Considerations and recommendations for selection and utilization of upper extremity clinical outcome assessments in human spinal cord injury trials.

STUDY DESIGN: This is a focused review article. OBJECTIVES: This review presents important features of clinical outcomes assessments (COAs) in human spinal cord injury research. Considerations for COAs by trial phase and International Classification of Functioning, Disability and Health are presented as well as strengths and recommendations for upper extremity COAs for research. Clinical trial tools and designs to address recruitment challenges are identified. METHODS: The methods include a summary of topics discussed during a two-day workshop, conceptual discussion of upper extremity COAs and additional focused literature review. RESULTS: COAs must be appropriate to trial phase and particularly in mid-late-phase trials, should reflect recovery vs. compensation, as well as being clinically meaningful. The impact and extent of upper vs. lower motoneuron disease should be considered, as this may affect how an individual may respond to a given therapeutic. For trials with broad inclusion criteria, the content of COAs should cover all severities and levels of SCI. Specific measures to assess upper extremity function as well as more comprehensive COAs are under development. In addition to appropriate use of COAs, methods to increase recruitment, such as adaptive trial designs and prognostic modeling to prospectively stratify heterogeneous populations into appropriate cohorts should be considered. CONCLUSIONS: With an increasing number of clinical trials focusing on improving upper extremity function, it is essential to consider a range of factors when choosing a COA. SPONSORS: Craig H. Neilsen Foundation, Spinal Cord Outcomes Partnership Endeavor.

Translating promising strategies for bowel and bladder management in spinal cord injury.

Loss of control over voiding following spinal cord injury (SCI) impacts autonomy, participation and dignity, and can cause life-threatening complications. The importance of SCI bowel and bladder dysfunction warrants significantly more attention from researchers in the field. To address this gap, key SCI clinicians, researchers, government and private funding organizations met to share knowledge and examine emerging approaches. This report reviews recommendations from this effort to identify and prioritize near-term treatment, investigational and translational approaches to addressing the pressing needs of people with SCI.

A novel method for oral stimulant administration in the neonate rat and similar species.

Sixty male and female Long-Evans hooded rats were administered 1, 2, or 5mg/kg methylphenidate (MPH) suspended in apple juice on postnatal day (P)15 or P40 using a novel, non-invasive oral administration technique. Plasma was collected 15 min after ingestion and analyzed by high performance liquid chromatography-mass spectrometry (HPLC-MS) to confirm appropriate concentrations. HPLC-MS plasma analysis showed levels comparable to previous gavage studies using MPH. We have used this method successfully in subsequent behavioral studies as well. Since therapeutic MPH in humans is typically administered orally, oral dosing methods that have been verified in the rodent model are of value. We recommend employment of this alternative oral dosing technique as it is minimally invasive, can be used anytime during postnatal development, and does not depend upon voluntary consumption.

Nicotine causes age-dependent changes in gene expression in the adolescent female rat brain.

Humans often start smoking during adolescence. Recent results suggest that rodents may also be particularly vulnerable to nicotine dependence during adolescence. We examined the effect of chronic nicotine exposure on gene expression profiles during adolescence in female rats, who were dosed with nicotine (and control animals were dosed with saline) via subcutaneously implanted osmotic minipumps. Brain samples were collected at four ages: before puberty (postnatal day 25), at about the time of puberty in females (postnatal day 35), and after puberty (postnatal days 45 and 55). The expression of 7931 genes in three brain areas was measured using DNA microarrays. Quantitative RT-PCR was also employed to confirm the expression patterns of selected genes. We used a novel clustering technique (principal cluster analysis) to classify 162 nicotine-regulated genes into five clusters, of which only one (cluster A) showed similar patterns of gene expression across all three brain areas (ventral striatum, prefrontal cortex, and hippocampus). Three clusters of genes (A, B, and C) showed dramatic peaks in their nicotine responses at the same age (p35). The other two clusters (D1 and D2) showed smaller peaks and/or valleys in their nicotine responses at p35 and p45. Thus, the age of maximal gene expression response to nicotine in female rats corresponds approximately to the age of maximal behavioral response and the age of puberty.

Long-term changes in fear conditioning and anxiety-like behavior following nicotine exposure in adult versus adolescent rats.

Adolescent nicotine exposure is associated with long-term use, and it has been suggested that this vulnerability to addiction may relate to lasting anxiogenic effects of the drug. However, few studies have addressed long-term effects of adolescent nicotine, and fewer yet have compared adolescent to adult exposure. Male and female Long-Evans rats continuously received nicotine bitartrate or sodium tartrate via osmotic mini-pumps over 15 days either during adolescence (p28-42) or adulthood (p85-99). Initial nicotine dose (free base) was either low (1 mg/kg/day) or high (2 mg/kg/day). Open field behavior and fear conditioning were assessed in adulthood, 1 month post-dosing. Animals pretreated with nicotine during adolescence showed less center time in a novel open field than sham controls. Conversely, the two nicotine doses differentially affected fear conditioning. Animals pretreated with low nicotine during adolescence demonstrated superior acquisition of the task compared to sham control animals; however, unlike either high nicotine-pretreated or sham control animals, they failed to extinguish the learned behavior. In contrast, animals pretreated during adulthood did not behave significantly different from sham controls on either task. Overall, nicotine-pretreatment during adolescence induced effects on behaviors related to fear and anxiety in adulthood, while comparable pretreatment during adulthood failed to produce significant residual effects.

Minimally invasive endovascular stent-electrode array for high-fidelity, chronic recordings of cortical neural activity.

High-fidelity intracranial electrode arrays for recording and stimulating brain activity have facilitated major advances in the treatment of neurological conditions over the past decade. Traditional arrays require direct implantation into the brain via open craniotomy, which can lead to inflammatory tissue responses, necessitating development of minimally invasive approaches that avoid brain trauma. Here we demonstrate the feasibility of chronically recording brain activity from within a vein using a passive stent-electrode recording array (stentrode). We achieved implantation into a superficial cortical vein overlying the motor cortex via catheter angiography and demonstrate neural recordings in freely moving sheep for up to 190 d. Spectral content and bandwidth of vascular electrocorticography were comparable to those of recordings from epidural surface arrays. Venous internal lumen patency was maintained for the duration of implantation. Stentrodes may have wide ranging applications as a neural interface for treatment of a range of neurological conditions.

Periadolescent nicotine administration produces enduring changes in dendritic morphology of medium spiny neurons from nucleus accumbens.

The objective of the current study was to examine how periadolescent nicotine exposure affects dendritic morphology of medium spiny neurons from the nucleus accumbens shell. Male Long-Evans hooded rats were chronically administered nicotine or saline for a period extending from postnatal day 22 (p22) to p69. Nicotine and saline administration was via subcutaneously implanted osmotic pumps. At p144, 75 days after conclusion of nicotine administration, brains were processed for Golgi-Cox staining. Medium spiny neurons from the nucleus accumbens shell were digitally reconstructed. It was found that neurons from nicotine-treated animals possessed significantly longer dendrites and a greater number of dendritic segments than control animals. A branch order analysis indicated that differences in dendritic length and segment number were most pronounced in third and fourth order segments. A subsequent behavioral experiment suggests that the observed anatomical changes are associated with enduring psychomotor differences. These findings indicate that periadolescent exposure to nicotine can result in long-lasting structural changes in the nucleus accumbens shell and are consistent with behavioral data suggesting that adolescent nicotine exposure may result in vulnerability to nicotine addiction in adulthood.

DARPA-funded efforts in the development of novel brain-computer interface technologies.

The Defense Advanced Research Projects Agency (DARPA) has funded innovative scientific research and technology developments in the field of brain-computer interfaces (BCI) since the 1970s. This review highlights some of DARPA's major advances in the field of BCI, particularly those made in recent years. Two broad categories of DARPA programs are presented with respect to the ultimate goals of supporting the nation's warfighters: (1) BCI efforts aimed at restoring neural and/or behavioral function, and (2) BCI efforts aimed at improving human training and performance. The programs discussed are synergistic and complementary to one another, and, moreover, promote interdisciplinary collaborations among researchers, engineers, and clinicians. Finally, this review includes a summary of some of the remaining challenges for the field of BCI, as well as the goals of new DARPA efforts in this domain.

Pollutant removal efficacy of three wet detention ponds.

Monthly inflow and outflow data were collected from three wet detention ponds in Wilmington, North Carolina, for a 29-mo period. Two ponds drained urban areas consisting primarily of residential, mixed services, and retail usage, while the third mainly drained residential and golf course areas. One of the urban ponds achieved significant reductions in total nitrogen, nitrate, ammonium, total phosphorus, orthophosphate, and fecal coliform bacterial counts. This pond was characterized by a high length to width ratio, with most inputs directed into the upper area, and extensive coverage by a diverse community of aquatic macrophyte vegetation. The second urban pond achieved significant reductions in turbidity and fecal coliform bacterial counts, but there were no significant differences between inflowing and outflowing water nutrient concentrations. There were substantial suburban runoff inputs entering the mid- and lower-pond areas that short-circuited pollutant removal contact time. The golf course pond showed significant increases in nitrate, ammonium, total phosphorus, and orthophosphate in the outflow relative to the inflow, probably as a result of course fertilization. However, nutrient concentrations in the outflow water were low compared with discharges from a selection of other area golf courses, possibly a result of the outflow passing through a wooded wetland following pond discharge. To achieve good reduction in a variety of pollutants, wet pond design should include maximizing the contact time of inflowing water with rooted vegetation and organic sediments. This can be achieved through a physical pond design that provides a high length to width ratio, and planting of native macrophyte species.

Low-dose adolescent nicotine and methylphenidate have additive effects on adult behavior and neurochemistry.

Adolescents with Attention Deficit Hyperactivity Disorder (ADHD) have higher rates of smoking than adolescents without ADHD. Since methylphenidate is the primary drug used to treat ADHD, it is likely that many adolescents are exposed to both methylphenidate and nicotine. Recent studies have established that adolescent nicotine induces long-term changes in several neurobehavioral variables. Limited data also suggest that adolescent methylphenidate may affect neural development. Nicotine tolerance is a well-established behavioral phenomenon in rodents, yet the underlying mechanism remains elusive. Recent theories suggest that changes in ventral striatal dopamine indices may relate to nicotine tolerance. As an initial determination of whether nicotine and methylphenidate have additive effects on neurobehavioral development, the present study investigated the combined effects of adolescent nicotine [2mg/kg/d] alone or in conjunction with methylphenidate [1.5mg/kg, 2× daily] following a one-month drug free period on adult behavioral tolerance to nicotine [0.5mg/kg s.c.] and its relation to dopamine receptor mRNA expression in the ventral striatum. Animals with chronic combined (nicotine+methylphenidate) adolescent exposure displayed stronger tolerance as adults to the nicotine-induced locomotor effects in comparison to animals with adolescent exposure to nicotine alone, methylphenidate alone, or controls. Combined chronic adolescent exposure significantly elevated adult D3nf mRNA expression levels in the nucleus accumbens, however a single nicotine injection in adults increased D3nf mRNA levels in naïve animals and decreased D3nf mRNA levels in those that had been previously exposed to combined stimulants during adolescence. Conversely, a single adult nicotine injection increased D1 mRNA levels in the adult nucleus accumbens, particularly in the shell, but only in rats previously exposed to nicotine or methylphenidate as adolescents. To our knowledge this is the first study that has shown long-term behavioral and neurochemical changes stemming from low chronic exposure of these two commonly co-consumed stimulants during adolescence.