Characterization and prediction of individual functional outcome trajectories in schizophrenia spectrum disorders (PREDICTS study): Study protocol.

Schizophrenia spectrum disorders (SSDs) are associated with significant functional impairments, disability, and low rates of personal recovery, along with tremendous economic costs linked primarily to lost productivity and premature mortality. Efforts to delineate the contributors to disability in SSDs have highlighted prominent roles for a diverse range of symptoms, physical health conditions, substance use disorders, neurobiological changes, and social factors. These findings have provided valuable advances in knowledge and helped define broad patterns of illness and outcomes across SSDs. Unsurprisingly, there have also been conflicting findings for many of these determinants that reflect the heterogeneous population of individuals with SSDs and the challenges of conceptualizing and treating SSDs as a unitary categorical construct. Presently it is not possible to identify the functional course on an individual level that would enable a personalized approach to treatment to alter the individual's functional trajectory and mitigate the ensuing disability they would otherwise experience. To address this ongoing challenge, this study aims to conduct a longitudinal multimodal investigation of a large cohort of individuals with SSDs in order to establish discrete trajectories of personal recovery, disability, and community functioning, as well as the antecedents and predictors of these trajectories. This investigation will also provide the foundation for the co-design and testing of personalized interventions that alter these functional trajectories and improve outcomes for people with SSDs.

Canadian epilepsy priority-setting partnership: Toward a new national research agenda.

BACKGROUND: Health research agendas are often set by researchers or by industry and may not reflect the needs and priorities of end users. This priority-setting partnership (PSP) for epilepsy was undertaken to identify the most pressing unanswered questions about epilepsy and seizures from the perspective of people with epilepsy (PWE) and their care providers. METHODS: Using the methodology developed by the James Lind Alliance (JLA), evidence uncertainties were gathered via online surveys from stakeholders across Canada. Submissions were formed into summary questions and checked against existing evidence to determine if they were true uncertainties. Verified uncertainties were then ranked by patients, caregivers, and healthcare providers and a final workshop was held to reach a consensus on the top 10 priorities. RESULTS: The final top 10 list reflects the priority areas of focus for research as identified by the Canadian epilepsy community, including genetic markers for diagnosis and treatment, concerns about living with the long-term effects of epilepsy, and addressing knowledge gaps in etiology and treatment approaches. CONCLUSION: This project represents the first systematic evidence of patient- and clinician-centered research priorities for epilepsy. The results of this priority-setting exercise provide an opportunity for researchers and funding agencies to align their agendas with the values and needs of the epilepsy community in order to improve clinical outcomes and quality of life (QOL) for PWE.

Do distance-delivery group interventions improve depression in people with epilepsy?

About one-third of people with epilepsy experience comorbid depression. The present study examined outcomes of a distance-delivery group intervention program designed to improve emotional well-being. Participants were 55 adults with epilepsy and self-reported depressive symptoms who were randomly assigned to take part in either a mindfulness-based cognitive behavioral therapy (CBT) program (UPLIFT, n = 20), an epilepsy information and self-management program (EpINFO, n = 24) that served as an active control group, or a wait-list control (WLC) group (n = 11). The Quick Inventory of Depressive Symptomatology (QIDS), Neurological Disorders Depression Inventory for Epilepsy (NDDIE), and the psychological health subscale of the World Health Organization Quality of Life (WHOQOL-BREF) scale were used to assess depression and psychological quality of life before and after treatment, and at short-term (six months) and long-term follow-up (one year) upon program completion. From pre- to posttreatment, a main effect of time was found, with participants in both the UPLIFT and EpINFO groups having reported to a similar degree a significant decrease in depressive symptoms and improved psychological health, improvements that were not seen in the WLC group. The time by group interaction effect was not significant. The effects seen at posttreatment in the UPLIFT and EpINFO groups remained at six months and one year after treatment. These data suggest that distance-delivery group intervention programs are effective at improving depression and psychological quality of life, with the EpINFO program offering benefits similar to the UPLIFT program.

Neurophysiological markers that predict and track treatment outcomes in childhood anxiety.

The present study examined the cortical processes that mediate cognitive regulation in response to emotion-eliciting stimuli, before and after anxious children participated in a cognitive behavioral therapy program. Electroencephalographic activity was recorded from anxious children (n = 24, 8 males) and comparison children (n = 16, 7 males) at pre-and post-treatment sessions. The change in anxiety T-scores from pre- to post-treatment was used to signify clinical improvement among anxious children (Improvers: n = 11 vs. Non-improvers: n = 13). Event-related potential components were recorded while children performed a Go/No-go task using emotional facial expressions. For the P1 component, believed to reflect attention and/or arousal processes, Non-improvers had greater activation levels relative to Improver and comparison groups at both sessions. Greater P1 amplitudes at pre-treatment predicted non-improvement following treatment. For the frontal N2 component, thought to reflect cognitive control processing, Improvers recruited greater activation from pre- to post-treatment, a change in activation that was predictive of treatment outcome. Non-improvers showed increased cortical activation within the time window of the P1, whether at pre- or post-treatment. These data suggest that heightened perceptual vigilance may have led to poorer outcomes. Improvers showed increased prefrontal activation within the time window of the N2 from pre- to post-treatment. These data suggest that increased cognitive control may have led to improved treatment outcomes. In sum, P1 activation may serve as a predictor of treatment outcome, while N2 activation may serve as an indicator of treatment response.

Neural mechanisms of emotion regulation in childhood anxiety.

BACKGROUND: The present study was designed to examine the cortical processes that mediate cognitive regulation in response to emotion-eliciting stimuli in anxious children. METHODS: Electroencephalographic (EEG) activity was recorded from clinically anxious children (n = 29) and typically developing children (n = 34). Event-related potential components were recorded while children performed a go/no-go task using facial stimuli depicting angry, calm, and happy expressions. RESULTS: Anxious children had significantly greater posterior P1 and frontal N2 amplitudes, components associated with attention/arousal and cognitive control, respectively, than typically developing children. Anxious children also had significantly greater error-related negativities and correct-response negativities relative to typically developing children. For the anxious group only, there were no differences in neural activation between face (emotion) types or trial (Go vs. No-go) types. A regression analysis revealed that No-go N2 amplitudes for calm faces predicted self-reported anxiety levels. CONCLUSIONS: Anxious children appeared to show increased cortical activation regardless of the emotional content of the stimuli. Anxious children also showed greater medial-frontal activity regardless of task demands and response accuracy. Taken together, these findings suggest indiscriminate cortical processes that may underlie the hypervigilant regulatory style seen in clinically anxious individuals.

Self-perceptions of social function 2 years after pediatric epilepsy surgery.

The present qualitative study explored how participants perceive their quality of life within the social domain 2 years following epilepsy surgery. Semistructured, open-ended interviews were conducted with 27 participants (11-21 years old), 2 years following epilepsy surgery. Thirteen of the 27 participants were seizure free. Data were transcribed and coded inductively to allow for the identification of salient themes. Many of the seizure-free participants reported greater independence following surgery. However, most participants, irrespective of seizure status, continued to report some problems with peer relations and isolation. These findings suggest that self-perceived improvements in social function among seizure-free participants may require longer than 2 years to develop.

Lack of laterality in the effects of right and left amygdala kindling on weight gain in female rats.

PURPOSE: Women with epilepsy often suffer from weight gain. A similar phenomenon is seen in female rats that are kindled from the amygdala. Interestingly, it has been reported that kindling of the left amygdala causes more weight gain than kindling of the right amygdala. The present study was designed to confirm and extend that effect. METHODS: Female Wistar rats were kindled from the left or right basolateral amygdala to a criterion of 40 stage 5 seizures. Control subjects were handled but not stimulated. Subjects were weighed weekly for the duration of the study. Twenty-four hours following the last kindled seizure, kindled subjects and their yoked controls were sacrificed and their brains and serum were extracted. RESULTS: Kindled subjects weighed significantly more than controls at the end of the kindling procedure and had significantly higher serum levels of leptin. No laterality effects were seen in either weight gain or leptin levels, however. CONCLUSION: Amygdala kindling increases weight gain and serum leptin levels in rats, but in the present study no laterality effects were seen.

The effects of right and left amygdala kindling on the female reproductive system in rats.

PURPOSE: Women with epilepsy often have comorbid reproductive dysfunction. Using the amygdala kindling model in rats, the present study examined the effects of seizures of limbic origin on the reproductive system. METHODS: Female Wistar rats were kindled from the left or right basolateral amygdala to a criterion of 40 stage V seizures. Sham-kindled subjects were handled but not stimulated. Vaginal cytology was assessed daily for the duration of the study. Twenty-four hours following the last kindled seizure, kindled subjects and their yoked controls were sacrificed and their brains and serum were extracted. RESULTS: Kindled subjects displayed significantly more abnormal estrous cycle days and significantly elevated levels of estradiol as compared to controls. There was, however, no total suppression of cycling. No laterality effects were seen for estrous cycle abnormalities. DISCUSSION: Seizures of limbic origin cause changes in estrous cycling. Right and left kindling seem to have a similar effect. These findings highlight the need for clinicians to monitor reproductive issues among individuals with epilepsy.

A ketogenic diet and diallyl sulfide do not elevate afterdischarge thresholds in adult kindled rats.

INTRODUCTION: Acetone has been shown to have broad-spectrum anticonvulsant actions in animal seizure models and has been hypothesized to play a role in the anticonvulsant mechanism of the ketogenic diet (KD). The present study examined the ability of a KD to elevate amygdaloid afterdischarge thresholds (ADT) in fully kindled rats. The effects of the KD were studied in the presence and absence of diallyl sulfide (DAS), an inhibitor of acetone metabolism. METHODS: Twenty-four adult male rats were kindled to 30 stage 5 seizures. Afterdischarge thresholds (ADT) were determined. Subjects were then administered one of the following diets: (1) KD+V (vehicle; KD+V); (2) KD+DAS; (3) control diet+V (CD+V); (4) CD+DAS. They were stimulated every second day. Blood sampling was performed every second day--on non-stimulating days--to determine levels of glucose, beta-hydroxybutyrate, acetoacetate, and acetone. After 20 days, ADTs were re-determined. RESULTS: Blood acetone concentrations were significantly higher in the KD+DAS group as compared to the other groups, although they did not reach "therapeutic levels". None of the treatments, however, elevated ADTs. CONCLUSIONS: The KD was unable to elevate amygdaloid ADTs in fully kindled rats. Although subjects in the KD+DAS group achieved significant elevations of blood acetone, these concentrations (e.g. 0.2 mM) were much lower than those (>2.0 mM) previously shown to confer anticonvulsant activity. There appears to be large difference between humans and rats in their ability to produce elevated blood acetone levels on the KD. These data suggest that adult rats are not ideal subjects for modeling the anticonvulsant actions of the KD.

Increased cerebral tissue oxygen tension after extensive hemodilution with a hemoglobin-based oxygen carrier.

Transfusion of anemic patients with hemoglobin-based oxygen carriers (HBOCs) may improve cerebral oxygen delivery. Conversely, cerebral vasoconstriction, associated with HBOC transfusion, could limit optimal cerebral tissue oxygenation. We hypothesized that hemodilution with a HBOC would maintain cerebral tissue oxygenation, despite the occurrence of cerebral vasoconstriction. Isoflurane-anesthetized rats (100% oxygen) underwent direct measurement of mean arterial blood pressure (MAP), caudate tissue oxygen tension (P(Br)o(2)), and regional cortical cerebral blood flow (rCBF) before and after 50% of the estimated blood volume (30 mL/kg) was exchanged with either an HBOC (hemoglobin raffimer; Hemolink) or pentastarch (n = 6). Hemodilution with hemoglobin raffimer caused a transient increase in P(Br)o(2) from 24.9 +/- 13.3 mm Hg to 32.2 +/- 19.1 mm Hg (P < 0.05), a sustained increase in MAP, and no change in rCBF. Arterial blood oxygen content was maintained despite an increase in methemoglobin and reduced oxygen saturation. Hemodilution with pentastarch caused a transient increase in MAP, no change in P(Br)o(2), and a sustained increase in rCBF (P < 0.05), whereas the hemoglobin concentration and oxygen content were significantly reduced. Hemodilution with hemoglobin raffimer augmented P(Br)o(2) and prevented the increase in rCBF observed after similar hemodilution with pentastarch. These data suggest that transfusion with hemoglobin raffimer may help to maintain cerebral oxygenation during severe anemia.

Hypercapnia increases cerebral tissue oxygen tension in anesthetized rats.

PURPOSE: To test the hypotheses that deliberate elevation of PaCO(2) increases cerebral tissue oxygen tension (PBrO(2)) by augmenting PaO(2) and regional cerebral blood flow (rCBF). METHODS: Anesthetized rats were exposed to increasing levels of inspired oxygen (O(2)) or carbon dioxide (CO(2); 5%, 10% and 15%, n = 6). Mean arterial blood pressure (MAP), PBrO(2) and rCBF were measured continuously. Blood gas analysis and hemoglobin concentrations were determined for each change in inspired gas concentration. Data are presented as mean +/- standard deviation with P < 0.05 taken to be significant. RESULTS: The PBrO(2) increased in proportion to arterial oxygenation (PaO(2)) when the percentage of inspired O(2) was increased. Proportional increases in PaCO(2) (48.7 +/- 4.9, 72.3 +/- 6.0 and 95.3 +/- 15.4 mmHg), PaO(2) (172.2 +/- 33.1, 191.7 +/- 42.5 and 216.0 +/- 41.8 mmHg), and PBrO(2) (29.1 +/- 9.2, 49.4 +/- 19.5 and 60.5 +/- 23.0 mmHg) were observed when inspired CO(2) concentrations were increased from 0% to 5%, 10% and 15%, respectively, while arterial pH decreased (P < 0.05 for each). Exposure to CO(2) increased rCBF from 1.04 +/- 0.67 to a peak value of 1.49 +/- 0.45 (P < 0.05). Following removal of exogenous CO(2), arterial blood gas values returned to baseline while rCBF and PBrO(2) remained elevated for over 30 min. The hypercapnia induced increase in PBrO(2) was threefold higher than that resulting from a comparable increase in PaO(2) achieved by increasing the inspired O(2) concentration (34.9 +/- 14.5 vs 11.4 +/- 5.0 mmHg, P < 0.05). CONCLUSION: These data support the hypothesis that the combined effect of increased CBF, PaO(2) and reduced pH collectively contribute to augmenting cerebral PBrO(2) during hypercapnia.

Hemodilutional anemia is associated with increased cerebral neuronal nitric oxide synthase gene expression.

Severe hemodilutional anemia may reduce cerebral oxygen delivery, resulting in cerebral tissue hypoxia. Increased nitric oxide synthase (NOS) expression has been identified following cerebral hypoxia and may contribute to the compensatory increase in cerebral blood flow (CBF) observed after hypoxia and anemia. However, changes in cerebral NOS gene expression have not been reported after acute anemia. This study tests the hypothesis that acute hemodilutional anemia causes cerebral tissue hypoxia, triggering changes in cerebral NOS gene expression. Anesthetized rats underwent hemodilution when 30 ml/kg of blood were exchanged with pentastarch, resulting in a final hemoglobin concentration of 51.0 +/- 1.2 g/l (n = 7 rats). Caudate tissue oxygen tension (Pbr(O(2))) decreased transiently from 17.3 +/- 4.1 to 14.4 +/- 4.1 Torr (P < 0.05), before returning to baseline after approximately 20 min. An increase in CBF may have contributed to restoring Pbr(O(2)) by improving cerebral tissue oxygen delivery. An increase in neuronal NOS (nNOS) mRNA was detected by RT-PCR in the cerebral cortex of anemic rats after 3 h (P < 0.05, n = 5). A similar response was observed after exposure to hypoxia. By contrast, no increases in mRNA for endothelial NOS or interleukin-1beta were observed after anemia or hypoxia. Hemodilutional anemia caused an acute reduction in Pbr(O(2)) and an increase in cerebral cortical nNOS mRNA, supporting a role for nNOS in the physiological response to acute anemia.