Many adolescents with sickle cell disease (SCD) experience recurrent and chronic pain, which has a negative impact on their health-related quality of life (HRQL). Cognitive-behavioral therapy (CBT) interventions can lead to improvement in pain and HRQL, yet due to barriers to care, most youth with SCD will not receive these interventions. To address this need for innovative programs targeting youth with SCD pain, we developed iCanCope, a tailored smartphone and web-based program that delivers a pain self-management intervention to youth with SCD. We describe the rationale, design, and implementation of a three-site parallel group randomized controlled trial with a sample of 160 adolescents with SCD and their parent caregivers. The iCanCope program includes pain self-management skills training (personalized CBT-based coping skills such as deep breathing, relaxation, and cognitive skills), goal setting, and social support. The attention control group is provided with access to a self-guided website with education about SCD. Assessments will occur at baseline (T1), immediately after completion of the intervention (12 weeks; T2) and at 6 months post-intervention (T3). Primary outcomes include coping strategies and pain intensity; secondary outcomes include physical, social, and emotional functioning, treatment satisfaction, health service use and caregiver response to youth pain behavior. Potential mediators (goal setting, self-management, and perceptions of social support) and moderators (e.g., demographic factors) will also be tested. The objective is to offer an effective, convenient, and low-cost psychosocial intervention to youth with SCD to enhance their self-management of pain.
Low blood docosahexaenoic acid (DHA) is reported in patients with phenylketonuria (PKU); however, the functional implications in adolescents and adults are unknown. This pilot study investigated the effect of supplemental DHA on cognitive performance in 33 females with PKU ages 12-47 years. Participants were randomly assigned to receive DHA (10 mg/kg/day) or placebo for 4.5 months. Performance on cognitive processing speed and executive functioning tasks was evaluated at baseline and follow up. Intention-to-treat and per protocol analyses were performed. At follow up, biomarkers of DHA status were significantly higher in the DHA-supplemented group. Performance on the cognitive tasks and reported treatment-related adverse events did not differ. While no evidence of cognitive effect was seen, a larger sample size is needed to be conclusive, which may not be feasible in this population. Supplementation was a safe and effective way to increase biomarkers of DHA status (www.clinicaltrials.gov; Identifier: NCT00892554).
Microinfarcts are small, but strikingly common, ischemic brain lesions in the aging human brain. There is mounting evidence that microinfarcts contribute to vascular cognitive impairment and dementia, but the origins of microinfarcts are unclear. Understanding the vascular pathologies that cause microinfarcts may yield strategies to prevent their occurrence and reduce their deleterious effects on brain function. Current thinking suggests that cortical microinfarcts arise from the occlusion of penetrating arterioles, which are responsible for delivering oxygenated blood to small volumes of tissue. Unexpectedly, pre-clinical studies have shown that the occlusion of penetrating venules, which drain deoxygenated blood from cortex, lead to microinfarcts that appear identical to those resulting from arteriole occlusion. Here we discuss the idea that cerebral venule pathology could be an overlooked source for brain microinfarcts in humans. (Figure presented.). This article is part of the Special Issue “Vascular Dementia”. Cover Image for this Issue: doi: 10.1111/jnc.14167.
Each year, about six million children, including 1.5 million infants, in the United States undergo surgery with general anesthesia, often requiring repeated exposures. However, a crucial question remains of whether neonatal anesthetics are safe for the developing central nervous system (CNS). General anesthesia encompasses the administration of agents that induce analgesic, sedative, and muscle relaxant effects. Although the mechanisms of action of general anesthetics are still not completely understood, recent data have suggested that anesthetics primarily modulate two major neurotransmitter receptor groups, either by inhibiting N-methyl-D-aspartate (NMDA) receptors, or conversely by activating γ-aminobutyric acid (GABA) receptors. Both of these mechanisms result in the same effect of inhibiting excitatory activity of neurons. In developing brains, which are more sensitive to disruptions in activity-dependent plasticity, this transient inhibition may have longterm neurodevelopmental consequences. Accumulating reports from preclinical studies show that anesthetics in neonates cause cellular toxicity including apoptosis and neurodegeneration in the developing brain. Importantly, animal and clinical studies indicate that exposure to general anesthetics may affect CNS development, resulting in long-lasting cognitive and behavioral deficiencies, such as learning and memory deficits, as well as abnormalities in social memory and social activity. While the casual relationship between cellular toxicity and neurological impairments is still not clear, recent reports in animal experiments showed that anesthetics in neonates can affect neurogenesis, which could be a possible mechanism underlying the chronic effect of anesthetics. Understanding the cellular and molecular mechanisms of anesthetic effects will help to define the scope of the problem in humans and may lead to preventive and therapeutic strategies. Therefore, in this review, we summarize the current evidence on neonatal anesthetic effects in the developmental CNS and discuss how factors influencing these processes can be translated into new therapeutic strategies.
Brain radiotherapy is frequently used successfully to treat brain tumors. However, radiotherapy is often associated with declines in short-term and long-term memory, learning ability, and verbal fluency. We previously identified a downregulation of the brain-derived neurotrophic factor (BDNF) following cranial irradiation in experimental animals. In the present study, we investigated whether targeting the BDNF high affinity receptor, tropomysin receptor kinase B (TrkB), could mitigate radiation-induced cognitive deficits. After irradiation, chronic treatment with a small molecule TrkB agonist, 7,8-dihydroxyflavone (DHF) in mice led to enhanced activation of TrkB and its downstream targets ERK and AKT, both important factors in neuronal development. DHF treatment significantly restored spatial, contextual, and working memory, and the positive effects persisted for at least 3 months after completion of the treatment. Consistent with preservation of cognitive functions, chronic DHF treatment mitigated radiation-induced suppression of hippocampal neurogenesis. Spine density and major components of the excitatory synapses, including glutamate receptors and postsynaptic density protein 95 (PSD-95), were also maintained at normal levels by DHF treatment after irradiation. Taken together, our results show that chronic treatment with DHF after irradiation significantly mitigates radiation-induced cognitive defects. This is achieved most likely by preservation of hippocampal neurogenesis and synaptic plasticity.
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Shariful A. Syed;
Eleanore Beurel;
David A. Loewenstein;
Jeffrey A. Lowell;
Boadie Dunlop;
Wade Craighead;
Helen Mayberg;
Firdaus Dhabhar;
W. Dalton Dietrich;
Robert W. Keane;
Juan Pablo de Rivero Vaccari;
Charles B. Nemeroff
Inflammation has been involved in the pathophysiology and treatment response of major depressive disorder (MDD). Plasma cytokine profiles of 171 treatment-naive MDD patients (none of the MDD patients received an adequate trial of antidepressants or evidence-based psychotherapy) and 64 healthy controls (HCs) were obtained. MDD patients exhibited elevated concentrations of 18 anti- and proinflammatory markers and decreased concentrations of 6 cytokines. Increased inflammasome protein expression was observed in MDD patients, indicative of an activated inflammatory response. The plasma of MDD patients was immunosuppressive on healthy donor peripheral blood mononuclear cells, inducing reduced activation of monocytes/dendritic cells and B cells and reduced T cell memory. Comparison between 33 non-responders and 71 responders at baseline and 12 weeks revealed that after treatment, anti-inflammatory cytokine levels increase in both groups, whereas 5 proinflammatory cytokine levels were stabilized in responders, but continued to increase in non-responders. MDD patients exhibit remodeling of their inflammatory landscape. Treatment-naive MDD patients have increased levels of pro- and anti-inflammatory markers, but overall the balance shifts toward immunosuppression of immune cells. Consistent with these findings, absence of response to antidepressant treatments has been associated with defective anti-inflammatory response.
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Sang Ah Lee;
Jonathan F. Miller;
Andrew J. Watrous;
Michael R. Sperling;
Ashwini Sharan;
Gregory A. Worrell;
Brent M. Berry;
Joshua P. Aronson;
Kathryn A. Davis;
Robert Gross;
Bradley Lega;
Sameer Sheth;
Sandhitsu Das;
Joel M. Stein;
Richard Gorniak;
Daniel S. Rizzuto;
Joshua Jacobs
Environmental boundaries play a crucial role in spatial navigation and memory across a wide range of distantly related species. In rodents, boundary representations have been identified at the single-cell level in the subiculum and entorhinal cortex of the hippocampal formation. Although studies of hippocampal function and spatial behavior suggest that similar representations might exist in humans, boundary-related neural activity has not been identified electrophysiologically in humans until now. To address this gap in the literature, we analyzed intracranial recordings from the hippocampal formation of surgical epilepsy patients (of both sexes) while they performed a virtual spatial navigation task and compared the power in three frequency bands (1–4, 4–10, and 30–90 Hz) for target locations near and far from the environmental boundaries. Our results suggest that encoding locations near boundaries elicited stronger theta oscillations than for target locations near the center of the environment and that this difference cannot be explained by variables such as trial length, speed, movement, or performance. These findings provide direct evidence of boundary-dependent neural activity localized in humans to the subiculum, the homolog of the hippocampal subregion in which most boundary cells are found in rodents, and indicate that this system can represent attended locations that rather than the position of one’s own body.
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Rachael S Allen;
Adam M Hanif;
Marissa A Gogniat;
Brian C Prall;
Raza Haider;
Moe H Aung;
Megan C Prunty;
Lukas M Mees;
Monica M Coulter;
Cara T Motz;
Jeffrey Boatright;
Machelle Pardue
Diabetic retinopathy is a leading cause of vision loss. Treatment options for early retinopathy are sparse. Exercise protects dying photoreceptors in models of retinal degeneration, thereby preserving vision. We tested the protective effects of exercise on retinal and cognitive deficits in a type 1 diabetes model and determined whether the TrkB pathway mediates this effect. Hyperglycaemia was induced in Long Evans rats via streptozotocin injection (STZ; 100 mg/kg). Following confirmed hyperglycaemia, both control and diabetic rats underwent treadmill exercise for 30 min, 5 days/week at 0 m/min (inactive groups) or 15 m/min (active groups) for 8 weeks. A TrkB receptor antagonist (ANA-12), or vehicle, was injected 2.5 h before exercise training. We measured spatial frequency and contrast sensitivity using optokinetic tracking biweekly post-STZ; retinal function using electroretinography at 4 and 8 weeks; and cognitive function and exploratory behaviour using Y-maze at 8 weeks. Retinal neurotrophin-4 was measured using ELISA. Compared with non-diabetic controls, diabetic rats showed significantly reduced spatial frequency and contrast sensitivity, delayed electroretinogram oscillatory potential and flicker implicit times and reduced cognitive function and exploratory behaviour. Exercise interventions significantly delayed the appearance of all deficits, except for exploratory behaviour. Treatment with ANA-12 significantly reduced this protection, suggesting a TrkB-mediated mechanism. Despite this, no changes in retinal neurotrohin-4 were observed with diabetes or exercise. Exercise protected against early visual and cognitive dysfunction in diabetic rats, suggesting that exercise interventions started after hyperglycaemia diagnosis may be a beneficial treatment. The translational potential is high, given that exercise treatment is non-invasive, patient controlled and inexpensive.
The pervasive reach of the inflammatory system is evidenced by its involvement in numerous disease states. Cardiovascular disease, marked by high levels of circulating inflammatory mediators, affects an estimated 83.6 million Americans. Similarly, human immunodeficiency virus (HIV) produces a paradoxical state of generalized immune activity despite widespread immunosuppression, and affects 35 million people worldwide. Patients living with HIV (PLWH) suffer from inflammatory conditions, including cardiovascular disease (CVD), at a rate exceeding the general population. In this combined disease state, immune mechanisms that are common to both CVD and HIV may interact to generate a progressive condition that contributes to the exacerbated pathogenesis of the other to the net effect of damage to the brain. In this review, we will outline inflammatory cell mediators that promote cardiovascular risk factors and disease initiation and detail how HIV-related proteins may accelerate this process. Finally, we examine the extent to which these comorbid conditions act as parallel, perpendicular, or progressive sequela of events to generate a neurodegenerative environment, and consider potential strategies that can be implemented to reduce the burden of CVD and inflammation in PLWH.
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Salman E. Qasim;
Jonathan Miller;
Cory S. Inman;
Robert Gross;
Jon Willie;
Bradley Lega;
Jui-Jui Lin;
Ashwini Sharan;
Chengyuan Wu;
Michael R. Sperling;
Sameer A. Sheth;
Guy M. McKhann;
Elliot H. Smith;
Catherine Schevon;
Joshua M. Stein;
Joel Jacobs
The medial temporal lobe is critical for both spatial navigation and memory. Although single neurons in the medial temporal lobe activate to represent locations in the environment during navigation, how this spatial tuning relates to memory for events involving those locations remains unclear. We examined memory-related changes in spatial tuning by recording single-neuron activity from neurosurgical patients performing a virtual-reality object–location memory task. We identified ‘memory-trace cells’ with activity that was spatially tuned to the retrieved location of the specific object that participants were cued to remember. Memory-trace cells in the entorhinal cortex, in particular, encoded discriminable representations of different memories through a memory-specific rate code. These findings indicate that single neurons in the human entorhinal cortex change their spatial tuning to target relevant memories for retrieval.