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Biomedical subjects

Michael Davis

Publications and source records attributed to Michael Davis.

At least 19 recordsLinked to original sources

Effects of D-cycloserine on extinction: translation from preclinical to clinical work.

Administration of benzodiazepines or serotonin reuptake inhibitors in combination with behavior therapy for the treatment of many anxiety disorders has generally lead to only modest gains. In this article we suggest that pharmacotherapy aimed not at treating the symptoms of anxiety but instead aimed at improving the learning that takes place in exposure therapy might actually improve the effectiveness of exposure therapy. This idea was based on animal work showing that the partial N-methyl-D-aspartate (NMDA) agonist D-cycloserine (DCS) facilitated extinction of fear when given either before or shortly after exposure to fearful cues, reduced return of fear that is normally seen when extinction training is followed by stress, and led to generalized extinction, where DCS given in combination with exposure to one fearful cue led to extinction to another cue previously paired with the same aversive event. These finding suggested that DCS might facilitate exposure-based psychotherapy, which was verified in a small clinical study showing that DCS facilitated exposure therapy for fear of heights in a well-controlled virtual reality environment.

Animals↗

The effect of gonadal hormones and gender on anxiety and emotional learning.

Disorders of anxiety and fear dysregulation are highly prevalent. These disorders affect women approximately 2 times more than they affect men, occur predominately during a woman's reproductive years, and are especially prevalent at times of hormonal flux. This implies that gender differences and sex steroids play a key role in the regulation of anxiety and fear. However, the underlying mechanism by which these factors regulate emotional states in either sex is still largely unknown. This review discusses animal studies describing sex-differences in and gonadal steroid effects on affect and emotional learning. The effects of gonadal hormones on the modulation of anxiety, with particular emphasis on progesterone's ability to reduce the responsiveness of female rats to corticotropin releasing factor and the sex-specific effect of testosterone in the reduction of anxiety in male rats, is discussed. In addition, gonadal hormone and gender modulation of emotional learning is considered and preliminary data are presented showing that estrogen (E2) disrupts fear learning in female rats, probably through the antagonistic effect of ERalpha and ERbeta activation.

Animals↗

Characterization of Bouveret's syndrome: a comprehensive review of 128 cases.

AIM: The aim of the study was to characterize the clinical presentation, evaluation, and therapy of Bouveret's syndrome, by comprehensively reviewing all the identified previously reported cases, to facilitate early diagnosis and thereby to improve the prognosis. METHODS: Relevant articles were identified by MEDLINE computerized searches, by consultation with all available reference books, and by review of the first author's teaching files. A new case in which the diagnosis of Bouveret's syndrome was missed at esophagogastroduodenoscopy (EGD)--despite endoscopic findings of gastric outlet obstruction caused by a hard, nonfleshy, and convex pyloric mass--prompted this review. RESULTS: Review of 128 reported cases identified syndromic characteristics. Patients on average were 74.1 +/- 11.1 (SD) yr old. The female-to-male sex ratio was 1.86. Prominent symptoms were nausea and vomiting in 87%, abdominal pain in 71%, hematemesis in 15%, recent weight loss in 14%, and anorexia in 13% of patients. Prominent signs were abdominal tenderness in 44%, signs of dehydration in 31%, and abdominal distention in 26% of patients. Endoscopy revealed gastroduodenal obstruction in nearly all cases, but identified the obstructing stone in only 69%. Abdominal ultrasound or computerized tomography was diagnostic in about 60% of cases. CONCLUSIONS: The following endoscopic findings are suggestive of Bouveret's syndrome: a dilated stomach containing old digested food from gastrointestinal obstruction together with a hard and nonfleshy mass at the obstruction. These endoscopic findings, in the setting of the currently reported characteristic epidemiologic and clinical findings, should strongly suggest this syndrome. Abdominal ultrasound or computerized tomography is recommended to confirm and extend the endoscopic diagnosis.

Cholelithiasis↗

Amygdala BDNF signaling is required for consolidation but not encoding of extinction.

Brain-derived neurotrophic factor (BDNF) acting through the tyrosine kinase B receptor (TrkB) is thought to be a critical mediator of learning. As there are no available selective antagonists of TrkB, we used a lentivirus encoding a dominant-negative TrkB (TrkB.t1) to antagonize BDNF signaling during extinction of conditioned fear. Whereas TrkB.t1-infected rats showed normal within-session extinction, their retention of extinction was impaired, suggesting that amygdala TrkB activation is required for the consolidation of stable extinction memories.

Amygdala↗

Modulation of fear-potentiated startle and vocalizations in juvenile rhesus monkeys by morphine, diazepam, and buspirone.

BACKGROUND: Modulation of the acoustic startle response by aversive sensory stimulation is a simple and objective indicator of emotionality in rodents and human beings that has been extremely valuable for the analysis of neural systems associated with fear and anxiety. We have described a paradigm for measuring fear-potentiated, whole-body acoustic startle in nonhuman primates and have developed a protocol for maintaining fear-potentiated startle over repeated sessions with minimal extinction to allow measurement of pharmacological effects on fear-potentiated startle by using within-subjects designs in relatively small groups of monkeys. METHODS: A novel, within-subjects testing protocol was used to examine the effects of three compounds in rhesus monkeys that have anxiolytic effects in rodents on fear-potentiated startle but that differ in their mechanism of action. Spontaneous vocalizations during testing also were recorded. Juvenile monkeys that were trained to associate a visual stimulus with a fear-inducing air blast to the face were tested after acute administration of different doses of buspirone diazepam, morphine, or vehicle. RESULTS: Monkeys rapidly developed a robust and persistent elevation of startle response in the presence of the CS during repeated testing sessions. Diazepam and morphine produced dose-related reductions of fear-potentiated startle. Buspirone did not significantly reduce fear-potentiated startle at the doses tested, although a trend was evident at the highest dose. All drugs reduced rates of coo vocalizations during startle testing. CONCLUSIONS: These fear-potentiated startle results suggest that rhesus monkeys have a pharmacological profile with respect to these compounds that is closer to humans than to rats. This demonstrates the value of examining the effects of drugs on fear-potentiated startle in nonhuman primates.

Animals↗

A comparison of socio-demographic and psychological factors between patients consenting to randomisation and those selecting treatment (the ProtecT study).

BACKGROUND: Patient preferences for treatment can pose problems for the conduct of randomised controlled trials: patients with a preference may refuse participation and thereby potentially compromise external validity. Moreover, randomising patients with a preference may affect treatment efficacy and threaten internal validity. AIMS: This study compared baseline characteristics and short-term psychological outcomes of patients who selected their treatment and those who agreed to random allocation. METHODS: Men participating in the prostate testing for cancer and treatment (ProtecT) study and who were randomised to active monitoring (n=138) were compared with those who had refused randomisation and selected this management (n=180). Socio-demographic data were collected at baseline, and anxiety and depression data were collected at baseline and six month follow-up. Socio-demographic characteristics were compared across these two groups in univariable analyses, and then linear regression was used to compare levels of anxiety and depression at follow-up with adjustments for confounders. RESULTS: Participants who selected active monitoring were more affluent (based on occupation details) and had less anxiety at baseline than those who were randomised. There were no differences with respect to age and marital status. Levels of anxiety and depression at six months follow-up were similar across the two groups of men. CONCLUSIONS: This study found some differences at baseline between the socio-demographic and psychological status of those randomised and self-selecting treatment, but no psychological differences at short-term follow-up. Further empirical evidence is required to assess whether preferences impact upon the process and outcome of randomised controlled trials.

Aged↗

Combining pharmacotherapy with cognitive behavioral therapy: traditional and new approaches.

Given the ever-increasing sources of trauma both nationally and globally, it is imperative to develop new and better treatments for anxiety disorders such as posttraumatic stress disorder (PTSD). This review is a collection of presentations that seek to do just that, either by using pharmacotherapy to try to prevent or erase the formation of traumatic fear memories, or to enhance exposure-based cognitive-behavioral therapy using pharmacological agents that have been effective in enhanced extinction of fear in rodents.

Cognitive Behavioral Therapy↗

Engineering ethics, individuals, and organizations.

This article evaluates a family of criticism of how engineering ethics is now generally taught. The short version of the criticism might be put this way: Teachers of engineering ethics devote too much time to individual decisions and not enough time to social context. There are at least six version of this criticism, each corresponding to a specific subject omitted. Teachers of engineering ethics do not (it is said) teach enough about: 1) the culture of organizations; 2) the organization of organizations; 3) the legal environment of organizations; 4) the role of professions in organizations; 5) the role of organizations in professions; or 6) the political environment of organizations. My conclusion is that, while all six are worthy subjects, there is neither much reason to believe that any of them are now absent from courses in engineering ethics nor an obvious way to decide whether they (individually or in combination) are (or are not) now being given their due. What we have here is a dispute about how much is enough. Such disputes are not to be settled without agreement concerning how we are to tell we have enough of this or that. Right now we seem to lack that agreement and not to have much reason to expect it any time soon.

Engineering↗

Integrating ethics into technical courses: micro-insertion.

Perhaps the most common reason science and engineering faculty give for not including 'ethics' (that is, research ethics, engineering ethics, or some discussion of professional responsibility) in their technical classes is that 'there is no room'. This article 1) describes a technique ('micro-insertion') that introduces ethics (and related topics) into technical courses in small enough units not to push out technical material, 2) explains where this technique might fit into the larger undertaking of integrating ethics into the technical (scientific or engineering) curriculum, and 3) concludes with some quantified evidence (collected over more than a decade) suggesting success. Integrating ethics into science and engineering courses is largely a matter of providing context for what is already being taught, context that also makes the material already being taught seem 'more relevant'.

Engineering↗

Pharmacological treatments that facilitate extinction of fear: relevance to psychotherapy.

SUMMARY: A great deal is now known about the mechanisms of conditioned fear acquisition and expression. More recently, the mechanisms of inhibition of conditioned fear have become the subject of intensive study. The major model system for the study of fear inhibition in the laboratory is extinction, in which a previously fear conditioned organism is exposed repeatedly to the fear-eliciting cue in the absence of any aversive event and the fear conditioned response declines. It is well established that extinction is a form of new learning as opposed to forgetting or "unlearning" of conditioned fear, and it is hypothesized that extinction develops when sensory pathways conveying sensory information to the amygdala come to engage GABAergic interneurons through forms of experience-dependent plasticity such as long-term potentiation. Several laboratories currently are investigating methods of facilitating fear extinction in animals with the hope that such treatments might ultimately prove to be useful in facilitating exposure-based therapy for anxiety disorders in clinical populations. This review discusses the advances that have been made in this field and presents the findings of the first major clinical study to examine the therapeutic utility of a drug that facilitates extinction in animals. It is concluded that extinction is an excellent model system for the study of fear inhibition and an indispensable tool for the screening of putative pharmacotherapies for clinical use.

Excitatory Amino Acid Agonists↗

Emotion, motivation, and the brain: reflex foundations in animal and human research.

This review will focus on a motivational circuit in the brain, centered on the amygdala, that underlies human emotion. This neural circuitry of appetitive/approach and defensive/avoidance was laid down early in our evolutionary history in primitive cortex, sub-cortex, and mid-brain, to mediate behaviors basic to the survival of individuals and the propagation of genes to coming generations. Thus, events associated with appetitive rewards, or that threaten danger or pain, engage attention and prompt information gathering more so than other input. Motive cues also occasion metabolic arousal, anticipatory responses, and mobilize the organism to prepare for action. Findings are presented from research with animals, elucidating these psychophysiological (e.g., cardiovascular, neuro-humoral) and behavioral (e.g., startle potentiation, "freezing") patterns in emotion, and defining their mediating brain circuits. Parallel results are described from experiments with humans, showing similar activation patterns in brain and body in response to emotion cues, co-varying with participants' reports of affective valence and increasing emotional arousal.

Amygdala↗

Neural systems involved in fear and anxiety measured with fear-potentiated startle.

A good deal is now known about the neural circuitry involved in how conditioned fear can augment a simple reflex (fear-potentiated startle). This involves visual or auditory as well as shock pathways that project via the thalamus and perirhinal or insular cortex to the basolateral amygdala (BLA). The BLA projects to the central (CeA) and medial (MeA) nuclei of the amygdala, which project indirectly to a particular part of the acoustic startle pathway in the brainstem. N-methyl-D-aspartate (NMDA) receptors, as well as various intracellular cascades in the amygdala, are critical for fear learning, which is then mediated by glutamate acting in the CeA. Less predictable stimuli, such as a long-duration bright light or a fearful context, activate the BLA, which projects to the bed nucleus of the stria terminalis (BNST), which projects to the startle pathway much as the CeA does. The anxiogenic peptide corticotropin-releasing hormone increases startle by acting directly in the BNST. CeA-mediated behaviors may represent stimulus-specific fear, whereas BNST-mediated behaviors are more akin to anxiety. NMDA receptors are also involved in extinction of conditioned fear, and both extinction in rats and exposure-based psychotherapy in humans are facilitated by an NMDA-partial agonist called D-cycloserine. ((c) 2006 APA, all rights reserved).

Amygdala↗

Contingency awareness and fear inhibition in a human fear-potentiated startle paradigm.

Fear-potentiated startle is defined as an increase in the magnitude of the startle reflex in the presence of a stimulus that was previously paired with an aversive event. It has been proposed that a subject's awareness of the contingencies in the experiment may affect fear-potentiated startle. The authors adapted a conditional discrimination procedure (AX+/BX-), previously validated in animals, to a human fear-potentiated startle paradigm in 50 healthy volunteers. This paradigm allows for an assessment of fear-potentiated startle during threat conditions as well as inhibition of fear-potentiated startle during safety conditions. A response keypad was used to assess contingency awareness on a trial-by-trial basis. Both aware and unaware subjects showed fear-potentiated startle. However, awareness was related to stimulus discrimination and fear inhibition.

Acoustic Stimulation↗

Profile of a metropolitan North American immigrant suicidal adolescent population.

OBJECTIVE: Canadian immigrant adolescents have a lower suicide rate than their nonimmigrant peers. We conducted a hypothesis-generating analysis to determine whether this lower rate correlated with level of drug use and (or) with diagnostic and demographic characteristics of Canadian immigrant adolescents presenting to an emergency room for crisis assessment. METHOD: Known risk factors for suicide were compared among immigrant youth, North American youth, and a culturally mixed group of youth at baseline and at 6-month follow-up. RESULTS: The immigrant group was only differentiated by a lower rate of reported drug use. CONCLUSION: The lower rate of reported drug use at the time of crisis may contribute to the lower suicide rate among immigrants.

Adolescent↗

Daily living with distress and enrichment: the moral experience of families with ventilator-assisted children at home.

OBJECTIVE: The growing shift toward home care services assumes that "being home is good" and that this is the most desirable option. Although ethical issues in medical decision-making have been examined in numerous contexts, home care decisions for technology-dependent children and the moral dilemmas that this population confronts remain virtually unknown. This study explored the moral dimension of family experience through detailed accounts of life with a child who requires assisted ventilation at home. This study involved an examination of moral phenomena inherent in (1) the individual experiences of the ventilator-assisted child, siblings, and parents and (2) everyday family life as a whole. METHODS: A qualitative method based on Richard Zaner's interpretive framework was selected for this study. The population of interest for this study was the families of children who are supported by a ventilator or a positive-pressure device at home. Twelve families (38 family members) were recruited through the Quebec Program for Home Ventilatory Assistance. Children in the study population fell into 4 diagnostic groups: (1) abnormal ventilatory control (eg, central hypoventilation syndrome), (2) neuromuscular disorders, (3) spina bifida, and (4) craniofacial or airway abnormalities resulting in upper airway obstruction. All 4 of these diagnostic groups were included in this study. Among the 12 children recruited, 4 received ventilation via tracheostomies, and 8 received ventilation with face masks. All of the latter received ventilation only at night, except for 1 child, who received ventilation 24 hours a day. Family moral experiences were investigated using semistructured interviews and fieldwork observations conducted in the families' homes. RESULTS: Data analysis identified 6 principal themes. The themes raised by families whose children received ventilation invasively via a tracheostomy were not systematically different or more distressed than were families of children with face masks. The principal themes were (1) confronting parental responsibility: parental responsibility was described as stressful and sometimes overwhelming. Parents needed to devote extraordinary care and attention to their children's needs. They struggled with the significant emotional strain, physical and psychological dependence of the child, impact on family relationships, living with the daily threat of death, and feeling that there was "no free choice" in the matter: they could not have chosen to let their child die. (2) Seeking normality: all of the families devoted significant efforts toward normalizing their experiences. They created common routines so that their lives could resemble those of "normal" families. These efforts seemed motivated by a fundamental striving for a stable family and home life. This "striving for stability" was sometimes undermined by limitations in family finances, family cohesion, and unpredictability of the child's condition. (3) Conflicting social values: families were offended by the reactions that they faced in their everyday community. They believe that the child's life is devalued, frequently referred to as a life not worth maintaining. They felt like strangers in their own communities, sometimes needing to seclude themselves within their homes. (4) Living in isolation: families reported a deep sense of isolation. In light of the complex medical needs of these children, neither the extended families nor the medical system could support the families' respite needs. (5) What about the voice of the child? The children in this study (patients and siblings) were generally silent when asked to talk about their experience. Some children described their ventilators as good things. They helped them breathe and feel better. Some siblings expressed resentment toward the increased attention that their ventilated sibling was receiving. (6) Questioning the moral order: most families questioned the "moral order" of their lives. They contemplated how "good things" and "bad things" are determined in their world. Parents described their life as a very unfair situation, yet there was nothing that they could do about it. Finally, an overarching phenomenon that best characterizes these families' experiences was identified: daily living with distress and enrichment. Virtually every aspect of the lives of these families was highly complicated and frequently overwhelming. An immediate interpretation of these findings is that families should be fully informed of the demands and hardships that would await them, encouraging parents perhaps to decide otherwise. This would be but a partial reading of the findings, because despite the enormous difficulties described by these families, they also reported deep enrichments and rewarding experiences that they could not imagine living without. Life with a child who requires assisted ventilation at home involves living every day with a complex tension between the distresses and enrichments that arise out of this experience. The conundrum inherent in this situation is that there are no simple means for reconciling this tension. This irreconcilability is particularly stressful for these families. Having their child permanently institutionalized or "disconnected" from ventilation (and life) would eliminate both the distresses and the enrichments. These options are outside the realm of what these families could live with, aside from the 1 family whose child is now permanently hospitalized, at a tremendous cost of guilt to the family. CONCLUSIONS: These findings make important contributions by (1) advancing our understanding of the moral experiences of this group of families; (2) speaking to the larger context of other technology-dependent children who require home care; (3) relating home care experiences to neonatal, critical care, and other hospital services, suggesting that these settings examine their approaches to this population that may impose preventable burdens on the lives of these children and their families; and (4) examining a moral problem with an empirical method. Such problems are typically investigated through conceptual analyses, without directly examining lived experience. These findings advance our thinking about how we ought to care for these children, through a better understanding of what it is like to care for them and the corresponding major distresses and rewarding enrichments. These findings call for an increased sensitization to the needs of this population among staff in critical care, acute, and community settings. Integrated community support services are required to help counter the significant distress endured by these families. Additional research is required to examine the experience of other families who have decided either not to bring home their child who requires ventilation or withdraw ventilation and let the child die.

Caregivers↗

Central oxytocin, vasopressin, and corticotropin-releasing factor receptor densities in the basal forebrain predict isolation potentiated startle in rats.

Individual differences in resiliency to particular stressors may be mediated by specific neuropeptide receptor patterns in the brain. Here, we explored this issue by using a multivariate approach to identify brain sites in which oxytocin (OTR), vasopressin (V1aR), and corticotropin-releasing factor type 1 (CRF1) or type 2 receptor binding covaried with a measure of isolation-induced anxiety: isolation potentiated startle (IPS). Partial least squares (PLS) analysis identified three binding sites, the shell of the nucleus accumbens (AccSh), lateral bed nucleus of the stria terminalis, and intermediate zone of the lateral septum, in which CRF1, V1aR, and OTR receptors, respectively, covaried with IPS. Multiple regression analysis demonstrated that the three binding sites accounted for more of the variation in IPS as a linear combination than when considered individually. Using the same multiple regression model, the linear combination of the same three binding sites/peptide receptors measured in a new group of animals successfully predicted their IPS values. There were no differences in binding between grouped and isolated animals, suggesting that the patterns are trait effects rather than a consequence of isolation. Based on the finding that CRF1 receptors in the AccSh were positively correlated with IPS, we infused CRF directly into the AccSh and found that it significantly potentiated startle after a short isolation period but not under grouped conditions. This result directly supported the predictions made by the combined PLS/regression approach. These results suggest that the integrated activity of neuropeptide systems mediating both social behavior and anxiety underlie IPS.

Acoustic Stimulation↗

Sex differences in hormonal modulation of anxiety measured with light-enhanced startle: possible role for arginine vasopressin in the male.

Increased acoustic startle in the presence of bright ambient light, a phenomenon called light-enhanced startle (LES), is dependent on the bed nucleus of the stria terminalis. In contrast to gonadally intact male rats, LES was seen reliably in castrated male rats and in female rats, although it fluctuated significantly with reproductive state. Replacement with testosterone (T) or combined estradiol (E2) and dihydrotestosterone (DHT), but not with either E2 or DHT alone, attenuated LES in castrated rats. However, replacement with T or E2 in ovariectomized rats did not decrease LES. In contrast, no sex difference was seen in the central amygdala-dependent acquisition or expression of fear-potentiated startle. In addition, T did not reduce expression of fear-potentiated startle in castrated rats. T-replaced castrated males injected centrally with mixed arginine vasopressin (AVP) V1a/b receptor antagonists daily throughout the replacement period failed to show a reduction in the expression of LES. These data suggest that T attenuates LES, but not fear-potentiated startle, through a mechanism that may involve AVP.

Animals↗