Mobile Neurofeedback for Pain Management in Veterans with TBI and PTSD.

OBJECTIVE: Chronic pain is common in military veterans with traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). Neurofeedback, or electroencephalograph (EEG) biofeedback, has been associated with lower pain but requires frequent travel to a clinic. The current study examined feasibility and explored effectiveness of neurofeedback delivered with a portable EEG headset linked to an application on a mobile device. DESIGN: Open-label, single-arm clinical trial. SETTING: Home, outside of clinic. SUBJECTS: N = 41 veterans with chronic pain, TBI, and PTSD. METHOD: Veterans were instructed to perform "mobile neurofeedback" on their own for three months. Clinical research staff conducted two home visits and two phone calls to provide technical assistance and troubleshoot difficulties. RESULTS: N = 36 veterans returned for follow-up at three months (88% retention). During this time, subjects completed a mean of 33.09 neurofeedback sessions (10 minutes each). Analyses revealed that veterans reported lower pain intensity, pain interference, depression, PTSD symptoms, anger, sleep disturbance, and suicidal ideation after the three-month intervention compared with baseline. Comparing pain ratings before and after individual neurofeedback sessions, veterans reported reduced pain intensity 67% of the time immediately following mobile neurofeedback. There were no serious adverse events reported. CONCLUSIONS: This preliminary study found that veterans with chronic pain, TBI, and PTSD were able to use neurofeedback with mobile devices independently after modest training and support. While a double-blind randomized controlled trial is needed for confirmation, the results show promise of a portable, technology-based neuromodulatory approach for pain management with minimal side effects.

The Effects of Health Anxiety and Litigation Potential on Symptom Endorsement, Cognitive Performance, and Physiological Functioning in the Context of a Food and Drug Administration Drug Recall Announcement.

Drug recalls and lawsuits against pharmaceutical manufacturers are accompanied by announcements emphasizing harmful drug side-effects. Those with elevated health anxiety may be more reactive to such announcements. We evaluated whether health anxiety and financial incentives affect subjective symptom endorsement, and objective outcomes of cognitive and physiological functioning during a mock drug recall. Hundred and sixty-one participants reported use of over-the-counter pain medications and presented with a fictitious medication recall via a mock Food and Drug Administration (FDA) website. The opportunity to join a class-action lawsuit was manipulated. We assessed health anxiety, recalled drug usage, blood pressure, heart rate, and performance on a computerized Trail Making Test (TMT). Symptom endorsement was strongly predicted by health anxiety. When combined, three health anxiety measures explained 28.5% variance (Cohen's d = 1.26). These effects remain strong after controlling for depression and anxiety. Litigation condition did not predict symptom endorsement. Blood pressure and heart rate were modestly predicted by health anxiety, but not by litigation condition. TMT performance was consistently predicted by health anxiety, with higher scores associated with poorer performance. Although there were no main effects for litigation, interactions consistently emerged for the TMT, with generally poorer performance for those with higher health anxiety in the non-litigation condition; whereas health anxiety was unrelated to performance for the litigation condition. All but one participant joined the litigation when given the opportunity, despite a healthy sample and minimal use of pain medication. Subsequent data from 67 individuals with no mention of the FDA scenario or litigation showed that health anxiety still significantly predicts symptom endorsement (12.6% variance), but the explained variance is less than half that obtained in the FDA scenario. The findings suggest that health anxiety plays a significant role in adverse symptom reporting, beyond anxiety or depression, and this effect is independent of the presence of the FDA recall. The lack of differences for health anxiety and symptom endorsement between litigation and non-litigation conditions rules out malingering. Although it is general practice in drug recalls to list potential adverse side effects caused by medications, this may elicit unintended symptom experiences and health anxious individuals may be more susceptible.

Retrograde amnesia for visual memories after hippocampal damage in rats.

It is generally believed that the hippocampus is not required for simple discrimination learning. However, a small number of studies have shown that hippocampus damage impairs retention of a previously learned visual discrimination task. We propose that, although simple discrimination learning may proceed in the absence of the hippocampus, it plays an important role in this type of learning when it is intact. In order to test the role of the hippocampus in simple discrimination learning, we performed a series of experiments utilizing a two-choice picture discrimination task. Our experiments confirm that rats readily learn simple two-choice picture discriminations after hippocampus damage. However, if such discriminations are first learned while the hippocampus is intact, subsequent hippocampus damage causes severe retrograde amnesia for the discriminations. Furthermore, retrograde amnesia for simple picture discriminations was equally severe when the interval between training and damage was 1 d or 60 d; remote picture memories are not spared. Similarly, the rule or schema underlying a recently or remotely acquired picture discrimination learning set was lost after hippocampus damage. The severity of retrograde amnesia for simple picture discriminations is negatively correlated with the volume of spared hippocampus tissue. Thus, the hippocampus plays an essential role in long-term memories supporting simple picture discriminations.

Persistent increases in the pool of doublecortin-expressing neurons in the hippocampus following spatial navigation training.

In addition to its role in neuronal migration during embryonic development, doublecortin (DCX) plays a role in hippocampal neurogenesis across the lifespan. Hippocampal neurons exhibit a high degree of synaptic plasticity while they are in the DCX phase. While previous studies have reported that behavioral training on hippocampus-dependent tasks can enhance neuron survival, little was known about the stage of development of those neurons and, particularly, whether a large pool of the surviving new neurons remains in the DCX phase for a prolonged period after training. Here we report that spatial navigation training increases the pool of neurons that are in the DCX phase 4 weeks after training ended. Thus, the stock of DCX-expressing neurons in the hippocampus is affected by whether a hippocampus-dependent task has been encountered during the preceding few weeks.

Self-Reported Mindful Attention and Awareness, Go/No-Go Response-Time Variability, and Attention-Deficit Hyperactivity Disorder.

The abilities to stabilize the focus of attention, notice attention lapses, and return attention to an intended object following lapses are precursors for mindfulness. Individuals diagnosed with attention-deficit hyperactivity disorder (ADHD) are deficient in the attentional and self-control skills that characterize mindfulness. The present study assessed the relationship between mindfulness and ADHD in young adults using the Mindful Attention and Awareness Scale (MAAS), a computerized Go/No-Go task (the Test of Variables of Attention (TOVA)), the World Health Organization Adult Self-Report Scale (ASRS), a tool used as an adult ADHD screen, the Beck Anxiety Inventory (BAI), and the Beck Depression Inventory-II (BDI-II). We recruited 151 adult volunteers (ages 18 to 40); 100 with confirmed ADHD diagnoses and 51 control participants. Overall, participants with prior diagnoses of ADHD scored lower on the MAAS than controls and ASRS scores were strongly negatively correlated MAAS scores. Attention performance index, response time, and response-time variability subscales of the TOVA were positively correlated with MAAS scores and negatively correlated with ASRS scores. Intrasubject response-time variability on the TOVA, a parameter associated with attention lapses, was also strongly negatively correlated with MAAS scores. Overall, participants' self-reported mindfulness, as measured by the MAAS, was strongly related to self-reports on a clinical measure of attention disorders, anxiety, depression, and multiple indices of concentration and mind wandering on a standardized Go/No-Go task, the TOVA.

Chlordiazepoxide interactions with scopolamine and dizocilpine: novel cooperative and antagonistic effects on spatial learning.

The authors investigated the effects on spatial behavior of coadministrations of a benzodiazepine, chlordiazepoxide (CDP), with a noncompetitive N-methyl-d-aspartate receptor antagonist (NMDAR), dizocilpine (DZP), and a muscarinic cholinergic receptor antagonist, scopolamine (SCP). Rats solved the Morris swim task in 2 settings; 1 in which a hidden escape platform was always in the same location (performance) and a 2nd in which the platform had been moved to a different location (acquisition) for repeated daily sessions. CDP (3.0 mg/kg) administered alone did not disrupt escape latencies or swim path accuracies. SCP and DZP each impaired acquisition and performance in a dose-dependent manner. CDP coadministered with 0.3 mg/kg SCP impaired escape only in the acquisition setting and when coadministered with 1.0 mg/kg SCP selectively exacerbated the escape impairment in the acquisition setting. CDP ameliorated deleterious effects of DZP in both settings.

An assessment of an automated EEG biofeedback system for attention deficits in a substance use disorders residential treatment setting.

Attention deficits are prevalent among individuals with substance use disorders and may interfere with recovery. The present study evaluated the effectiveness of an automated electroencephalogram (EEG) biofeedback system in recovering illicit substance users who had attention deficits upon admission to a comprehensive residential treatment facility. All participants (n = 95) received group, family, and individual counseling. Participants were randomly assigned to 1 of 3 groups that either received 15 sessions of automated EEG biofeedback (AEB), 15 sessions of clinician guided EEG biofeedback (CEB), or 15 additional therapy sessions (AT). For the AEB and CEB groups, operant contingencies reinforced EEG frequencies in the 15-18 Hz (ß) and 12-15 Hz (sensorimotor rhythm, "SMR") ranges and reduce low frequencies in the 1-12 Hz (Δ, θ, and α) and 22-30 Hz (high ß) ranges. The Test of Variables of Attention (TOVA), a "Go-NoGo" task, was the outcome measure. Attention scores did not change on any TOVA measure in the AT group. Reaction time variability, omission errors, commission errors, and d' improved significantly (all p values < .01) in the AEB and CEB groups. AEB and CEB did not differ significantly from each other on any measure. The results demonstrate that automated neurofeedback can effectively improve attention in recovering illicit substance users in the context of a comprehensive residential substance abuse treatment facility.

Deficiencies in the detection of cognitive deficits.

Numerous studies purport to show that cardiopulmonary bypass (CPB) surgery is associated with persistent postoperative cognitive decline. In J. R. Keith et al. (2002), the authors argued that reports of post-CPB cognitive declines have often been quantified using data analysis methods that were based on tenuous assumptions and overlooked problems associated with familywise Type I errors. Four peers who are recognized for their expertise in neuropsychological outcomes research evaluated the arguments developed in the J. R. Keith et al. article, critiqued the study presented in that article, and offered suggestions for how to investigate whether cognitive decline occurs reliably after CPB. In this reply article, the authors respond to the open-peer commentaries made regarding the J. R. Keith et al. study.

Assessing postoperative cognitive change after cardiopulmonary bypass surgery.

Cognitive decline after cardiopulmonary bypass (CPB) surgery has been a concern since the advent of CPB procedures. A primary focus of many studies on this topic has been to quantify the incidence of post-CPB cognitive impairment. However, studies that have used traditional parametric statistics have generally failed to confirm that long-lasting (> or = 1 month) cognitive declines occur reliably after CPB surgery. For the present study, the authors used a split-plot analysis of variance model that revealed preoperative memory impairments in the CPB patients and new postoperative impairments of attention. The authors discuss the assumptions of, and problems associated with, analysis methods that are often used to quantify the incidence of cognitive impairment following CPB surgery.

Repeated spatial acquisition: effects of NMDA antagonists and morphine.

Effects of morphine and 2 N-methyl-D-aspartate (NMDA) receptor antagonists, phencyclidine and LY235959, were studied using a within-subject, repeated-acquisition/performance procedure adapted to the Morris Swim Task. In the performance component, subjects swam to a hidden platform that was always in the same location in the pool. In the acquisition component, the platform was moved to a different place for each session. Baseline training produced rapid and direct swims to the platform in the performance component and steep within-session learning curves in the acquisition component. All 3 compounds increased swim distances, escape latencies, and slowed swim speed in a dose-dependent manner, but only morphine consistently produced selective impairments on acquisition. NMDA antagonists generally affected acquisition only at doses that also disrupted performance, although phencyclidine produced selective effects in some animals. These outcomes were different than those from studies of response chains in primates, suggesting that task and species variables may be important determinants of drug effects on acquisition.

Navigation in the Morris swim task as a baseline for drug discrimination: a demonstration with morphine.

A morphine versus saline discrimination was demonstrated using the Morris swim task as the behavioral baseline. The apparatus was a large circular pool filled with water made opaque by floating polypropylene pellets. Rats were placed in the tank in randomly selected locations (12 trials per session) and could escape by swimming to a platform submerged 2 cm below the surface. Morphine (5.6 mg/kg) or saline was injected prior to training sessions. The position of the platform in a given session depended on the drug condition, thus forming the basis for discriminative responding. Three of the 4 rats acquired the discrimination, as evidenced by direct swims to the condition-appropriate platform. Generalization probe sessions were conducted following acquisition. Probe sessions were preceded by injections of morphine (0, 1.0, 3.0, 5.6, or 10.0 mg/kg) and involved placing the rat in the pool for 1 min without a platform. Swim patterns revealed a gradient, with probe swimming more concentrated in the area of the morphine platform position after higher morphine doses. In addition, dose-dependent increases in the likelihood of swimming first to the morphine-associated platform location were obtained. These results illustrate the generality of drug discrimination across different behavioral procedures, and of particular interest with respect to spatial learning, demonstrate interoceptive stimulus control of navigation.

Does 5-bromo-2'-deoxyuridine (BrdU) disrupt cell proliferation and neuronal maturation in the adult rat hippocampus in vivo?

5-Bromo-2'-deoxyuridine (BrdU) is frequently used as a mitotic marker in studies of cell proliferation. Recent studies have reported cytotoxic effects of BrdU on neural progenitor cells in embryonic and neonatal brains in vivo and in adult tissue studied in vitro. The present study was conducted to assess whether BrdU interferes with cell proliferation and neuronal maturation in the rat adult hippocampus in vivo. BrdU effects across a wide range of doses (40-480 mg/kg) on cell proliferation and the population of immature neurons in the adult hippocampus were investigated using immunohistochemical labeling methods for the cell cycle marker Ki67 and a marker for immature neurons, doublecortin. BrdU did not influence cell proliferation in the dentate gyrus or the population of immature neurons observed in the adult hippocampus relative to those observed in saline treated controls. Thus, in contrast with reports of deleterious effects of BrdU in embryonic and neonatal tissue and adult tissue studied in vitro, BrdU does not appear to have cytotoxic effects on proliferating hippocampal cells or immature neurons in vivo in rats.

Fluoxetine and the dentate gyrus: memory, recovery of function, and electrophysiology.

Chronic fluoxetine increases neurogenesis in the dentate gyrus (DG). In view of the widespread clinical use of fluoxetine and the well-established role of the DG in memory, surprisingly few studies have examined the effects of fluoxetine on memory and hippocampal electrophysiology. Additionally, few studies have evaluated the potential for fluoxetine to promote recovery of function after DG damage. Therefore, we studied the effects of long-term administration of fluoxetine on both spatial-reference memory and working memory, recovery of function after intrahippocampal colchicine infusions, which can destroy 50-70% of DG granule cells, and electrophysiological responses in the DG to perforant path stimulation in freely moving rats. Chronic fluoxetine did not affect matching-to-place or reference-memory performance in intact rats in the Morris water-maze task. Surprisingly, in rats with DG damage, recovery of function on both tasks was adversely affected by chronic fluoxetine. Finally, unlike an earlier study that reported fluoxetine-induced increases in hippocampal population spike amplitudes and excitatory postsynaptic potential slopes in urethane-anesthetized rats, electrophysiological measures in DG of freely moving rats were not affected by chronic fluoxetine treatment.

Adrenalectomy-induced granule cell degeneration in the hippocampus causes spatial memory deficits that are not reversed by chronic treatment with corticosterone or fluoxetine.

Long-term adrenalectomy (ADX) causes a nearly complete and selective loss of granule cells in the dentate gyrus (DG) of the hippocampus. Previously, learning and memory deficits have been observed following ADX-induced granule cell degeneration for tasks that require the hippocampus. Our objective here was to determine whether corticosterone (CORT) replacement and treatment with the neurogenic compound fluoxetine could reverse behavioral deficits after ADX. We trained ADX and control rats in a moving, hidden platform version of the Morris water task before chronic administration (6 weeks) of CORT and either fluoxetine or vehicle. After treatment, all rats were retested in the Morris water task. Brains were labeled for the endogenous neurogenic markers Ki67 and doublecortin. Here we provide evidence that neurogenesis persists at a normal rate in the hippocampus after long-term ADX. After 8 weeks of CORT and fluoxetine administration, ADX-fluoxetine rats did not differ significantly compared to ADX-vehicle rats receiving CORT or compared to control rats in the number of Ki67 or doublecortin labeled cells. ADX-fluoxetine rats also did not significantly differ from ADX-vehicle rats in regards to granule cell layer thickness. Our results indicate that long-term ADX is associated with impaired spatial ability in the Morris water task and that neither chronic treatment with CORT, nor with CORT and fluoxetine are capable of altering the Morris water task deficit.