amepre.2004.09.003.

**PMID:** 15626549

**Citation:** Hudak A, Warner M, Marquez de la Plata C, Moore C, Harper C, Diaz-Arrastia R. Brain morphometry changes and depressive symptoms after traumatic brain injury. Psychiatry Res. 2011 Mar 31;191(3):160-5. doi: 10.1016/j.pscychresns.2010.10.003.

**PMID:** 21310594

**Citation:** Jorge RE, Robinson RG, Arndt SV, Starkstein SE, Forrester AW, Geisler F. Depression following traumatic brain injury: a 1 year longitudinal study. J Affect Disord. 1993 Apr;27(4):233-43. doi: 10.1016/0165-0327(93)90047-n.

**PMID:** 8509524

**Citation:** Fann JR, Katon WJ, Uomoto JM, Esselman PC. Psychiatric disorders and functional disability in outpatients with traumatic brain injuries. Am J Psychiatry. 1995 Oct;152(10):1493-9. doi: 10.1176/ajp.152.10.1493.

**PMID:** 7573589

**Citation:** van Reekum R, Bolago I, Finlayson MA, Garner S, Links PS. Psychiatric disorders after traumatic brain injury. Brain Inj. 1996 May;10(5):319-27. doi: 10.1080/026990596124340.

**PMID:** 8735663

**Citation:** Gomez-Hernandez R, Max JE, Kosier T, Paradiso S, Robinson RG. Social impairment and depression after traumatic brain injury. Arch Phys Med Rehabil. 1997 Dec;78(12):1321-6. doi: 10.1016/s0003-9993(97)90304-x.

**PMID:** 9421985

**Citation:** Rapoport MJ, Kiss A, Feinstein A. The impact of major depression on outcome following mild-to-moderate traumatic brain injury in older adults. J Affect Disord. 2006 Jun;92(2-3):273-6. doi: 10.1016/j.jad.2005.05.022. Epub 2006 Feb 28.

**PMID:** 16504305

**Citation:** Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS; National Comorbidity Survey Replication. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003 Jun 18;289(23):3095-105. doi: 10.1001/jama.289.23.3095.

**PMID:** 12813115

**Citation:** Silver JM, Kramer R, Greenwald S, Weissman M. The association between head injuries and psychiatric disorders: findings from the New Haven NIMH Epidemiologic Catchment Area Study. Brain Inj. 2001 Nov;15(11):935-45. doi: 10.1080/02699050110065295.

**PMID:** 11689092

**Citation:** Simpson G, Tate R. Suicidality after traumatic brain injury: demographic, injury and clinical correlates. Psychol Med. 2002 May;32(4):687-97. doi: 10.1017/s0033291702005561.

**PMID:** 12102383

**Citation:** Teasdale TW, Engberg AW. Suicide after traumatic brain injury: a population study. J Neurol Neurosurg Psychiatry. 2001 Oct;71(4):436-40. doi: 10.1136/jnnp.71.4.436.

**PMID:** 11561024

**Citation:** Satz P, Forney DL, Zaucha K, Asarnow RR, Light R, McCleary C, Levin H, Kelly D, Bergsneider M, Hovda D, Martin N, Namerow N, Becker D. Depression, cognition, and functional correlates of recovery outcome after traumatic brain injury. Brain Inj. 1998 Jul;12(7):537-53. doi: 10.1080/026990598122313.

**PMID:** 9653518

**Citation:** Deb S, Lyons I, Koutzoukis C, Ali I, McCarthy G. Rate of psychiatric illness 1 year after traumatic brain injury. Am J Psychiatry. 1999 Mar;156(3):374-8. doi: 10.1176/ajp.156.3.374.

**PMID:** 10080551

**Citation:** Levin HS, Brown SA, Song JX, McCauley SR, Boake C, Contant CF, Goodman H, Kotrla KJ. Depression and posttraumatic stress disorder at three months after mild to moderate traumatic brain injury. J Clin Exp Neuropsychol. 2001 Dec;23(6):754-69. doi: 10.1076/jcen.23.6.754.1021.

**PMID:** 11910542

**Citation:** Rapoport MJ, McCullagh S, Streiner D, Feinstein A. The clinical significance of major depression following mild traumatic brain injury. Psychosomatics. 2003 Jan-Feb;44(1):31-7. doi: 10.1176/appi.psy.44.1.31.

**PMID:** 12515835

**Citation:** Franulic A, Carbonell CG, Pinto P, Sepulveda I. Psychosocial adjustment and employment outcome 2, 5 and 10 years after TBI. Brain Inj. 2004 Feb;18(2):119-29. doi: 10.1080/0269905031000149515.

**PMID:** 14660225

**Citation:** Jorge RE, Robinson RG, Moser D, Tateno A, Crespo-Facorro B, Arndt S. Major depression following traumatic brain injury. Arch Gen Psychiatry. 2004 Jan;61(1):42-50. doi: 10.1001/archpsyc.61.1.42.

**PMID:** 14706943

**Citation:** Rapoport MJ, McCullagh S, Shammi P, Feinstein A. Cognitive impairment associated with major depression following mild and moderate traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2005 Winter;17(1):61-5. doi: 10.1176/jnp.17.1.61.

**PMID:** 15746484

**Citation:** Trivedi MH, Greer TL, Grannemann BD, Chambliss HO, Jordan AN. Exercise as an augmentation strategy for treatment of major depression. J Psychiatr Pract. 2006 Jul;12(4):205-13. doi: 10.1097/00131746-200607000-00002.

**PMID:** 16883145

**Citation:** Barbour KA, Edenfield TM, Blumenthal JA. Exercise as a treatment for depression and other psychiatric disorders: a review. J Cardiopulm Rehabil Prev. 2007 Nov-Dec;27(6):359-67. doi: 10.1097/01.HCR.0000300262.69645.95.

**PMID:** 18197069

**Citation:** Cassilhas RC, Viana VA, Grassmann V, Santos RT, Santos RF, Tufik S, Mello MT. The impact of resistance exercise on the cognitive function of the elderly. Med Sci Sports Exerc. 2007 Aug;39(8):1401-7. doi: 10.1249/mss.0b013e318060111f.

**PMID:** 17762374

**Citation:** Singh NA, Stavrinos TM, Scarbek Y, Galambos G, Liber C, Fiatarone Singh MA. A randomized controlled trial of high versus low intensity weight training versus general practitioner care for clinical depression in older adults. J Gerontol A Biol Sci Med Sci. 2005 Jun;60(6):768-76. doi: 10.1093/gerona/60.6.768.

**PMID:** 15983181

**Citation:** Stein PN, Motta RW. Effects of aerobic and nonaerobic exercise on depression and self-concept. Percept Mot Skills. 1992 Feb;74(1):79-89. doi: 10.2466/pms.1992.74.1.79.

**PMID:** 1561044

**Citation:** Doyne EJ, Ossip-Klein DJ, Bowman ED, Osborn KM, McDougall-Wilson IB, Neimeyer RA. Running versus weight lifting in the treatment of depression. J Consult Clin Psychol. 1987 Oct;55(5):748-54. doi: 10.1037//0022-006x.55.5.748. No abstract available.

**PMID:** 3454786

**Citation:** Chen JK, Johnston KM, Petrides M, Ptito A. Neural substrates of symptoms of depression following concussion in male athletes with persisting postconcussion symptoms. Arch Gen Psychiatry. 2008 Jan;65(1):81-9. doi: 10.1001/archgenpsychiatry.2007.8.

**PMID:** 18180432

**Citation:** Jorge RE, Acion L, Starkstein SE, Magnotta V. Hippocampal volume and mood disorders after traumatic brain injury. Biol Psychiatry. 2007 Aug 15;62(4):332-8. doi: 10.1016/j.biopsych.2006.07.024. Epub 2006 Nov 21.

**PMID:** 17123480

**Citation:** Colcombe SJ, Erickson KI, Scalf PE, Kim JS, Prakash R, McAuley E, Elavsky S, Marquez DX, Hu L, Kramer AF. Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci. 2006 Nov;61(11):1166-70. doi: 10.1093/gerona/61.11.1166.

**PMID:** 17167157

**Citation:** Pajonk FG, Wobrock T, Gruber O, Scherk H, Berner D, Kaizl I, Kierer A, Muller S, Oest M, Meyer T, Backens M, Schneider-Axmann T, Thornton AE, Honer WG, Falkai P. Hippocampal plasticity in response to exercise in schizophrenia. Arch Gen Psychiatry. 2010 Feb;67(2):133-43. doi: 10.1001/archgenpsychiatry.2009.193.

**PMID:** 20124113

**Citation:** Langlois JA, Rutland-Brown W, Thomas KE. Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths. Atlanta (GA): Centers for Disease Control and Prevention, Nation Center for Injury Prevention and Control. 2006.

**Citation:** Thurman DJ, Alverson C, Dunn KA, Guerrero J, Sniezek JE. Traumatic brain injury in the United States: A public health perspective. J Head Trauma Rehabil. 1999 Dec;14(6):602-15. doi: 10.1097/00001199-199912000-00009.

**PMID:** 10671706

**Citation:** Finkelstein E, Corso P, Miller T and associates. The Incidence and Economic Burden of Injuries in the United States. New York (NY): Oxford University Press. 2006.

**Citation:** Mooney G, Speed J. The association between mild traumatic brain injury and psychiatric conditions. Brain Inj. 2001 Oct;15(10):865-77. doi: 10.1080/02699050110065286.

**PMID:** 11595083

**Citation:** Underhill AT, Lobello SG, Stroud TP, Terry KS, Devivo MJ, Fine PR. Depression and life satisfaction in patients with traumatic brain injury: a longitudinal study. Brain Inj. 2003 Nov;17(11):973-82. doi: 10.1080/0269905031000110418.

**PMID:** 14514448

**Citation:** Lee H, Kim SW, Kim JM, Shin IS, Yang SJ, Yoon JS. Comparing effects of methylphenidate, sertraline and placebo on neuropsychiatric sequelae in patients with traumatic brain injury. Hum Psychopharmacol. 2005 Mar;20(2):97-104. doi: 10.1002/hup.668.

**PMID:** 15641125

**Citation:** Olfson M, Marcus SC. National patterns in antidepressant medication treatment. Arch Gen Psychiatry. 2009 Aug;66(8):848-56. doi: 10.1001/archgenpsychiatry.2009.81.

**PMID:** 19652124

**Citation:** Fann JR, Hart T, Schomer KG. Treatment for depression after traumatic brain injury: a systematic review. J Neurotrauma. 2009 Dec;26(12):2383-402. doi: 10.1089/neu.2009.1091.

**PMID:** 19698070

**Citation:** Topolovec-Vranic J, Cullen N, Michalak A, Ouchterlony D, Bhalerao S, Masanic C, Cusimano MD. Evaluation of an online cognitive behavioural therapy program by patients with traumatic brain injury and depression. Brain Inj. 2010;24(5):762-72. doi: 10.3109/02699051003709599.

**PMID:** 20370383

**Citation:** Bombardier CH, Bell KR, Temkin NR, Fann JR, Hoffman J, Dikmen S. The efficacy of a scheduled telephone intervention for ameliorating depressive symptoms during the first year after traumatic brain injury. J Head Trauma Rehabil. 2009 Jul-Aug;24(4):230-8. doi: 10.1097/HTR.0b013e3181ad65f0.

**PMID:** 19625862

**Citation:** Trivedi MH, Greer TL, Grannemann BD, Church TS, Galper DI, Sunderajan P, Wisniewski SR, Chambliss HO, Jordan AN, Finley C, Carmody TI. TREAD: TReatment with Exercise Augmentation for Depression: study rationale and design. Clin Trials. 2006;3(3):291-305. doi: 10.1191/1740774506cn151oa.

**PMID:** 16895046

**Citation:** Singh NA, Clements KM, Singh MA. The efficacy of exercise as a long-term antidepressant in elderly subjects: a randomized, controlled trial. J Gerontol A Biol Sci Med Sci. 2001 Aug;56(8):M497-504. doi: 10.1093/gerona/56.8.m497.

**PMID:** 11487602

**Citation:** Gordon WA, Sliwinski M, Echo J, McLoughlin M, Sheerer MS, Meili TE. The benefits of exercise in individuals with traumatic brain injury: a retrospective study. J Head Trauma Rehabil. 1998 Aug;13(4):58-67. doi: 10.1097/00001199-199808000-00006.

**PMID:** 9651240

**Citation:** Driver S, Ede A. Impact of physical activity on mood after TBI. Brain Inj. 2009 Mar;23(3):203-12. doi: 10.1080/02699050802695574.

**PMID:** 19205956

**Citation:** Maletic V, Robinson M, Oakes T, Iyengar S, Ball SG, Russell J. Neurobiology of depression: an integrated view of key findings. Int J Clin Pract. 2007 Dec;61(12):2030-40. doi: 10.1111/j.1742-1241.2007.01602.x. Epub 2007 Oct 17.

**PMID:** 17944926

**Citation:** McEwen BS. Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism. 2005 May;54(5 Suppl 1):20-3. doi: 10.1016/j.metabol.2005.01.008.

**PMID:** 15877308

**Citation:** Lee AL, Ogle WO, Sapolsky RM. Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord. 2002 Apr;4(2):117-28. doi: 10.1034/j.1399-5618.2002.01144.x.

**PMID:** 12071509

**Citation:** Aihara M, Ida I, Yuuki N, Oshima A, Kumano H, Takahashi K, Fukuda M, Oriuchi N, Endo K, Matsuda H, Mikuni M. HPA axis dysfunction in unmedicated major depressive disorder and its normalization by pharmacotherapy correlates with alteration of neural activity in prefrontal cortex and limbic/paralimbic regions. Psychiatry Res. 2007 Aug 15;155(3):245-56. doi: 10.1016/j.pscychresns.2006.11.002. Epub 2007 Jun 22.

**PMID:** 17587554

**Citation:** Starkman MN, Gebarski SS, Berent S, Schteingart DE. Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome. Biol Psychiatry. 1992 Nov 1;32(9):756-65. doi: 10.1016/0006-3223(92)90079-f.

**PMID:** 1450290

**Citation:** Van Den Eede F, Van den Bossche B, Hulstijn W, Sabbe BG, Cosyns P, Claes SJ. Combined dexamethasone/CRF test in remitted outpatients with recurrent major depressive disorder. J Affect Disord. 2006 Jul;93(1-3):259-63. doi: 10.1016/j.jad.2006.03.020. Epub 2006 May 4.

**PMID:** 16677715

**Citation:** Holsboer F. The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J Psychiatr Res. 1999 May-Jun;33(3):181-214. doi: 10.1016/s0022-3956(98)90056-5.

**PMID:** 10367986

**Citation:** Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000 Nov;23(5):477-501. doi: 10.1016/S0893-133X(00)00159-7.

**PMID:** 11027914

**Citation:** Ghigo E, Masel B, Aimaretti G, Leon-Carrion J, Casanueva FF, Dominguez-Morales MR, Elovic E, Perrone K, Stalla G, Thompson C, Urban R. Consensus guidelines on screening for hypopituitarism following traumatic brain injury. Brain Inj. 2005 Aug 20;19(9):711-24. doi: 10.1080/02699050400025315.

**PMID:** 16195185

**Citation:** Fedoroff JP, Starkstein SE, Forrester AW, Geisler FH, Jorge RE, Arndt SV, Robinson RG. Depression in patients with acute traumatic brain injury. Am J Psychiatry. 1992 Jul;149(7):918-23. doi: 10.1176/ajp.149.7.918.

**PMID:** 1609872

**Citation:** Jorge R, Robinson RG. Mood disorders following traumatic brain injury. NeuroRehabilitation. 2002;17(4):311-24. No abstract available.

**PMID:** 12547979

**Citation:** Ernst C, Olson AK, Pinel JP, Lam RW, Christie BR. Antidepressant effects of exercise: evidence for an adult-neurogenesis hypothesis? J Psychiatry Neurosci. 2006 Mar;31(2):84-92.

**PMID:** 16575423

**Citation:** Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med. 1998 Nov;4(11):1313-7. doi: 10.1038/3305.

**PMID:** 9809557

**Citation:** Koolschijn PC, van Haren NE, Lensvelt-Mulders GJ, Hulshoff Pol HE, Kahn RS. Brain volume abnormalities in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Hum Brain Mapp. 2009 Nov;30(11):3719-35. doi: 10.1002/hbm.20801.

**PMID:** 19441021

**Citation:** Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry. 2004 Nov;161(11):1957-66. doi: 10.1176/appi.ajp.161.11.1957.

**PMID:** 15514393

**Citation:** Yucel K, McKinnon MC, Chahal R, Taylor VH, Macdonald K, Joffe R, MacQueen GM. Anterior cingulate volumes in never-treated patients with major depressive disorder. Neuropsychopharmacology. 2008 Dec;33(13):3157-63. doi: 10.1038/npp.2008.40. Epub 2008 Mar 26.

**PMID:** 18368034

**Citation:** Mak AK, Wong MM, Han SH, Lee TM. Gray matter reduction associated with emotion regulation in female outpatients with major depressive disorder: a voxel-based morphometry study. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Oct 1;33(7):1184-90. doi: 10.1016/j.pnpbp.2009.06.025. Epub 2009 Jul 19.

**PMID:** 19596037

**Citation:** Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry. 2000 Oct;57(10):925-35. doi: 10.1001/archpsyc.57.10.925.

**PMID:** 11015810

**Citation:** Czeh B, Lucassen PJ. What causes the hippocampal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated? Eur Arch Psychiatry Clin Neurosci. 2007 Aug;257(5):250-60. doi: 10.1007/s00406-007-0728-0.

**PMID:** 17401728

**Citation:** Henn FA, Vollmayr B. Neurogenesis and depression: etiology or epiphenomenon? Biol Psychiatry. 2004 Aug 1;56(3):146-50. doi: 10.1016/j.biopsych.2004.04.011.

**PMID:** 15271582

**Citation:** Duman RS. Depression: a case of neuronal life and death? Biol Psychiatry. 2004 Aug 1;56(3):140-5. doi: 10.1016/j.biopsych.2004.02.033.

**PMID:** 15271581

**Citation:** Cotter DR, Pariante CM, Everall IP. Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Res Bull. 2001 Jul 15;55(5):585-95. doi: 10.1016/s0361-9230(01)00527-5.

**PMID:** 11576755

**Citation:** Rajkowska G. Cell pathology in mood disorders. Semin Clin Neuropsychiatry. 2002 Oct;7(4):281-92. doi: 10.1053/scnp.2002.35228.

**PMID:** 12382210

**Citation:** van Praag H, Shubert T, Zhao C, Gage FH. Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci. 2005 Sep 21;25(38):8680-5. doi: 10.1523/JNEUROSCI.1731-05.2005.

**PMID:** 16177036

**Citation:** van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13427-31. doi: 10.1073/pnas.96.23.13427.

**PMID:** 10557337

**Citation:** van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci. 1999 Mar;2(3):266-70. doi: 10.1038/6368.

**PMID:** 10195220

**Citation:** Erickson KI, Prakash RS, Voss MW, Chaddock L, Hu L, Morris KS, White SM, Wojcicki TR, McAuley E, Kramer AF. Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus. 2009 Oct;19(10):1030-9. doi: 10.1002/hipo.20547.

**PMID:** 19123237

**Citation:** Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol. 2000 Oct 2;425(4):479-94. doi: 10.1002/1096-9861(20001002)425:43.0.co;2-3.

**PMID:** 10975875

**Citation:** Louissaint A Jr, Rao S, Leventhal C, Goldman SA. Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron. 2002 Jun 13;34(6):945-60. doi: 10.1016/s0896-6273(02)00722-5.

**PMID:** 12086642

**Citation:** Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, McKhann GM, Sloan R, Gage FH, Brown TR, Small SA. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5638-43. doi: 10.1073/pnas.0611721104. Epub 2007 Mar 20.

**PMID:** 17374720

**Citation:** Warner-Schmidt JL, Duman RS. VEGF as a potential target for therapeutic intervention in depression. Curr Opin Pharmacol. 2008 Feb;8(1):14-9. doi: 10.1016/j.coph.2007.10.013. Epub 2007 Dec 3.

**PMID:** 18061540

**Citation:** Mira H, Andreu Z, Suh H, Lie DC, Jessberger S, Consiglio A, San Emeterio J, Hortiguela R, Marques-Torrejon MA, Nakashima K, Colak D, Gotz M, Farinas I, Gage FH. Signaling through BMPR-IA regulates quiescence and long-term activity of neural stem cells in the adult hippocampus. Cell Stem Cell. 2010 Jul 2;7(1):78-89. doi: 10.1016/j.stem.2010.04.016.

**PMID:** 20621052

**Citation:** Piser TM. Linking the cytokine and neurocircuitry hypotheses of depression: a translational framework for discovery and development of novel anti-depressants. Brain Behav Immun. 2010 May;24(4):515-24. doi: 10.1016/j.bbi.2010.02.006. Epub 2010 Mar 1.

**PMID:** 20193757

**Citation:** Gervasoni N, Aubry JM, Bondolfi G, Osiek C, Schwald M, Bertschy G, Karege F. Partial normalization of serum brain-derived neurotrophic factor in remitted patients after a major depressive episode. Neuropsychobiology. 2005;51(4):234-8. doi: 10.1159/000085725. Epub 2005 May 12.

**PMID:** 15897674

**Citation:** Aydemir O, Deveci A, Taneli F. The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study. Prog Neuropsychopharmacol Biol Psychiatry. 2005 Feb;29(2):261-5. doi: 10.1016/j.pnpbp.2004.11.009. Epub 2004 Dec 23.

**PMID:** 15694233

**Citation:** Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H, Shinoda N, Okada S, Iyo M. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry. 2003 Jul 1;54(1):70-5. doi: 10.1016/s0006-3223(03)00181-1.

**PMID:** 12842310

**Citation:** Gonul AS, Akdeniz F, Taneli F, Donat O, Eker C, Vahip S. Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci. 2005 Dec;255(6):381-6. doi: 10.1007/s00406-005-0578-6. Epub 2005 Apr 6.

**PMID:** 15809771

**Citation:** Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci. 1995 Nov;15(11):7539-47. doi: 10.1523/JNEUROSCI.15-11-07539.1995.

**PMID:** 7472505

**Citation:** Warner-Schmidt JL, Duman RS. VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4647-52. doi: 10.1073/pnas.0610282104. Epub 2007 Mar 5.

**PMID:** 17360578

**Citation:** Sen S, Duman R, Sanacora G. Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry. 2008 Sep 15;64(6):527-32. doi: 10.1016/j.biopsych.2008.05.005. Epub 2008 Jun 24.

**PMID:** 18571629

**Citation:** Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci. 2002 Apr 15;22(8):3251-61. doi: 10.1523/JNEUROSCI.22-08-03251.2002.

**PMID:** 11943826

**Citation:** Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav. 1997 Jan;56(1):131-7. doi: 10.1016/S0091-3057(96)00169-4.

**PMID:** 8981620

**Citation:** Koponen E, Rantamaki T, Voikar V, Saarelainen T, MacDonald E, Castren E. Enhanced BDNF signaling is associated with an antidepressant-like behavioral response and changes in brain monoamines. Cell Mol Neurobiol. 2005 Sep;25(6):973-80. doi: 10.1007/s10571-005-8468-z.

**PMID:** 16392030

**Citation:** Hoshaw BA, Malberg JE, Lucki I. Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects. Brain Res. 2005 Mar 10;1037(1-2):204-8. doi: 10.1016/j.brainres.2005.01.007.

**PMID:** 15777771

**Citation:** Kiraly MA, Kiraly SJ. The effect of exercise on hippocampal integrity: review of recent research. Int J Psychiatry Med. 2005;35(1):75-89. doi: 10.2190/HX7L-4B40-PQNY-2A4P.

**PMID:** 15977946

**Citation:** Vaynman S, Ying Z, Gomez-Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci. 2004 Nov;20(10):2580-90. doi: 10.1111/j.1460-9568.2004.03720.x.

**PMID:** 15548201

**Citation:** Fabel K, Fabel K, Tam B, Kaufer D, Baiker A, Simmons N, Kuo CJ, Palmer TD. VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur J Neurosci. 2003 Nov;18(10):2803-12. doi: 10.1111/j.1460-9568.2003.03041.x.

**PMID:** 14656329

**Citation:** Mossberg KA, Amonette WE, Masel BE. Endurance training and cardiorespiratory conditioning after traumatic brain injury. J Head Trauma Rehabil. 2010 May-Jun;25(3):173-83. doi: 10.1097/HTR.0b013e3181dc98ff.

**PMID:** 20473091

**Citation:** Beck, Aaron T., Robert A. Steer, and Gregory K. Brown. BDI-II, Beck Depression Inventory: Manual. San Antonio, Tex: Psychological Corp, 1996

**Citation:** Jezierski MK, Sohrabji F. Region- and peptide-specific regulation of the neurotrophins by estrogen. Brain Res Mol Brain Res. 2000 Dec 28;85(1-2):77-84. doi: 10.1016/s0169-328x(00)00244-8.

**PMID:** 11146109

**Citation:** Borg G. Perceived exertion as an indicator of somatic stress. Scand J Rehabil Med. 1970;2(2):92-8. No abstract available.

**PMID:** 5523831

**Citation:** Borg, GAV. Physical Performance and Perceived Exertion. Lund, Sweden: Gleerup.

**Citation:** Nelson ME, Rejeski WJ, Blair SN, Duncan PW, Judge JO, King AC, Macera CA, Castaneda-Sceppa C. Physical activity and public health in older adults: recommendation from the American College of Sports Medicine and the American Heart Association. Med Sci Sports Exerc. 2007 Aug;39(8):1435-45. doi: 10.1249/mss.0b013e3180616aa2.

**PMID:** 17762378

**Citation:** Haskell WL, Lee IM, Pate RR, Powell KE, Blair SN, Franklin BA, Macera CA, Heath GW, Thompson PD, Bauman A. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Med Sci Sports Exerc. 2007 Aug;39(8):1423-34. doi: 10.1249/mss.0b013e3180616b27.

**PMID:** 17762377

**Citation:** Dale AM, Sereno MI. Improved Localizadon of Cortical Activity by Combining EEG and MEG with MRI Cortical Surface Reconstruction: A Linear Approach. J Cogn Neurosci. 1993 Spring;5(2):162-76. doi: 10.1162/jocn.1993.5.2.162.

**PMID:** 23972151

**Citation:** Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):11050-5. doi: 10.1073/pnas.200033797.

**PMID:** 10984517

**Citation:** Fischl B, Liu A, Dale AM. Automated manifold surgery: constructing geometrically accurate and topologically correct models of the human cerebral cortex. IEEE Trans Med Imaging. 2001 Jan;20(1):70-80. doi: 10.1109/42.906426.

**PMID:** 11293693

**Citation:** Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, van der Kouwe A, Killiany R, Kennedy D, Klaveness S, Montillo A, Makris N, Rosen B, Dale AM. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron. 2002 Jan 31;33(3):341-55. doi: 10.1016/s0896-6273(02)00569-x.

**PMID:** 11832223

**Citation:** Fischl B, Salat DH, van der Kouwe AJ, Makris N, Segonne F, Quinn BT, Dale AM. Sequence-independent segmentation of magnetic resonance images. Neuroimage. 2004;23 Suppl 1:S69-84. doi: 10.1016/j.neuroimage.2004.07.016.

**PMID:** 15501102

**Citation:** Fischl B, Sereno MI, Dale AM. Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. Neuroimage. 1999 Feb;9(2):195-207. doi: 10.1006/nimg.1998.0396.

**PMID:** 9931269

**Citation:** Fischl B, Sereno MI, Tootell RB, Dale AM. High-resolution intersubject averaging and a coordinate system for the cortical surface. Hum Brain Mapp. 1999;8(4):272-84. doi: 10.1002/(sici)1097-0193(1999)8:43.0.co;2-4.

**PMID:** 10619420

**Citation:** Fischl B, van der Kouwe A, Destrieux C, Halgren E, Segonne F, Salat DH, Busa E, Seidman LJ, Goldstein J, Kennedy D, Caviness V, Makris N, Rosen B, Dale AM. Automatically parcellating the human cerebral cortex. Cereb Cortex. 2004 Jan;14(1):11-22. doi: 10.1093/cercor/bhg087.

**PMID:** 14654453

**Citation:** Han X, Jovicich J, Salat D, van der Kouwe A, Quinn B, Czanner S, Busa E, Pacheco J, Albert M, Killiany R, Maguire P, Rosas D, Makris N, Dale A, Dickerson B, Fischl B. Reliability of MRI-derived measurements of human cerebral cortical thickness: the effects of field strength, scanner upgrade and manufacturer. Neuroimage. 2006 Aug 1;32(1):180-94. doi: 10.1016/j.neuroimage.2006.02.051. Epub 2006 May 2.

**PMID:** 16651008

**Citation:** Jovicich J, Czanner S, Greve D, Haley E, van der Kouwe A, Gollub R, Kennedy D, Schmitt F, Brown G, Macfall J, Fischl B, Dale A. Reliability in multi-site structural MRI studies: effects of gradient non-linearity correction on phantom and human data. Neuroimage. 2006 Apr 1;30(2):436-43. doi: 10.1016/j.neuroimage.2005.09.046. Epub 2005 Nov 21.

**PMID:** 16300968

**Citation:** Segonne F, Dale AM, Busa E, Glessner M, Salat D, Hahn HK, Fischl B. A hybrid approach to the skull stripping problem in MRI. Neuroimage. 2004 Jul;22(3):1060-75. doi: 10.1016/j.neuroimage.2004.03.032.

**PMID:** 15219578

**Citation:** Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage. 1999 Feb;9(2):179-94. doi: 10.1006/nimg.1998.0395.

**PMID:** 9931268

**Citation:** Salat DH, Buckner RL, Snyder AZ, Greve DN, Desikan RS, Busa E, Morris JC, Dale AM, Fischl B. Thinning of the cerebral cortex in aging. Cereb Cortex. 2004 Jul;14(7):721-30. doi: 10.1093/cercor/bhh032. Epub 2004 Mar 28.

**PMID:** 15054051

**Citation:** Kuperberg GR, Broome MR, McGuire PK, David AS, Eddy M, Ozawa F, Goff D, West WC, Williams SC, van der Kouwe AJ, Salat DH, Dale AM, Fischl B. Regionally localized thinning of the cerebral cortex in schizophrenia. Arch Gen Psychiatry. 2003 Sep;60(9):878-88. doi: 10.1001/archpsyc.60.9.878.

**PMID:** 12963669

**Citation:** Rosas HD, Liu AK, Hersch S, Glessner M, Ferrante RJ, Salat DH, van der Kouwe A, Jenkins BG, Dale AM, Fischl B. Regional and progressive thinning of the cortical ribbon in Huntington's disease. Neurology. 2002 Mar 12;58(5):695-701. doi: 10.1212/wnl.58.5.695.

**PMID:** 11889230

**Citation:** Kashihara K, Maruyama T, Murota M, Nakahara Y. Positive effects of acute and moderate physical exercise on cognitive function. J Physiol Anthropol. 2009 Jun;28(4):155-64. doi: 10.2114/jpa2.28.155.

**PMID:** 19652447

**Citation:** McDermott LM, Ebmeier KP. A meta-analysis of depression severity and cognitive function. J Affect Disord. 2009 Dec;119(1-3):1-8. doi: 10.1016/j.jad.2009.04.022. Epub 2009 May 9.

**PMID:** 19428120

**Citation:** Bagiella E, Novack TA, Ansel B, Diaz-Arrastia R, Dikmen S, Hart T, Temkin N. Measuring outcome in traumatic brain injury treatment trials: recommendations from the traumatic brain injury clinical trials network. J Head Trauma Rehabil. 2010 Sep-Oct;25(5):375-82. doi: 10.1097/HTR.0b013e3181d27fe3.

**PMID:** 20216459

**Citation:** Benton AL, Hamsher KD, Sivan AB. Multilingual Aphasia Examination. Manual of instructions. AJA Associates, Iowa City. 2000.

**Citation:** Reitan RM, Wolfson D. The Halstead-Reitan neuropsychological test battery: Theory and clinical interpretation. Neuropsychology Press, Tucson, AZ. 1993.

**Citation:** Reitan RM Trail Making Test. Manual for administration and scoring. Reitan Neuropsychology Laboratory, Tucson, AZ. 1992.

**Citation:** Dodrill CB. A neuropsychological battery for epilepsy. Epilepsia. 1978 Dec;19(6):611-23. doi: 10.1111/j.1528-1157.1978.tb05041.x.

**PMID:** 738230

**Citation:** Wechsler D. Wechsler Adult Intelligence Scale (WAIS-III). The Psychological Corporation, San Antonio, TX. 1997.

**Citation:** Delis DCK, Joel H, Kaplan E, Ober BA. California Verbal Learning Test. PsychCorp, A brand of Harcourt Assessment, Inc. 2000.

**Citation:** Diener E, Emmons RA, Larsen RJ, Griffin S. The Satisfaction With Life Scale. J Pers Assess. 1985 Feb;49(1):71-5. doi: 10.1207/s15327752jpa4901_13.

**PMID:** 16367493

**Citation:** Noble BJ, Borg GA, Jacobs I, Ceci R, Kaiser P. A category-ratio perceived exertion scale: relationship to blood and muscle lactates and heart rate. Med Sci Sports Exerc. 1983;15(6):523-8.

**PMID:** 6656563

**Citation:** Rappaport M, Hall KM, Hopkins K, Belleza T, Cope DN. Disability rating scale for severe head trauma: coma to community. Arch Phys Med Rehabil. 1982 Mar;63(3):118-23.

**PMID:** 7073452

**Citation:** Gouvier WD, Blanton PD, LaPorte KK, Nepomuceno C. Reliability and validity of the Disability Rating Scale and the Levels of Cognitive Functioning Scale in monitoring recovery from severe head injury. Arch Phys Med Rehabil. 1987 Feb;68(2):94-7.

**PMID:** 3813863

**Citation:** Wilson JT, Pettigrew LE, Teasdale GM. Structured interviews for the Glasgow Outcome Scale and the extended Glasgow Outcome Scale: guidelines for their use. J Neurotrauma. 1998 Aug;15(8):573-85. doi: 10.1089/neu.1998.15.573.

**PMID:** 9726257

**Citation:** Chew E, Zafonte RD. Pharmacological management of neurobehavioral disorders following traumatic brain injury--a state-of-the-art review. J Rehabil Res Dev. 2009;46(6):851-79. doi: 10.1682/jrrd.2008.09.0120.

**PMID:** 20104408

**Citation:** Neurobehavioral Guidelines Working Group; Warden DL, Gordon B, McAllister TW, Silver JM, Barth JT, Bruns J, Drake A, Gentry T, Jagoda A, Katz DI, Kraus J, Labbate LA, Ryan LM, Sparling MB, Walters B, Whyte J, Zapata A, Zitnay G. Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain injury. J Neurotrauma. 2006 Oct;23(10):1468-501. doi: 10.1089/neu.2006.23.1468.

**PMID:** 17020483

**Citation:** Cohen J. Statistical Power Analysis for the Behavioral Sciences, (revised edition). New York. NY: Academic Press, 1977

#### See Also Links

**Label:** Arhinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts freely available online

**URL:** http://surfer.nmr.mgh.harvard.edu

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000001526

- Term: Behavioral Symptoms

- ID: D000001927

- Term: Brain Diseases

- ID: D000002493

- Term: Central Nervous System Diseases

- ID: D000009422

- Term: Nervous System Diseases

- ID: D000006259

- Term: Craniocerebral Trauma

- ID: D000020196

- Term: Trauma, Nervous System

### Condition Browse Module - Browse Branches

- Abbrev: BC10

- Name: Nervous System Diseases

- Abbrev: BC26

- Name: Wounds and Injuries

- Abbrev: All

- Name: All Conditions

- Abbrev: BXM

- Name: Behaviors and Mental Disorders

### Condition Browse Module - Browse Leaves

- ID: M5207

- Name: Brain Injuries

- Relevance: HIGH

- As Found: Brain Injury

- ID: M7058

- Name: Depression

- Relevance: HIGH

- As Found: Depression

- ID: M7061

- Name: Depressive Disorder

- Relevance: LOW

- As Found: Unknown

- ID: M628

- Name: Brain Injuries, Traumatic

- Relevance: HIGH

- As Found: Traumatic Brain Injury

- ID: M17685

- Name: Wounds and Injuries

- Relevance: HIGH

- As Found: Injury

- ID: M4818

- Name: Behavioral Symptoms

- Relevance: LOW

- As Found: Unknown

- ID: M5204

- Name: Brain Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M5742

- Name: Central Nervous System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M9349

- Name: Craniocerebral Trauma

- Relevance: LOW

- As Found: Unknown

- ID: M22023

- Name: Trauma, Nervous System

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000001930

- Term: Brain Injuries

- ID: D000070642

- Term: Brain Injuries, Traumatic

- ID: D000014947

- Term: Wounds and Injuries

- ID: D000003863

- Term: Depression

### Misc Info Module

- Version Holder: 2024-05-24
