Human umbilical cord plasma proteins revitalize hippocampal function in aged mice.

Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation, an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation and downregulated in the aged brain. In addition to revitalizing other aged tissues, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters, although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown. We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of such plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing- or disease-associated hippocampal dysfunction.

The immunomodulatory, antitumor and antimetastatic responses of melanoma-bearing normal and alcoholic mice to sunitinib and ALT-803: a combinatorial treatment approach.

ALT-803, a novel IL-15/IL-15 receptor alpha complex, and the tyrosine kinase inhibitor, sunitinib, were examined for their single and combined effects on the growth of subcutaneous B16BL6 melanoma and on lymph node and lung metastasis. The study was conducted in immunocompetent C57BL/6 mice drinking water (Water mice) and in mice that chronically consumed alcohol (Alcohol mice), which are deficient in CD8(+) T cells. Sunitinib inhibited melanoma growth and was more effective in Alcohol mice. ALT-803 did not alter tumor growth or survival in Water or Alcohol mice. Combined ALT-803 and sunitinib inhibited melanoma growth and increased survival, and these effects were greater than sunitinib alone in Water mice. ALT-803 and alcohol independently suppressed lymph node and lung metastasis, whereas sunitinib alone or in combination with ALT-803 increased lymph node and lung metastasis in Water and Alcohol mice. Initially, ALT-803 increased IFN-γ-producing CD8(+)CD44(hi) memory T cells and CD8(+)CD44(hi)CD62L(lo) effector memory T cells and sunitinib decreased immunosuppressive MDSC and T regulatory cells (Treg). However, the impact of these treatments diminished with time. Subcutaneous tumors from Water mice showed increased numbers of CD8(+) T cells, CD8(+)CD44(hi) T cells, NK cells, and MDSC cells and decreased Treg cells after ALT-803 treatment.

Feasibility and acceptability for LION, a fully remote, randomized clinical trial within the VA for light therapy to improve sleep in Veterans with and without TBI: An MTBI2 sponsored protocol: LION: A remote RCT protocol within VA.

Sleep-wake disturbances frequently present in Veterans with mild traumatic brain injury (mTBI). These TBI-related sleep impairments confer significant burden and commonly exacerbate other functional impairments. Therapies to improve sleep following mTBI are limited and studies in Veterans are even more scarce. In our previous pilot work, morning bright light therapy (MBLT) was found to be a feasible behavioral sleep intervention in Veterans with a history of mTBI; however, this was single-arm, open-label, and non-randomized, and therefore was not intended to establish efficacy. The present study, LION (light vs ion therapy) extends this preliminary work as a fully powered, sham-controlled, participant-masked randomized controlled trial (NCT03968874), implemented as fully remote within the VA (target n=120 complete). Randomization at 2:1 allocation ratio to: 1) active: MBLT (n=80), and 2) sham: deactivated negative ion generator (n=40); each with identical engagement parameters (60-min duration; within 2-hrs of waking; daily over 28-day duration). Participant masking via deception balanced expectancy assumptions across arms. Outcome measures were assessed following a 14-day baseline (pre-intervention), following 28-days of device engagement (post-intervention), and 28-days after the post-intervention assessment (follow-up). Primary outcomes were sleep measures, including continuous wrist-based actigraphy, self-report, and daily sleep dairy entries. Secondary/exploratory outcomes included cognition, mood, quality of life, circadian rhythm via dim light melatonin onset, and biofluid-based biomarkers. Participant drop out occurred in <10% of those enrolled, incomplete/missing data was present in <15% of key outcome variables, and overall fidelity adherence to the intervention was >85%, collectively establishing feasibility and acceptability for MBLT in Veterans with mTBI.

Photosensitivity Is Associated with Chronic Pain following Traumatic Brain Injury.

Individuals with a history of traumatic brain injury (TBI) report increased rates of chronic pain. Photosensitivity is also a common chronic symptom following TBI and is prevalent among other types of chronic pain. The aim of this study was to better understand the relationship between chronic pain, pain-related disability, and photosensitivity in a TBI population. We quantified participants' visual photosensitivity thresholds (VPT) using an Ocular Photosensitivity Analyzer and measured pressure-pain sensitivity using pressure algometry. Participants also completed a battery of self-report measures related to chronic pain, TBI history, and mental health. A total of 395 participants completed testing, with 233 reporting a history of TBI. The TBI group was divided into 120 symptomatic TBI participants (s-TBI), and 113 asymptomatic TBI participants (a-TBI) based on their Neurobehavioral Symptom Inventory (NSI) scores. Participants in the s-TBI group scored significantly higher on self-reported chronic pain measures compared with a-TBI and no-TBI participants, including the Symptom Impact Questionnaire Revised (SIQR; p < 0.001) and the Michigan Body Map (MBM; p < 0.001). Despite differences in chronic pain complaints, groups displayed similar pressure-pain thresholds (p = 0.270). Additionally, s-TBI participants were more sensitive to light (lower VPT, p < 0.001), and VPT was correlated with SIQR scores across all participants (R = -0.452, p < 0.001). These data demonstrate that photosensitivity is associated with self-reported chronic pain and disability in individuals with chronic TBI symptomatology. Photosensitivity could therefore serve as a simple, more highly quantitative marker of high-impact chronic pain after TBI.

Feasibility and preliminary efficacy for morning bright light therapy to improve sleep and plasma biomarkers in US Veterans with TBI. A prospective, open-label, single-arm trial.

Mild traumatic brain injury (TBI) is associated with persistent sleep-wake dysfunction, including insomnia and circadian rhythm disruption, which can exacerbate functional outcomes including mood, pain, and quality of life. Present therapies to treat sleep-wake disturbances in those with TBI (e.g., cognitive behavioral therapy for insomnia) are limited by marginal efficacy, poor patient acceptability, and/or high patient/provider burden. Thus, this study aimed to assess the feasibility and preliminary efficacy of morning bright light therapy, to improve sleep in Veterans with TBI (NCT03578003). Thirty-three Veterans with history of TBI were prospectively enrolled in a single-arm, open-label intervention using a lightbox (~10,000 lux at the eye) for 60-minutes every morning for 4-weeks. Pre- and post-intervention outcomes included questionnaires related to sleep, mood, TBI, post-traumatic stress disorder (PTSD), and pain; wrist actigraphy as a proxy for objective sleep; and blood-based biomarkers related to TBI/sleep. The protocol was rated favorably by ~75% of participants, with adherence to the lightbox and actigraphy being ~87% and 97%, respectively. Post-intervention improvements were observed in self-reported symptoms related to insomnia, mood, and pain; actigraphy-derived measures of sleep; and blood-based biomarkers related to peripheral inflammatory balance. The severity of comorbid PTSD was a significant positive predictor of response to treatment. Morning bright light therapy is a feasible and acceptable intervention that shows preliminary efficacy to treat disrupted sleep in Veterans with TBI. A full-scale randomized, placebo-controlled study with longitudinal follow-up is warranted to assess the efficacy of morning bright light therapy to improve sleep, biomarkers, and other TBI related symptoms.

Different Methods for Traumatic Brain Injury Diagnosis Influence Presence and Symptoms of Post-Concussive Syndrome in United States Veterans.

Common methods for evaluating history of traumatic brain injury (TBI) include self-report, electronic medical record review (EMR), and structured interviews such as the Head Trauma Events Characteristics (HTEC). Each has strengths and weaknesses, but little is known regarding how TBI diagnostic rates or the associated symptom profile differ among them. This study examined 200 Veterans recruited within the VA Portland Health Care System, each evaluated for TBI using self-report, EMR, and HTEC. Participants also completed validated questionnaires assessing chronic symptom severity in broad health-related domains (pain, sleep, quality of life, post-concussive symptoms). The HTEC was more sensitive (80% of participants in our cohort) than either self-report or EMR alone (40%). As expected from the high sensitivity, participants screening positive for TBI through the HTEC included many people with mild or no post-concussive symptoms. Participants were grouped according to degree of concordance across these diagnostic methods: no TBI, n = 43; or TBI-positive in any one method (TBI-1dx, n = 53), positive in any two (TBI-2dx, n = 45), or positive in all three (TBI-3dx, n = 59). The symptom profile of the TBI-1dx group was indistinguishable from the no TBI group. The TBI-3dx group had the most severe symptom profile. Our results show that understanding the exact methods used to ascertain TBI is essential when interpreting results from other studies, given that results and conclusions may differ dramatically depending on the method. This issue will become even more critical when interpreting data merged from multiple sources within newer, centralized repositories (e.g., Federal Interagency Traumatic Brain Injury Research [FITBIR]).

Cyclic ovarian hormone modulation of supraspinal Δ9-tetrahydrocannabinol-induced antinociception and cannabinoid receptor binding in the female rat.

Estrous cycle-related fluctuations in delta-9-tetrahydrocannabinol (THC)-induced antinociception have been observed in the rat. The aim of this study was to determine which major ovarian hormone modulates the antinociceptive effects of i.c.v. THC, and whether hormone modulation of THC's behavioral effects could be due to changes in brain cannabinoid receptors (CBr). Vehicle (oil) or hormones (estradiol or progesterone, or both) were administered to female rats on days 3 and 7 post-ovariectomy. On the morning or afternoon of day 8 or day 9, vehicle or THC (100 µg) was administered i.c.v. Paw pressure, tail withdrawal, locomotor activity and catalepsy tests were conducted over a 3-h period. Estradiol (with and without progesterone) enhanced THC-induced paw pressure antinociception only. Ovarian hormones time-dependently modulated CBr in brain structures that mediate antinociception and locomotor activity, but the changes observed in CBr did not parallel changes in behavior. However, the time course of CBr changes must be further elucidated to determine the functional relationship between receptor changes and antinociceptive sensitivity to THC.