Safety of Deutetrabenazine for the Treatment of Tardive Dyskinesia and Chorea Associated with Huntington Disease.

INTRODUCTION: Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor used to treat tardive dyskinesia (TD) and chorea associated with Huntington disease (HD). To enhance detection of safety signals across individual trials, integrated safety analyses of deutetrabenazine in TD and HD chorea were conducted. METHODS: For TD, safety data were integrated from two 12-week pivotal studies (ARM-TD and AIM-TD) and through week 15 of the open-label extension (OLE) study (RIM-TD). Data were analyzed by deutetrabenazine treatment group and placebo. For HD, safety data were integrated from the 12-week pivotal study (First-HD) and through week 15 of the OLE study (ARC-HD) for patients previously receiving placebo. Integrated deutetrabenazine data were compared with placebo from the pivotal study. RESULTS: For TD, deutetrabenazine (n = 384) was generally well tolerated compared with placebo (n = 130). Adverse event (AE) incidence was numerically higher in the response-driven deutetrabenazine vs the fixed-dose deutetrabenazine and placebo groups, respectively (any AE, 59.5% vs 44.4-50.0% and 53.8%; treatment-related AE, 38.1% vs 18.1-25.0% and 30.8%). Serious AEs were reported for 2.8-8.3% of patients in the deutetrabenazine groups and 6.9% in the placebo group. Common AEs (≥ 4%) included headache, somnolence, nausea, anxiety, fatigue, dry mouth, and diarrhea. AE incidence was higher during the titration vs maintenance periods. For HD, AE incidence was numerically higher with deutetrabenazine (n = 84) vs placebo (n = 45; any AE, 64.3% vs 60.0%; treatment-related AE, 38.1% vs 26.7%); serious AEs were reported for similar proportions for the deutetrabenazine and placebo groups, 2.4% and 2.2%, respectively. Common AEs (≥ 4%) included irritability, fall, depression, dry mouth, and fatigue. CONCLUSIONS: Data from an integrated analysis of studies in TD and an integrated analysis of studies of chorea in HD showed that deutetrabenazine has a favorable safety profile and is well tolerated across indications. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT02291861, NCT02195700, NCT01795859, NCT02198794, NCT01897896.

Unintended movements are often the first sign of Huntington disease. This type of unintended movement is called chorea in Huntington disease. Tardive dyskinesia causes unintended body movements. Deutetrabenazine is a medicine used to treat both types of movements. This report summarizes deutetrabenazine safety across five clinical studies. Safety was assessed via adverse events (side effects). Adverse events were compared between deutetrabenazine and inactive treatment (placebo). Serious adverse events were also compared. Serious adverse events cause substantial impairment or disruption. In tardive dyskinesia and chorea in Huntington disease studies, most patients kept taking deutetrabenazine. Adverse events were not a common reason to stop treatment. For tardive dyskinesia, adverse event rates were similar between deutetrabenazine (≤ 60%) and placebo (54%). Serious adverse event rates were also similar for deutetrabenazine (≤ 8%) and placebo (7%). Adverse events tended to be reported earlier in treatment. Common adverse events were headache, sleepiness, nausea, anxiety, fatigue, dry mouth, and diarrhea. For chorea in Huntington disease, adverse event rates were similar for deutetrabenazine (64%) and placebo (60%). Serious adverse event rates were also similar for deutetrabenazine (2%) and placebo (2%). Irritability, fall, depression, dry mouth, and fatigue were common adverse events. Adverse events were similar between deutetrabenazine and placebo in both conditions. Deutetrabenazine was well tolerated for patients with either tardive dyskinesia or chorea in Huntington disease.

Application of the Bayesian network theory in clinical trial data: Severity shift in spasticity numeric rating scale in patients with multiple sclerosis.

BACKGROUND: Data digitization expands data collection opportunities, representing both a chance to understand interrelationships between variables and a challenge to identify the most appropriate clinical factors. Applications of causal inference techniques to clinical trial data is becoming very attractive, especially with the intent to provide insights into the relationships between baseline characteristics and outcomes. Graphical representations of model structures and conditional probabilities can be powerful tools to illustrate relationships in a high-dimensional data setting. METHODS: We review and apply Bayesian network theory to a clinical case study, presenting an analytical approach to investigating and visualizing causal relationships. We propose the use of the adherence score to compare data networks' patterns based on different variables' discretization. Data from adult patients with spasticity related to multiple sclerosis (MSS) from two randomized placebo-controlled clinical trials of nabiximols were used as analysis sets. The training and validation sets included 106 (53 treated, 53 placebo) and 155 (76 treated, 79 placebo) participants, respectively. The primary objective was to create a network and estimate the causal dependencies between participants' characteristics, changes in MSS severity as reflected by shifts in the patient-reported numeric rating scale (NRS), and changes in symptoms, functional abilities, and quality of life factors. RESULTS: A causal network was identified between the key factors of assigned treatment, end of study spasticity NRS, and mental health/vitality subscales of the 36-Item Short Form Health Survey questionnaire (4 nodes and 3 edges; adherence score = 93%). In patients with mild spasticity, the impact of nabiximols on mental health or vitality subscales resulted in a probability ratio of 1.63. The decomposed mediation effect of spasticity NRS was observed through a mediation analysis between treatment and mental health (99.4%) or vitality (93.7%) subscales. CONCLUSIONS: The use of innovative methods such as causal networks is highly encouraged to identify dependent relationships among key factors in clinical trial data and drive insights for additional research.

Assessing the educational needs of physicians in the management of patients with Tourette syndrome: results of a United States survey on practicing clinicians and caregivers.

OBJECTIVE: To better understand current practices of U.S.-based physicians in the management of Tourette syndrome (TS) and identify gaps that may be addressed by future education. METHODS: Two survey instruments were developed to gather data on management of TS and perceptions from physicians and caregivers of children with TS. The clinician survey was developed in consultation with a TS physician expert and utilized clinical vignettes to assess and quantify practice patterns. The caregiver survey was adapted from the clinician survey and other published studies and gathered details on diagnosis, treatment, and perceptions regarding management. RESULTS: Data included responses from 138 neurologists (including 57 pediatric neurologists), 162 psychiatrists (including 42 pediatric psychiatrists), and 67 caregivers. Most (65%) pediatric neurologists rely solely on clinical findings to make a diagnosis, whereas the majority of other specialists utilize additional testing (eg, neuroimaging, lab testing, and genetics). Most psychiatrists (96%) utilize standardized criteria to make a diagnosis, whereas 22% of neurologists do not. Many physicians (44% of psychiatrists and 20% of neurologists) use pharmacotherapy to treat a patient with "slightly bothersome" tics and no functional impairment, whereas caregivers favored behavioral therapy. Most (76%) caregivers preferred to make the final treatment decision, whereas 80% of physicians preferred equal or physician-directed decision-making. CONCLUSIONS: This study provides insight into practice patterns and perceptions of U.S.-based neurologists and psychiatrists in managing TS. Results highlight the potential value of physician education, including diagnostic approach, tic management and monitoring, involvement of caregivers in decision-making, and updates on TS management.

Early versus delayed treatment with glatiramer acetate: Analysis of up to 27 years of continuous follow-up in a US open-label extension study.

BACKGROUND: Glatiramer acetate (GA) is US-approved for relapsing multiple sclerosis. OBJECTIVES: To describe GA long-term clinical profile. To compare effectiveness of early start (ES) versus delayed start (DS; up to 3 years) with GA. METHODS: Phase 3 trial participants entered a randomized placebo-controlled period then an open-label extension (OLE) with GA. RESULTS: Overall, 208 out of 251 (82.9%) randomized participants entered the OLE; 24 out of 101 (23.8%, ES) and 28 out of 107 (26.2%, DS) participants completed the OLE. Median GA treatment was 9.8 (0.1-26.3) years. Annualized change in Expanded Disability Status Scale (EDSS) score was lower with ES versus DS (p = 0.0858: full study; p = 0.002; Year 5). Participants with improved/stable EDSS was consistently higher with ES versus DS: 40.3% versus 31.6% (p = 0.1590; full study); 70.8% versus 55.6% (p = 0.015; Year 5). ES prolonged time-to-6-month confirmed disease worsening (CDW) versus DS (9.8 vs 6.7 years), time-to-12-month CDW (18.9 vs 11.6 years), and significantly reduced time-to-second-6-month CDW (p = 0.0441). No new safety concerns arose. CONCLUSION: GA long-term treatment maintained clinical benefit with a similar safety profile to phase 3 results; a key limitation was that only 25% of participants completed the OLE. Early initiation of GA had sustained benefits versus delayed treatment.

Long-term efficacy and safety of three times weekly dosing regimen of glatiramer acetate in relapsing multiple sclerosis patients: Seven-year results of the Glatiramer Acetate Low-frequency Administration (GALA) open-label extension study.

OBJECTIVE: Describe the long-term outcomes of early-start (ES) and delayed-start (DS) glatiramer acetate 40 mg/mL treatment three times weekly (GA40) for up to seven years in the Glatiramer Acetate Low-frequency Administration (GALA) study in patients with relapsing multiple sclerosis (RMS). METHODS: Patients were evaluated every three to six months. The primary efficacy endpoint was annualized relapse rate (ARR); additional endpoints were exploratory or post hoc. For efficacy, data from the entire exposure period were used for the ES and DS cohorts. For safety, exposure only under GA40 was considered. RESULTS: Of the patients who continued into the open-label extension (OLE), 580/834 (70%) ES and 261/419 (62%) DS completed the OLE. For the entire placebo-controlled and OLE study period, ARR was 0.26 for ES and 0.31 for DS patients (risk ratio = 0.83; 95% confidence interval [CI]: 0.70-0.99). ES prolonged median time to first relapse versus DS (4.9 versus 4.3 years; hazard ratio = 0.82; 95% CI: 0.6-0.96). OLE-only results showed DS patients experienced similar efficacy for relapse and disability outcomes as ES patients. Adverse events were consistent with the well-established GA safety profile. CONCLUSIONS: GA40 treatment conferred clinical benefit up to seven years, resulting in sustained efficacy and was generally well tolerated in RMS patients.

Efficacy and Safety of Fixed-Dose Deutetrabenazine in Children and Adolescents for Tics Associated With Tourette Syndrome: A Randomized Clinical Trial.

Importance: Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics, often accompanied by behavioral and psychiatric comorbidities. Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor approved in the US for the treatment of chorea associated with Huntington disease and tardive dyskinesia. Objective: To report results of the ARTISTS 2 (Alternatives for Reducing Tics in Tourette Syndrome 2) study examining deutetrabenazine for treatment of Tourette syndrome. Design, Setting, and Participants: This phase 3, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted over 8 weeks with a 1-week follow-up (June 21, 2018, to December 9, 2019). Children and adolescents aged 6 to 16 years with a diagnosis of Tourette syndrome and active tics causing distress or impairment were enrolled in the study. Children were recruited from 52 sites in 10 countries. Data were analyzed from February 4 to April 22, 2020. Interventions: Participants were randomized (1:1:1) to low-dose deutetrabenazine (up to 36 mg/d), high-dose deutetrabenazine (up to 48 mg/d), or a matching placebo, which were titrated over 4 weeks to the target dose followed by a 4-week maintenance period. Main Outcomes and Measures: The primary efficacy end point was change from baseline to week 8 in the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) for high-dose deutetrabenazine. Key secondary end points included changes in YGTSS-TTS for low-dose deutetrabenazine, Tourette Syndrome Clinical Global Impression score, Tourette Syndrome Patient Global Impression of Impact score, and Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Activities of Daily Living subscale score. Safety assessments included incidence of treatment-emergent adverse events, laboratory parameters, vital signs, and questionnaires. Results: The study included 158 children and adolescents (mean [SD] age, 11.7 [2.6] years). A total of 119 participants (75%) were boys; 7 (4%), Asian; 1 (1%), Black; 32 (20%), Hispanic; 4 (3%), Native American; 135 (85%), White; 2 (1%), multiracial; 9 (6%), other race; and 1 (0.6%), of unknown ethnic origin. Fifty-two participants were randomized to the high-dose deutetrabenazine group, 54 to the low-dose deutetrabenazine group, and 52 to the placebo group. Baseline characteristics for participants were similar between groups. Of the total 158 participants, 64 (41%) were aged 6 to 11 years, and 94 (59%) were aged 12 to 16 years at baseline. Mean time since Tourette syndrome diagnosis was 3.3 (2.8) years, and mean baseline YGTSS-TTS was 33.8 (6.6) points. At week 8, the difference in YGTSS-TTS was not significant between the high-dose deutetrabenazine and placebo groups (least-squares mean difference, -0.8 points; 95% CI, -3.9 to 2.3 points; P = .60; Cohen d, -0.11). There were no nominally significant differences between groups for key secondary end points. Treatment-emergent adverse events were reported for 34 participants (65%) treated with high-dose deutetrabenazine, 24 (44%) treated with low-dose deutetrabenazine, and 25 (49%) treated with placebo and were generally mild or moderate. Conclusions and Relevance: In this fixed-dose randomized clinical trial of deutetrabenazine in children and adolescents with Tourette syndrome, the primary efficacy end point was not met. No new safety signals were identified. Trial Registration: ClinicalTrials.gov Identifier: NCT03571256.

Treatment patterns following initiation of generic glatiramer acetate among patients with multiple sclerosis from two large real-world databases in the United States.

INTRODUCTION: To better understand treatment patterns in US patients with multiple sclerosis (MS) initiating generic glatiramer acetate (GA), this study examined adherence, discontinuation and switching patterns from generic follow-on glatiramer acetate (FOGA) therapy in real-world patient cohorts. METHODS: Retrospective analyses utilized data from two large US databases (administrative claims and linked electronic medical records). Eligible adult MS patients had ≥1 pharmacy claim for FOGA during the identification period; the first FOGA claim was the index date. All analyses were descriptive; proportion of days covered (PDC) was calculated as a measure of adherence to FOGA during the follow-up period. RESULTS: The first cohort consisted of 95 patients, with 93.6% having a branded GA claim for Copaxone during the baseline period. Half these patients (48.4%) had high adherence to FOGA therapy (PDC: 0.8-1.0). Fifty-five patients (57.9%) initially discontinued FOGA with a mean persistence of 112 days. Of those who discontinued, 7.3% had no subsequent disease-modifying therapy (DMT), 30.9% restarted FOGA and 61.8% did not restart FOGA. The second cohort consisted of 1957 patients, with 63.8% having a branded GA claim for Copaxone during the baseline period and 33.5% were treatment naïve. The majority of patients (61.9%) had high adherence to FOGA therapy. A total of 1597 patients (81.6%) initially discontinued FOGA with a mean persistence of 93 days. Of those who discontinued, 55.8% switched to another DMT, 16.7% restarted FOGA and 37.5% had no subsequent DMT. CONCLUSION: Adherence to FOGA therapy was reasonably high across cohorts; however, most patients discontinued their initial FOGA within four months of the index date and most switches from FOGA were to branded GA products.

Influence of Serotonin Transporter SLC6A4 Genotype on the Effect of Psychosocial Stress on Cognitive Performance: An Exploratory Pilot Study.

BACKGROUND AND OBJECTIVE: Previous research has shown an effect of various psychosocial stressors on unconstrained cognitive flexibility, such as searching through a large set of potential solutions in the lexical-semantic network during verbal problem-solving. Functional magnetic resonance imaging has shown that the presence of the short (S) allele (lacking a 43-base pair repeat) of the promoter region of the gene (SLC6A4) encoding the serotonin transporter (5-HTT) protein is associated with a greater amygdalar response to emotional stimuli and a greater response to stressors. Therefore, we hypothesized that the presence of the S-allele is associated with greater stress-associated impairment in performance on an unconstrained cognitive flexibility task, anagrams. METHODS: In this exploratory pilot study, 28 healthy young adults were genotyped for long (L)-allele versus S-allele promoter region polymorphism of the 5-HTT gene, SLC6A4. Participants solved anagrams during the Trier Social Stress Test, which included public speaking and mental arithmetic stressors. We compared the participants' cognitive response to stress across genotypes. RESULTS: A Gene×Stress interaction effect was observed in this small sample. Comparisons revealed that participants with at least one S-allele performed worse during the Stress condition. CONCLUSIONS: Genetic susceptibility to stress conferred by SLC6A4 appeared to modulate unconstrained cognitive flexibility during psychosocial stress in this exploratory sample. If confirmed, this finding may have implications for conditions associated with increased stress response, including performance anxiety and cocaine withdrawal. Future work is needed both to confirm our findings with a larger sample and to explore the mechanisms of this proposed effect.

Stress Increases Peripheral Axon Growth and Regeneration through Glucocorticoid Receptor-Dependent Transcriptional Programs.

Stress and glucocorticoid (GC) release are common behavioral and hormonal responses to injury or disease. In the brain, stress/GCs can alter neuron structure and function leading to cognitive impairment. Stress and GCs also exacerbate pain, but whether a corresponding change occurs in structural plasticity of sensory neurons is unknown. Here, we show that in female mice (Mus musculus) basal GC receptor (Nr3c1, also known as GR) expression in dorsal root ganglion (DRG) sensory neurons is 15-fold higher than in neurons in canonical stress-responsive brain regions (M. musculus). In response to stress or GCs, adult DRG neurite growth increases through mechanisms involving GR-dependent gene transcription. In vivo, prior exposure to an acute systemic stress increases peripheral nerve regeneration. These data have broad clinical implications and highlight the importance of stress and GCs as novel behavioral and circulating modifiers of neuronal plasticity.

Different immune cells mediate mechanical pain hypersensitivity in male and female mice.

A large and rapidly increasing body of evidence indicates that microglia-to-neuron signaling is essential for chronic pain hypersensitivity. Using multiple approaches, we found that microglia are not required for mechanical pain hypersensitivity in female mice; female mice achieved similar levels of pain hypersensitivity using adaptive immune cells, likely T lymphocytes. This sexual dimorphism suggests that male mice cannot be used as proxies for females in pain research.

Macrophage migration inhibitory factor (MIF) is essential for inflammatory and neuropathic pain and enhances pain in response to stress.

Stress and glucocorticoids exacerbate pain via undefined mechanisms. Macrophage migration inhibitory factor (MIF) is a constitutively expressed protein that is secreted to maintain immune function when glucocorticoids are elevated by trauma or stress. Here we show that MIF is essential for the development of neuropathic and inflammatory pain, and for stress-induced enhancement of neuropathic pain. Mif null mutant mice fail to develop pain-like behaviors in response to inflammatory stimuli or nerve injury. Pharmacological inhibition of MIF attenuates pain-like behaviors caused by nerve injury and prevents sensitization of these behaviors by stress. Conversely, injection of recombinant MIF into naïve mice produces dose-dependent mechanical sensitivity that is exacerbated by stress. MIF elicits pro-inflammatory signaling in microglia and activates sensory neurons, mechanisms that underlie pain. These data implicate MIF as a key regulator of pain and provide a mechanism whereby stressors exacerbate pain. MIF inhibitors warrant clinical investigation for the treatment of chronic pain.

Semi-automated Sholl analysis for quantifying changes in growth and differentiation of neurons and glia.

There is a need to develop therapies that promote growth or remyelination of mammalian CNS axons. Although the feasibility of pre-clinical treatment strategies should be tested in animal models, in vitro assays are usually faster and less expensive. As a result, in vitro models are ideal for screening large numbers of potential therapeutics prior to use in more complex in vivo systems. In 1953, Sholl introduced a technique that is a reliable and sensitive method for quantifying indices of neurite outgrowth. However, application of the technique is limited because it is labor-intensive. Several methods have been developed to reduce the analysis time for the Sholl technique; but these methods require extensive pre-processing of digital images, they introduce user bias or they have not been compared to manual analysis to ensure accuracy. Here we describe a new, semi-automated Sholl technique for quantifying neuronal and glial process morphology. Using MetaMorph, we developed an unbiased analysis protocol that can be performed approximately 3x faster than manual quantification with a comparable level of accuracy regardless of cell morphology. The laborious image processing typical of most computer-aided analysis is avoided by embedding image correction functions into the automated portion of the analysis. The sensitivity and validity of the technique was confirmed by quantifying neuron growth treated with growth factors or oligodendroglial maturation in the presence or absence of thyroid hormone. Thus, this technique provides a rapid and sensitive method for quantifying changes in cell morphology and screening for treatment effects in multiple cell types in vitro.

Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord.

Macrophages dominate sites of CNS injury in which they promote both injury and repair. These divergent effects may be caused by distinct macrophage subsets, i.e., "classically activated" proinflammatory (M1) or "alternatively activated" anti-inflammatory (M2) cells. Here, we show that an M1 macrophage response is rapidly induced and then maintained at sites of traumatic spinal cord injury and that this response overwhelms a comparatively smaller and transient M2 macrophage response. The high M1/M2 macrophage ratio has significant implications for CNS repair. Indeed, we present novel data showing that only M1 macrophages are neurotoxic and M2 macrophages promote a regenerative growth response in adult sensory axons, even in the context of inhibitory substrates that dominate sites of CNS injury (e.g., proteoglycans and myelin). Together, these data suggest that polarizing the differentiation of resident microglia and infiltrating blood monocytes toward an M2 or "alternatively" activated macrophage phenotype could promote CNS repair while limiting secondary inflammatory-mediated injury.

Neuroinflammation in spinal cord injury: therapeutic targets for neuroprotection and regeneration.

Traumatic spinal cord injury triggers a complex local inflammatory reaction capable of enhancing repair and exacerbating pathology. The composition and effector potential of the post-injury cellular and molecular immune cascade changes as a function of time and distance from the lesion. Production along this time-space continuum of cytokines, proteases, and growth factors establishes dynamic environments that lead to the death, damage, repair or growth of affected neurons and glia. Microenvironmental cues, therefore, generated by the cells therein, may determine these distinct fates of repair versus pathology. To harness repair, it is necessary to manipulate the assembly and phenotype of cells that comprise the neuroinflammatory response to injury. Here, the potential of the neuroinflammatory response to cause outcomes such as pain, regeneration, and functional recovery is reviewed.

Stress exacerbates neuropathic pain via glucocorticoid and NMDA receptor activation.

There is growing recognition that psychological stress influences pain. Hormones that comprise the physiological response to stress (e.g., corticosterone; CORT) may interact with effectors of neuropathic pain. To test this hypothesis, mice received a spared nerve injury (SNI) after exposure to 60 min restraint stress. In stressed mice, allodynia was consistently increased. The mechanism(s) underlying the exacerbated pain response involves CORT acting via glucocorticoid receptors (GRs); RU486, a GR antagonist, prevented the stress-induced increase in allodynia whereas exogenous administration of CORT to non-stressed mice reproduced the allodynic response caused by stress. Since nerve injury-induced microglial activation has been implicated in the onset and propagation of neuropathic pain, we evaluated cellular and molecular indices of microglial activation in the context of stress. Activation of dorsal horn microglia was accelerated by stress; however, this effect was transient and was not associated with the onset or maintenance of a pro-inflammatory phenotype. Stress-enhanced allodynia was associated with increased dorsal horn extracellular signal-regulated kinase phosphorylation (pERK). ERK activation could indicate a stress-mediated increase in glutamatergic signaling, therefore mice were treated prior to SNI and stress with memantine, an N-methyl-D-aspartate receptor (NMDAR) antagonist. Memantine prevented stress-induced enhancement of allodynia after SNI. These data suggest that the hormonal responses elicited by stress exacerbate neuropathic pain through enhanced central sensitization. Moreover, drugs that inhibit glucocorticoids (GCs) and/or NMDAR signaling could ameliorate pain syndromes caused by stress.

2006 Curt P. Richter award winner: Social influences on stress responses and health.

Both positive and negative social interactions can modulate the hypothalamic-pituitary-adrenal (HPA) axis and influence recovery from injuries and illnesses, such as wounds, stroke, and cardiac arrest. Stress exacerbates neuronal death following stroke and cardiac arrest, and delays cutaneous wound healing, via a common mechanism involving stress-induced increases in corticosterone, acting on glucocorticoid receptors. In contrast, hamsters and mice that form social bonds are buffered against stress and heal cutaneous wounds more quickly than socially isolated animals, presumably because the physical contact experienced by the pairs releases oxytocin, which in turn suppresses the HPA axis and facilitates wound healing. Social housing also decreases stroke-induced neuronal death and improves functional recovery, but the mechanism appears to involve suppressing the inflammatory response that accompanies stroke, rather than alterations in HPA axis activity. An interaction between the HPA axis and immune system determines stroke outcome in neonatally manipulated mice that exhibit life-long dampening of the HPA axis. Taken together, these studies provide support for the detrimental effects of stress and identify potential mechanisms underlying the well-documented clinical observation that social support positively influences human health.

Beta-adrenergic modulation of cognitive flexibility during stress.

Stress-induced activation of the locus ceruleus-norepinephrine (LC-NE) system produces significant cognitive and behavioral effects, including enhanced arousal and attention. Improvements in discrimination task performance and memory have been attributed to this stress response. In contrast, for other cognitive functions that require cognitive flexibility, increased activity of the LC-NE system may produce deleterious effects. The aim of the present study was to determine the effect of pharmacological modulation of the LC-NE system on stress-induced impairments in cognitive flexibility performance in healthy individuals. Cognitive performance, plus psychological and physiological parameters for 16 adults without any history of anxiety disorders, was assessed during four test sessions: stress and no-stress, with each condition tested after administration of propranolol and placebo. The Trier Social Stress Test, a public-speaking and mental arithmetic stressor, was presented to participants for the stress sessions, whereas a similar, but nonstressful, control task (reading, counting) was utilized for the no-stress sessions. Tests of cognitive flexibility included lexical-semantic and associative problem-solving tasks (anagrams, Compound Remote Associates Test). Visuo-spatial memory and motor processing speed tests served as control tasks. Results indicate that (1) stress impaired performance on cognitive flexibility tasks, but not control tasks; (2) compared to placebo, cognitive flexibility improved during stress with propranolol. Therefore, psychological stress, such as public speaking, negatively impacts performance on tasks requiring cognitive flexibility in normal individuals, and this effect is reversed by beta-adrenergic antagonism. This may provide support for the hypothesis that stress-related impairments in cognitive flexibility are related to the noradrenergic system.

The effect of auditory stressors on cognitive flexibility.

Stress is known to activate the noradrenergic system which may have a modulatory influence on cognitive flexibility. We investigated whether an auditory stressor would thus affect performance on cognitive flexibility. A task utilizing cognitive flexibility and two memory tasks were presented in both stressful and non-stressful condition. In the stressful condition performance was impaired for the cognitive flexibility task but not for the memory tasks, arguing against the stressor serving as a general distracter. These findings suggest that stress caused by an auditory stressor may negatively impact performance on more complex tasks requiring a rapid search of the semantic and lexical associative networks.