Research


Current Studies

Cognitive Rehabilitation for Homeless OEF/OIF/OND Veterans (4/1/16-12/31/20)

Cognitive Rehabilitation for Homeless OEF/OIF/OND Veterans (Date: 4/1/16-12/31/20). Principal Investigator. I01RX001972. Funding: VA RRD Merit

Abstract: Ending homelessness among Veterans by 2015 is a national priority. Although there are many routes to homelessness, the end result of homelessness frequently involves a failure in planning, problem-solving, or both. Planning and problem-solving are executive functions dependent upon intact brain functioning, and these and other neurocognitive abilities may be impaired in up to 80% of homeless individuals, affecting their organization, judgment, decision-making, and ability to benefit from psychosocial rehabilitation interventions. Thus, cognitive impairment may be an underappreciated yet pervasive barrier to efforts toward ending homelessness. Causes of cognitive impairment in homeless individuals include traumatic brain injury, psychiatric illness, substance abuse, and other medical conditions. Cognitive impairment may interact with these conditions to result in poor housing outcomes, poor treatment adherence, and risk of continued homelessness. Cognitive assessment and rehabilitation in the setting of homeless services is not common, with no known studies to date of cognitive rehabilitation for homeless individuals. We have a golden opportunity to address these research gaps by studying Veterans at the Aspire Center, a 40-bed Residential Rehabilitation Treatment Program (domiciliary) serving homeless returning Veterans with mental health conditions (psychiatric illness, substance abuse, and traumatic brain injuries). In a 15-week randomized controlled trial, Veterans with cognitive or functional impairments will receive an evidence-based, 10-week Compensatory Cognitive Training (CCT) intervention or an education control condition to examine the effects of cognitive rehabilitation in this Veteran population. CCT aims to improve real-world cognitive performance by teaching strategies to improve prospective memory (remembering to do things), attention, learning/memory, and executive functioning. Strategies to reduce stress and improve sleep are also included. CCT has been shown to improve cognition, functional capacity, neurobehavioral symptom severity, and quality of life in individuals with cognitive impairment associated with psychiatric illness and in Veterans with TBI. During the trial, assessments will be administered at baseline, 5 weeks, 10 weeks, and 15 weeks, and monthly follow-up phone calls will assess housing and employment/education status for one year following program discharge. We expect CCT-associated improvements in cognition and functional skills (co-primary outcomes) and generalization to reduced levels of disability, along with improved community reintegration outcomes (better housing stability and participation in work or school). By attending to and treating the cognitive impairments that many of these Veterans will have, we can potentially alter the course of the Veterans’ trajectories and prevent future homelessness and its negative health consequences, resulting in both healthcare cost savings and improved quality of life for Veterans.


Study Coordinator: Ingrid Contreras, BS

Cognitive Rehabilitation for Older Veterans with Mild Cognitive Impairment (1/1/18-12/31/22)

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.


Study Coordinator: Elizabeth Twamley, PhD

Personalized, Augmented Cognitive Training (PACT) for Service Members and Veterans with a History of TBI (9/30/19-9/29/22)

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

TTI-0102, a Cysteamine Precursor for Mild to Moderate TBI: Dosing and Feasibility Study (4/1/20-3/31/22)

TTI-0102, a Cysteamine Precursor for Mild to Moderate TBI: Dosing and Feasibility Study (Date: 4/1/20-3/31/22). Principal Investigator. I21RX003323. Funding: VA RRD SPiRE Award.

Abstract: Approximately 12-23% of returning service members report a history of traumatic brain injury, mostly mild (mTBI). Post-concussive symptoms such as memory problems, irritability, and difficulty concentrating are common after TBI and may become chronic, interfering with successful return to duty or civilian reintegration, reducing quality of life, and increasing health care utilization for Veterans. In those whose TBI-related symptoms persist, there is accumulating evidence for increased morbidity (e.g., worse PTSD symptoms, chronic hypopituitarism, dementia), spurring efforts to improve diagnosis and intervention. Following a primary TBI injury, secondary injury and persistent symptoms may evolve through a complex cascade of events that culminate in inflammation, alterations in mitochondrial bioenergetics, and diminished blood brain barrier integrity, ultimately yielding a chronic disease state. To date, Veterans receiving strategy-based cognitive rehabilitation for TBI (CCT/CogSMART) have shown improvement in cognition and subjective neuropsychiatric symptoms. CCT is an evidence-based cognitive rehabilitation intervention emphasizing training in cognitive strategies to improve post-concussive symptoms, attention, learning/memory, and executive functioning. However, no pharmaceuticals have been developed for direct or adjunct-to CCT use to maximize treatment outcomes. Given that inflammation has been observed in TBI, PTSD, and in co-occurring TBI/PTSD, it may be an important aspect of the TBI/PTSD disease state that could be manipulated to promote healing. We are proposing to study TTI-0102, a cysteamine precursor that shows anti-inflammatory activity, as a potential adjunct to CCT for Veterans with TBI-related symptoms. TTI-0102 is a safe, easily administered, highly-water soluble compound that readily crosses the blood brain barrier. Compared with cysteamine, TTI-0102 degrades more slowly, dampening peak drug concentrations and sustaining drug plasma concentrations in a narrow therapeutic range. Developed to treat cystinosis, cysteamine is now believed to have potential for treatment of neurodegenerative disorders. The goal of this proof of concept study is first, in Phase I (Year 1), to use symptom change (i.e., objective cognitive performance and subjective cognitive and neuropsychiatric symptoms) and biological profiles (i.e., metabolomics, inflammatory peptides [interleukin-6 and C-reactive protein], and brain-derived neurotrophic factor) to learn optimal dosing of TTI-0102 and to assess mechanism of action, and in Phase II (Year 2), to implement a feasibility trial in Veterans with a history of mild to moderate TBI and PTSD. In Phase I, 3 groups of 10 Veterans each will be randomly assigned to receive TTI-0102 2 grams/day, 4 grams/day, or placebo for 12 weeks. Baseline and post-treatment measures of objective cognition and subjective cognitive and neuropsychiatric symptoms will be administered, and plasma will be collected to measure the metabolomic, inflammatory, and protein biomarkers. In Phase II (Year 2), 12 different Veterans (6 per group) will be enrolled in a pilot randomized controlled trial (RCT) to assess the feasibility and acceptability of trial procedures. Participants in Phase II will be randomized to receive TTI-0102 (dose determined in Phase I) or placebo for 12 weeks as an adjunct to evidence-based CCT. The results of these double-blind, placebo-controlled trials will be used to plan a larger, fully-powered trial.


Study Coordinator: Chantal Müller-Cohn, BA

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. (in press). Cognitive Rehabilitation and Exposure/Sorting Therapy for late-life hoarding: effects on neuropsychological performance. The Journals of Gerontology, Series B.













Photo courtesy of Carl Schy