Research


Current Studies

Cognitive Rehabilitation for Older Veterans with Mild Cognitive Impairment (1/1/18-6/30/2024)

Cognitive Rehabilitation for Older Veterans with Mild Cognitive Impairment (Date: 1/1/18-12/31/22). Principal Investigator. I01CX001592. Funding: VA CSRD Merit

Abstract: Due to the aging of the United States population, age-related cognitive problems resulting from Alzheimer’s disease and other causes of dementia are increasingly prevalent. Before individuals are diagnosed with dementia, they typically exhibit a period of “mild cognitive impairment” (MCI). Mild cognitive problems associated with MCI frequently impact an individual’s ability to perform everyday tasks, including working, independent living, and medication adherence. Veterans are at increased risk of cognitive decline, and the Veterans Healthcare Administration (VA) is now providing health care to surging numbers of older Veterans with MCI who report significant cognitive complaints, difficulties with everyday functioning, and concerns about impending dementia. Despite high patient demand, few cognitive rehabilitation interventions exist that specifically address the needs of older Veterans with MCI that are widely accessible, patient-centered, and evidence-based. To our knowledge, no randomized controlled trials have been conducted that evaluate the efficacy of manualized, brief and inexpensive, yet comprehensive (multi-modal) cognitive rehabilitation interventions for older Veterans with MCI. Hence, the primary objective of this study is to evaluate the efficacy of Motivationally Enhanced Compensatory Cognitive Training (ME-CCT), a manualized cognitive rehabilitation group treatment for older Veterans with MCI. The study’s specific aims are to determine whether ME-CCT is effective for: 1) improving objective cognitive performance and functional capacity, 2) improving subjective cognitive complaints, subjective functioning, and collateral measures of everyday function, and 3) increasing modifiable protective factors (e.g., diet, exercise) associated with reduced risk for MCI. We will also explore mediators and moderators of treatment effects. The overall goal is to evaluate a manualized group treatment for the symptoms of MCI that can be readily implemented in VA treatment settings. The study design makes use of the convergent availability of resources at the two participating VA Healthcare Systems in San Diego, California and Portland, Oregon to conduct a randomized controlled trial of ME-CCT. The study will recruit a sample of 216 Veterans (108 at each site) who meet criteria for MCI. Inclusion criteria will be: 1) Veterans 55 years old or older enrolled at one of the participating VAs who are able to provide informed consent, 2) Independently living, 3) Meet criteria for MCI based on previously published criteria (Petersen, 2004; Petersen, 2011), and 4) Willingness to participate in audio-recorded group sessions. Exclusion criteria will be: 1) Current substance use disorder with less than 30 days abstinence, 2) History of schizophrenia, schizoaffective disorder, or other primary psychotic disorder, 3) History of significant head trauma with loss of consciousness >30 minutes, and 4) Auditory or visual impairments that would prevent ability to participate in the cognitive rehabilitation group. Eligible participants will be randomly assigned to either the ME-CCT or an active control group, Goal-focused Supportive Contact (SC). The SC group will provide the same frequency and amount of therapist and peer contact as ME-CCT, but without specific training in cognitive strategies, lifestyle strategies, or motivational enhancement. 8 2-hour long weekly sessions will be delivered in both conditions. Both groups will undergo evaluations at baseline, 4 weeks (midway through the intervention), 8 weeks (immediately following the end of the intervention), and 21 weeks (3 months after completion of the intervention).


Study Coordinator: Hannah Lykins, BS

TAILORED: Training for Independent Living through Observant Robots and Design (8/1/19-7/31/23)

TAILORED: Training for Independent Living through Observant Robots and Design (Date: 8/1/19-7/31/23). Co-Principal Investigator. 1915734. Funding: NSF Smart and Connected Health

Abstract: The goal of this project is to create human-centered robotics technology to provide personalized neurorehabilitation to support older adults with mild cognitive impairment. The project investigates innovative approaches to this research area, and will make the following contributions to smart and connected health: create new approaches to support longitudinal, personalized robot learning in real-world environments; pioneer novel methods for delivering and sustaining cognitive neurorehabilitation, currently one of the only known treatments to prolong independence and slow the onset of disability caused by MCI; and contribute new methods to the fields of human-robot interaction (HRI), aging science, and behavioral science to support the co-creation of new technologies and new intervention delivery methods with older adults with cognitive impairments, their caregivers, and their providers. Harnessing technology to provide cognitive support and rehabilitation for older adults could potentially assist millions of people to maintain or improve their functioning and quality of life, and maintain their ability to live independently. Ultimately, these improvements could alleviate significant human suffering and lower healthcare costs for millions of people.

This project will inform multiple key research questions including: uncovering new methods for longitudinal preference learning, particularly with regard to how time-varying contextual bandits under concept drift can be employed across multimodal datasets; identifying principles for engaging in community-focused, stakeholder-centered research with people with MCI, with a particular focus on designing for resilience and autonomy; discovering how hybrid approaches to cognitive training delivered via a robot can inform cognitive functioning; and exploring how to design interventions for sustainability, both for people with MCI and other populations. The project team will also engage the public in intergenerational research between older adults and college students, empower older adults with cognitive impairments and their family members by giving them a voice in technology creation, recruit research students from groups underrepresented in computing and behavioral science, and broadly disseminate the research via publications, representations, and publicly available software frameworks with models, algorithms, and evaluation metrics.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Personalized, Augmented Cognitive Training (PACT) for Service Members and Veterans with a History of TBI (9/30/19-9/29/23)

Personalized, Augmented Cognitive Training (PACT) for Service Members and Veterans with a History of TBI (Date: 9/30/19-9/29/22). Co-Principal Investigator. W81XWH1910656. Funding: DoD

Background: Mild traumatic brain injury (TBI) is a common medical condition that occurs when a head injury causes someone to lose consciousness, feel dazed or confused, or be unable to remember events occurring immediately after the injury. While most individuals with mild TBI recover within weeks or months, some individuals with mild TBI report chronic symptoms such as difficulty with cognitive skills like attention, learning, or memory, along with other symptoms such as irritability or headache. Previous studies, including those conducted by our scientific team, have shown that cognitive rehabilitation can help patients with persistent symptoms after mild TBI return to full duty, work, school, and other important life activities. Specifically, cognitive rehabilitation can provide lasting improvements in thinking abilities, functional capacity, post-concussive symptoms, and quality of life after mild TBI. However, effective interventions are still out of reach for many service members and Veterans with TBI. For patients who have returned to duty, employment, or education, scheduling up to 60 hours of treatment (a typical treatment schedule in many settings) may not be feasible. Additionally, some patients may live in areas where it is burdensome to make numerous visits to a medical center. In response to these needs, our team has created a new treatment, Personalized Augmented Cognitive Training (PACT). PACT compresses treatment into six hours of once-weekly personalized, one-on-one training by selecting treatment modules based on patient needs and priorities—substantially reducing the total amount of time required to complete treatment. PACT can be offered either in-person (in clinic) or via home-based video telemedicine (i.e., Skype), depending upon patients’ preferences. Additionally, PACT includes training and encouragement for service members and Veterans to make self-directed use of mobile apps that train cognitive skills and strategies. Objectives: The primary goal of this study is to evaluate whether PACT is effective at improving cognition, symptoms, and functional outcomes among military service members and Veterans with a history of mild TBI. We also seek to learn more about factors that can enhance or interfere with treatment, such as number of previous TBIs, presence of post-traumatic stress; and choice of in-person vs. video telemedicine delivery of care. Military/Veteran Impact: Over 300,000 U.S. military personnel have sustained an mTBI since 2000. Persistent post-concussive symptoms can result in reduced quality of life, reduced operational readiness, and difficulty with community reintegration. Cognitive rehabilitation has been shown to be effective, however, access to care is often disrupted by intensive treatment schedules, difficulties with transportation, and a lack of personalization based on patient’s individual challenges and preferences. This study will evaluate a new approach to improve service members’ and Veterans’ access to effective cognitive intervention for mild TBI. If study results demonstrate that the PACT intervention is successful in reducing symptom, improving cognition, or enhancing functional recovery, this safe and non-invasive intervention could implemented very rapidly within a wide range of DoD and VA settings, enhancing recovery, improving quality of life, and bolstering occupational performance.


Study Coordinator: Michelle Seewald, MA

Combined Neuromodulation and Cognitive Training for Post-mTBI Depression (9/30/22-2/29/26)

Combined Neuromodulation and Cognitive Training for Post-mTBI Depression (9/30/22-2/29/26)


Background: Depression is common following mild traumatic brain injury (mTBI) and often co-occurs with cognitive post-concussive symptoms in domains such as attention, learning/memory, and executive functioning. Depression and cognitive impairments can each worsen the other, leading to poor role functioning and quality of life. Combined interventions targeting both depression and cognitive performance following mTBI are urgently needed to enhance recovery and prevent chronic disability. We propose to evaluate the efficacy of Personalized Augmented Cognitive Training (PACT) plus intermittent theta burst stimulation (iTBS) in Service Members, Veterans, and civilians with depression and a history of mTBI. PACT is a personalized, streamlined version of CogSMART, which has been shown to reduce symptoms and improve cognition in Veterans with TBI. In our DoD-funded study of Service Members and Veterans with a history of mTBI, PACT has yielded positive effects on depressive symptoms and cognitive performance in the domains of attention, learning/memory, and executive functioning. iTBS is a more rapid form of repetitive transcranial magnetic stimulation (rTMS), a non-invasive, FDA-approved treatment for depression. iTBS yields comparable outcomes to standard rTMS, but with much shorter session times. Combining iTBS with PACT offers a potentially high-value, time-efficient, and personalized treatment approach for patients with comorbid mTBI and depression.


Hypothesis/Objective: Our proposed clinical trial will evaluate the efficacy of PACT+iTBS on depressive symptoms (primary outcome) and cognition, post-concussive symptoms, functioning, and quality of life (secondary outcomes) in Service Members, Veterans, and civilians with depression and a history of mTBI.


Specific Aims: Aim 1. Investigate the efficacy of a personalized medicine approach to cognitive training plus neuromodulation in Service Members, Veterans, and civilians with chronic mTBI and depression by conducting a randomized controlled trial of PACT+iTBS vs. PACT+sham iTBS for 4 weeks, with assessments at baseline, 2 weeks, 4 weeks, and 8 weeks. H1: PACT+iTBS, compared to PACT+sham iTBS, will result in significantly greater improvement in depressive symptoms (primary outcome). H2: PACT+iTBS, compared to PACT+sham iTBS, will result in significantly greater improvement in a) cognitive performance, b) post-concussive symptoms, c) functional status, d) quality of life, and e) Patient Global Impression of Change (PGIC) (secondary outcomes). Aim 2. Investigate mechanisms of PACT+iTBS effects on functional status and quality of life. H3: Improved a) depressive symptoms, b) post-concussive symptoms, c) objective cognition, and d) left DLPFC-subgenual anterior cingulate functional connectivity will mediate improvements in 1) functional status, 2) quality of life, and 3) PGIC. Exploratory Aim 3. Investigate potential moderators of PACT+iTBS effects, including patient factors (active duty/Veteran/civilian status, baseline cognitive profile, baseline depressive symptoms, presence of comorbid PTSD, TBI characteristics, baseline left DLPFC-subgenual anterior cingulate functional connectivity) and treatment factors (e.g., number of PACT and iTBS sessions completed).


Study Design: Participants will include 72 active duty Service Members, Veterans, and civilians with diagnosed depression and a history of mTBI. Individuals with common TBI comorbidities (e.g., PTSD) will be included to maximize generalizability of results. All participants will receive PACT (6 sessions over 4 weeks) and will be randomized to receive iTBS or sham iTBS (20 sessions over 4 weeks). Comprehensive in-person assessments will be conducted at baseline (pre-treatment), 2 weeks (mid-treatment), 4 weeks (post-treatment), and 8 weeks (follow-up). Neuroimaging will be conducted at baseline and 4 weeks.


Clinical Impact: This pragmatic clinical trial will demonstrate the efficacy of PACT+iTBS for improving post-mTBI depression and other outcomes and generate valuable knowledge about mechanisms and moderators of treatment effects. Our Community Advisory Board (CAB) and Lived Experience Consultants (LECs) will provide valuable perspectives on military and Veteran patient and provider experiences and priorities, enhancing the clinical impact of the study. The proposed project is relevant to Focus Area 3 (treatments that promote sustained functional recovery in the chronic phase of mild traumatic brain injury).


Relevance to Military Health: U.S. military personnel have sustained over 444,000 TBIs since 2000 and over one-third of those with mTBI histories meet criteria for depression. If effective, the PACT+iTBS intervention could be quickly exported to military and Veteran treatment facilities to reach a large number of patients with post-TBI depression. By optimizing treatment in this way, we hope to enhance recovery, improve quality of life, and bolster operational and occupational performance.


Study Coordinator: Michelle Seewald, MA

Selected Clinical Trial Results

Twamley, E.W., Vella, L., Burton, C.Z., Becker, D.R., Bell, M.D., & Jeste, D.V. (2012). The efficacy of supported employment for middle-aged and older people with schizophrenia. Schizophrenia Research, 135, 100-104.

Twamley, E.W., Vella, L., Burton, C.Z., Heaton, R.K., & Jeste, D.V. (2012). Compensatory Cognitive Training for psychosis: Effects in a randomized controlled trial. Journal of Clinical Psychiatry, 73, 1212-1219.

Twamley, E.W., Jak, A.J., Delis, D.C., Bondi, M.W., & Lohr, J.B. (2014). Cognitive Symptom Management and Rehabilitation Therapy (CogSMART) for Veterans with traumatic brain injury: A pilot randomized controlled trial. Journal of Rehabilitation Research and Development, 51, 59-69.

Twamley, E.W., Thomas, K.R., Gregory, A.M., Jak, A.J., Bondi, M.W., Delis, D.C., & Lohr, J.B. (2015). CogSMART compensatory cognitive training for traumatic brain injury: Effects over one year. Journal of Head Trauma Rehabilitation, 30, 391-401.

Mendella, P.D., Burton, C.Z., Tasca, G.A., Roy, P., St. Louis, L., & Twamley, E.W. (2015). Compensatory Cognitive Training for people with first-episode schizophrenia: Results from a pilot randomized controlled trial. Schizophrenia Research, 162, 108-111.

Storzbach, D., Twamley, E.W. (co-first authors), Roost, M.S., Golshan, S., Williams, R.M., O’Neil, M., Jak, A.J., Turner, A.P., Kowalski, H.M., Pagulayan, K.F., & Huckans, M. (2017). Compensatory Cognitive Training for Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) veterans with mild traumatic brain injury. Journal of Head Trauma Rehabilitation, 32, 16-24.

Ayers, C.R., Dozier, M.E., Twamley, E.W., Saxena, S., Granholm, E., Mayes, T.L., & Wetherell, J.L. (2018). Cognitive Rehabilitation and Exposure/Sorting Therapy (CREST) for hoarding disorder among older adults: a randomized clinical trial. Journal of Clinical Psychiatry, 79, 16m11072.

Twamley, E.W., Thomas, K.R., Burton, C.Z., Vella, L., Jeste, D.V., Heaton, R.K., & McGurk, S.R. (2019). Compensatory Cognitive Training for people with severe mental illnesses in supported employment: a randomized controlled trial. Schizophrenia Research, 203, 41-48.

Jak, A.J., Jurick, S. M., Crocker, L.D., Sanderson-Cimino, M., Aupperle, R., Rodgers, C.S., Thomas, K., Boyd, B., Norman, S.B., Lang, A.J., Keller, A.V., Schiehser, D. & Twamley, E.W. (2019). SMART-CPT treatment for veterans with comorbid posttraumatic stress disorder and history of traumatic brain injury: A randomized controlled trial. Journal of Neurology, Neurosurgery, and Psychiatry, 90, 333-341.

Ayers, C.R., Davidson, E.J., Dozier, M.E., & Twamley, E.W. (2020). Cognitive Rehabilitation and Exposure/Sorting Therapy for late-life hoarding: effects on neuropsychological performance. The Journals of Gerontology, Series B Psychological Sciences, 75, 1193-1198.

Granholm, E., Twamley, E.W. (co-first authors), Mahmood, Z., Keller, A.V., Lykins, H.C., Parrish, E.M., Thomas, M.L., Perivoliotis, D., & Holden, J.L. (2022). Integrated Cognitive-Behavioral Social Skills Training and Compensatory Cognitive Training for negative symptoms of psychosis: Effects in a pilot randomized controlled trial. Schizophrenia Bulletin, 48, 359-370.