Réjean M. Guerriero

Glutamate and GABA imbalance following traumatic brain injury.

Traumatic brain injury (TBI) leads to multiple short- and long-term changes in neuronal circuits that ultimately conclude with an imbalance of cortical excitation and inhibition. Changes in neurotransmitter concentrations, receptor populations, and specific cell survival are important contributing factors. Many of these changes occur gradually, which may explain the vulnerability of the brain to multiple mild impacts, alterations in neuroplasticity, and delays in the presentation of posttraumatic epilepsy. In this review, we provide an overview of normal glutamate and GABA homeostasis and describe acute, subacute, and chronic changes that follow injury. We conclude by highlighting opportunities for therapeutic interventions in this paradigm.

L-Type Ca2+ Channels Mediate Adaptation of Extracellular Signal-Regulated Kinase 1/2 Phosphorylation in the Ventral Tegmental Area after Chronic Amphetamine Treatment

L-type Ca2+ channels (LTCCs) play an important role in chronic psychostimulant-induced behaviors. However, the Ca2+ second messenger pathways activated by LTCCs after acute and recurrent psychostimulant administration that contribute to drug-induced molecular adaptations are poorly understood. Using a chronic amphetamine treatment paradigm in rats, we have examined the role of LTCCs in activating the mitogen-activated protein (MAP) kinase pathway in the ventral tegmental area (VTA), a primary target for the reinforcing properties of psychostimulants. Using immunoblot and immunohistochemical analyses, we find that in chronic saline-treated rats a challenge injection of amphetamine increases phosphorylation of MAP [extracellular signal-regulated kinase 1/2 (ERK1/2)] kinase in the VTA that is independent of LTCCs. However, in chronic amphetamine-treated rats there is no increase in amphetamine-mediated ERK1/2 phosphorylation unless LTCCs are blocked, in which case there is robust phosphorylation in VTA dopamine neurons. Examination of the expression of phosphatases reveals an increase in calcineurin [protein phosphatase 2B (PP2B)] and MAP kinase phosphatase-1 (MKP-1) in the VTA. Using in situ hybridization histochemistry and immunoblot analyses, we further examined the mRNA and protein expression of the LTCC subtypes Cav1.2 and Cav1.3 in VTA dopamine neurons in drug-naive animals and in rats after chronic amphetamine treatment. We found an increase in Cav1.2 mRNA and protein levels, with no change in Cav1.3. Together, our results suggest that one aspect of LTCC-induced changes in second messenger pathways after chronic amphetamine exposure involves activation of the MAP kinase phosphatase pathway by upregulation of Cav1.2 in VTA dopaminergic neurons.

Epidemiology, trends, assessment and management of sport-related concussion in United States high schools.

Purpose of review Sport-related concussion affects athletes at every level of participation. The short and long-term effects of concussions that occur during childhood and adolescence are not fully understood. The purpose of this review is to describe the current burden of disease, current practice patterns and current recommendations for the assessment and management of sport-related concussions sustained by United States high school athletes. Recent findings Millions of high school students participate in organized sports in the United States. Current estimates suggest that, across all sports, approximately 2.5 concussions occur for every 10 000 athletic exposures, in which an athletic exposure is defined as one athlete participating in one game or practice. At schools that employ at least one athletic trainer, most high school athletes who sustain sport-related concussions will be cared for by athletic trainers and primary care physicians. Approximately 40% will undergo computerized neurocognitive assessment. Summary The number of high school athletes being diagnosed with sport-related concussions is rising. American football has the highest number of concussions in high school with girls’ soccer having the second highest total number. Fortunately, coaches are becoming increasingly aware of these injuries and return-to-play guidelines are being implemented.

Preadolescent Methylphenidate versus Cocaine Treatment Differ in The Expression of Cocaine-Induced Locomotor Sensitization During Adolescence and Adulthood

BACKGROUND Methylphenidate (MPH), the most commonly prescribed medication for childhood attention-deficit/hyperactivity disorder (ADHD), shares chemical and mechanistic similarities to cocaine which has stimulated research to address the addiction liability following treatment. METHODS Utilizing locomotor sensitization we examined the consequences of recurrent MPH versus cocaine treatment during preadolescence in altering cocaine-induced locomotor behavior in adolescent and adult mice. Black Swiss Webster mice were treated with MPH, cocaine, or saline during preadolescence. To test whether MPH pretreatment during preadolescence contributed to an altered sensitivity to cocaine during adolescence, these mice were treated with recurrent cocaine or saline during adolescence. All mice were challenged with cocaine as adults. RESULTS Recurrent MPH treatment, unlike cocaine treatment in preadolescent mice, had no effect on locomotor sensitization to cocaine during adolescence or adulthood, as compared with saline controls. Furthermore, unlike cocaine, administration of MPH in adolescence did not augment the response to cocaine challenge. CONCLUSIONS MPH treatment during preadolescence does not increase subsequent sensitivity to cocaine, whereas cocaine treatment does. Thus, MPH treatment during preadolescence does not appear to persistently induce long-term adaptations, which may underlie an enhanced liability for subsequent drug abuse.

Augmented constitutive CREB expression in the nucleus accumbens and striatum may contribute to the altered behavioral response to cocaine of adult mice exposed to cocaine in utero

Neuroadaptations occurring in the mesolimbic dopamine pathway following recurrent exposure to drugs of abuse have been correlated with a behavioral phenomenon known as behavioral sensitization. We have developed an animal model of prenatal cocaine exposure and, using a postnatal sensitization protocol, have examined the subsequent sensitivity of offspring to cocaine. Pregnant Swiss Webster dams were injected twice daily from embryonic day 8 to 17, inclusive, with cocaine (COC40: administered cocaine HCl at a dose of 40 mg/kg/day, and COC20: administered cocaine HCl at a dose of 20 mg/kg/day), or saline (SAL). The SPF40 group (saline pair-fed), a nutritional control group, was ‘pair-fed’ with COC40 dams. Activity was recorded for 30 min during a 3-day saline habituation, a 14-day ‘initiation’ phase, when animals received cocaine (15 mg/kg) or saline every other day, and following a 21-day ‘withdrawal’ period when all mice were challenged with cocaine. COC40 offspring, as compared with SAL controls, did not habituate to a novel environment, demonstrated increased cocaine-induced stereotypy on Coc 1 (first cocaine injection), and blunted locomotor sensitization on challenge as measured by the percentage of each animal’s baseline locomotion. Tissue samples of the nucleus accumbens (NAc) and striatum (Str) of all four prenatal treatment groups were examined to determine whether alterations in the transcription factor CREB or glutamate receptor subunit, GluR1, induced by prenatal cocaine treatment may have contributed to the altered behavioral responses. Immunoblot quantitation revealed significantly increased constitutive CREB expression in the NAc and Str of COC40 mice as compared with SAL controls. Such alterations in constitutive CREB levels may contribute to some of the behavioral differences reported in adult mice exposed to cocaine in utero.

Augmented D1 Dopamine Receptor Signaling and Immediate-Early Gene Induction in Adult Striatum After Prenatal Cocaine

BACKGROUND Prenatal exposure to cocaine can impede normal brain development, triggering a range of neuroanatomical and behavioral anomalies that are evident throughout life. Mouse models have been especially helpful in delineating neuro-teratogenic consequences after prenatal exposure to cocaine. The present study employed a mouse model to investigate alterations in D(1) dopamine receptor signaling and downstream immediate-early gene induction in the striatum of mice exposed to cocaine in utero. METHODS Basal, forskolin-, and D(1) receptor agonist-induced cyclic adenosine monophosphate (cAMP) levels were measured ex vivo in the adult male striatum in mice exposed to cocaine in utero. Further studies assessed cocaine-induced zif 268 and homer 1 expression in the striatum of juvenile (P15), adolescent (P36), and adult (P60) male mice. RESULTS The D(1) dopamine receptor agonist SKF82958 induced significantly higher levels of cAMP in adult male mice treated with cocaine in utero compared with saline control subjects. No effects of the prenatal treatment were found for cAMP formation induced by forskolin. After an acute cocaine challenge (15 mg/kg, IP), these mice showed greater induction of zif 268 and homer 1, an effect that was most robust in the medial part of the mid-level striatum and became more pronounced with increasing age. CONCLUSIONS Together these findings indicate abnormally enhanced D(1) receptor signal transduction in adult mice after prenatal cocaine exposure. Such changes in dopamine receptor signaling might underlie aspects of long-lasting neuro-teratogenic effects evident in some humans after in utero exposure to cocaine and identify the striatum as one target potentially vulnerable to gestational cocaine exposure.

Augmentation of Cocaine-Sensitized Dopamine Release in the Nucleus Accumbens of Adult Mice following Prenatal Cocaine Exposure

Behavioral changes in adult mice after prenatal exposure to cocaine have been identified. Mice exposed to cocaine in utero (40 or 20 mg/kg/day) and controls were given a sensitizing cocaine regimen (15 mg/kg every other day × 7 doses), withdrawn for 21 days, and challenged with 15 mg/kg cocaine. In vivo microdialysis for dopamine (DA), serotonin, and their metabolites in awake behaving mice on the first, seventh and challenge doses showed increased cocaine-stimulated DA release in the nucleus accumbens, which was significantly enhanced after prenatal cocaine exposure. This effect was not due to fetal malnutrition or changes in the total tissue DA content. Early developmental cocaine exposure may alter adaptation of brain reward systems to chronic psychostimulant exposure in adulthood.

Time to electroencephalography is independently associated with outcome in critically ill neonates and children

To identify factors associated with in‐hospital mortality in neonates and children undergoing continuous electroencephalography (cEEG) monitoring in the intensive care unit (ICU).

Increased Pediatric Functional Neurological Symptom Disorders After the Boston Marathon Bombings: A Case Series

BACKGROUND Functional neurological symptom disorders are frequently the basis for acute neurological consultation. In children, they are often precipitated by high-frequency everyday stressors. The extent to which a severe traumatic experience may also precipitate functional neurological abnormalities is unknown. METHODS For the 2-week period after the Boston Marathon bombings, we prospectively collected data on patients whose presentation suggested a functional neurological symptom disorder. We assessed clinical and demographic variables, duration of symptoms, extent of educational impact, and degree of connection to the Marathon bombing. We contacted all patients at 6 months after presentation to determine the outcome and accuracy of the diagnosis. RESULTS In a parallel study, we reported a baseline of 2.6 functional neurological presentations per week in our emergency room. In the week after the Marathon bombings, this frequency tripled. Ninety-one percent of presentations were delayed by 1 week, with onset around the first school day after a city-wide lockdown. Seventy-three percent had a history of a prior psychiatric diagnosis. At the 6 months follow-up, no functional neurological symptom disorder diagnoses were overturned and no new organic diagnosis was made. CONCLUSIONS Pediatric functional neurological symptom disorder may be precipitated by both casual and high-intensity stressors. The 3.4-fold increase in incidence after the Boston Marathon bombings and city-wide lockdown demonstrates the marked effect that a community-wide tragedy can have on the mental health of children. Care providers must be aware of functional neurological symptom disorders after stressful community events in vulnerable patient populations, particularly those with prior psychiatric diagnoses.

Optimizing Neurocritical Care Follow-up through the Integration of Neuropsychology

BACKGROUND Pediatric critical care survivors often suffer persisting multisystem health problems and are left with treatment needs that go unmet due to limits in current care models. We proposed that integration of neuropsychology into neurocritical care follow-up provides incremental benefit to the identification and treatment of persisting complications and reduction in co-morbidities. BASIC PROCEDURES The aims of this study were three-fold. First, we described pilot programs at two pediatric hospitals as models for implementing systematic follow-up care with interdisciplinary clinic teams consisting of critical care, neurology, and neuropsychology. Second, we described working models specific to neuropsychological service delivery in these programs. Third, we presented preliminary data from the first six months of one of the pilot programs in order to examine incremental benefit of neuropsychology in improving patient care and parent satisfaction. MAIN FINDINGS A total of 16 patients (age range three to 17 years) were seen by neuropsychology within the first six months of the program. Results showed that integration of neuropsychology into follow-up care resulted in recommendations being made for services or concerns not already addressed in 81% of cases. Parents reported high satisfaction, endorsing the highest possible rating on 96% of all items. Parents reported that neuropsychological consultation improved their understanding and communication with their child, and helped them know what to expect from their child during postacute recovery. CONCLUSIONS The results of this pilot study suggest that integration of neuropsychology into neurocritical care follow-up programs contributes to parent satisfaction and may provide incremental benefit to patient care.