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Psiquiatría/historia , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Estados UnidosRESUMEN
Panic disorder patients are exquisitely and specifically sensitive to hypercapnia. The demonstration that carbon dioxide provokes panic in fear-unresponsive amygdala-calcified Urbach-Wiethe patients emphasizes that panic is not fear nor does it require the activation of the amygdala. This is consonant with increasing evidence suggesting that panic is mediated caudally at midbrain's dorsal periaqueductal gray matter (DPAG). Another startling feature of the apparently spontaneous clinical panic is the counterintuitive lack of increments in corticotropin, cortisol and prolactin, generally considered 'stress hormones'. Here we show that the stress hormones are not changed during DPAG-evoked panic when escape is prevented by stimulating the rat in a small compartment. Neither did the corticotropin increase when physical exertion was statistically adjusted to the same degree as non-stimulated controls, as measured by lactate plasma levels. Conversely, neuroendocrine responses to foot-shocks were independent from muscular effort. Data are consonant with DPAG mediation of panic attacks.
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Hormona Adrenocorticotrópica/sangre , Corticosterona/sangre , Trastorno de Pánico/sangre , Pánico/fisiología , Sustancia Gris Periacueductal , Esfuerzo Físico/fisiología , Prolactina/sangre , Animales , Conducta Animal , Modelos Animales de Enfermedad , Estimulación Eléctrica , Reacción de Fuga , Hidrocortisona/sangre , Ácido Láctico/sangre , Masculino , Ratas , Ratas WistarRESUMEN
Between 1950 and 1969, on a serendipitous basis, psychiatric drug development flourished. However, there has been a steep decline in the development of new medication classes. Instead of new molecular entities, slight molecular modifications producing “me-too” drugs attempted to garner market share. With failing profitability, industry is now withdrawing from psychiatric medication development. Managed care drastically shortened contact between patients and clinicians, so the possible observation of unexpected benefits has been nullified. The randomized, parallel-groups design met FDA requirements for specific pharmacological efficacy. However, it does not determine whether a patient who improved while drug-treated required the drug or would have gotten better on his own. Further, pathophysiology benefit remains obscure. The major psychotropic drugs have no benefits for normal subjects. Their remarkable benefits must stem from a necessary interaction with a pathophysiological state. Therefore, understanding therapeutic benefit by treating normal subjects becomes unlikely. The claim that therapeutic knowledge in psychiatry proceeds from bench to bedside has proven vacuous, primarily because of our limited understanding of brain pathophysiology. The utility of the alternative intensive design for understanding diagnosis, therapeutic benefit, and pathophysiology is emphasized.
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Humanos , Fármacos del Sistema Nervioso Central , Descubrimiento de Drogas/tendencias , Industria Farmacéutica/tendencias , Ensayos Clínicos como AsuntoRESUMEN
Between 1950 and 1969, on a serendipitous basis, psychiatric drug development flourished. However, there has been a steep decline in the development of new medication classes. Instead of new molecular entities, slight molecular modifications producing "me-too" drugs attempted to garner market share. With failing profitability, industry is now withdrawing from psychiatric medication development. Managed care drastically shortened contact between patients and clinicians, so the possible observation of unexpected benefits has been nullified. The randomized, parallel-groups design met FDA requirements for specific pharmacological efficacy. However, it does not determine whether a patient who improved while drug-treated required the drug or would have gotten better on his own. Further, pathophysiology benefit remains obscure. The major psychotropic drugs have no benefits for normal subjects. Their remarkable benefits must stem from a necessary interaction with a pathophysiological state. Therefore, understanding therapeutic benefit by treating normal subjects becomes unlikely. The claim that therapeutic knowledge in psychiatry proceeds from bench to bedside has proven vacuous, primarily because of our limited understanding of brain pathophysiology. The utility of the alternative intensive design for understanding diagnosis, therapeutic benefit, and pathophysiology is emphasized.
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Fármacos del Sistema Nervioso Central , Descubrimiento de Drogas/tendencias , Industria Farmacéutica/tendencias , Ensayos Clínicos como Asunto , HumanosRESUMEN
The present paper is the edited version of our presentations at the "First World Symposium On Translational Models Of Panic Disorder", in Vitoria, E.S., Brazil, on November 16-18, 2012. We also review relevant work that appeared after the conference. Suffocation-False Alarm Theory (Klein, 1993) postulates the existence of an evolved physiologic suffocation alarm system that monitors information about potential suffocation. Panic attacks maladaptively occur when the alarm is erroneously triggered. The expanded Suffocation-False Alarm Theory (Preter and Klein, 2008) hypothesizes that endogenous opioidergic dysregulation may underlie the respiratory pathophysiology and suffocation sensitivity in panic disorder. Opioidergic dysregulation increases sensitivity to CO2, separation distress and panic attacks. That sudden loss, bereavement and childhood separation anxiety are also antecedents of "spontaneous" panic requires an integrative explanation. Our work unveiling the lifelong endogenous opioid system impairing effects of childhood parental loss (CPL) and parental separation in non-ill, normal adults opens a new experimental, investigatory area.
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Ansiedad de Separación , Asfixia/etiología , Modelos Biológicos , Péptidos Opioides/metabolismo , Trastorno de Pánico/complicaciones , Dióxido de Carbono/metabolismo , HumanosAsunto(s)
Fármacos del Sistema Nervioso Central/farmacología , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Diseño de Fármacos , Animales , Fármacos del Sistema Nervioso Central/economía , Ensayos Clínicos como Asunto/métodos , Industria Farmacéutica/economía , Industria Farmacéutica/métodos , Humanos , Proyectos de Investigación , Factores de TiempoRESUMEN
BACKGROUND: Clinical trials testing the effectiveness of interventions for addictions, HIV transmission risk, and other behavioral health problems are important to advancing evidence-based treatment. Such trials are expensive and time-consuming to conduct, but the underlying effect sizes tend to be modest, and often findings are disappointing, failing to show evidence of treatment effects. OBJECTIVES: To demonstrate how appropriate covariation for baseline severity can enhance detection of treatment effects. METHODS: Explication and case example. RESULTS: Baseline severity (the score of the outcome measure at baseline, prior to randomization) is often strongly associated with outcome in such studies. Covariation for baseline score may enhance detection of treatment effects, because the variance explained by the baseline score is removed from the error variance in the estimate of the difference in outcome between treatments. Alternatively, the effect of treatment may manifest in the form of a baseline-by-treatment interaction. Common interaction patterns include that treatment may be more effective among patients with higher levels of baseline severity, or treatment may be more effective among patients with low severity at baseline ('relapse prevention' effect). Such effects may be important to developing treatment guidelines and offer clues toward understanding the mechanisms of action of treatments and of the disorders. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This article illustrates principles of covariation for baseline and the baseline-by-treatment interaction in nontechnical graphical terms, and discusses examples from clinical trials. Implications for the design and analysis of clinical trials are discussed, and it is argued that covariation for baseline severity of the outcome measure and testing of the baseline-by-treatment interaction should be considered for inclusion in the primary outcome analyses of treatment effectiveness trials of substantial size.
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Conductas Relacionadas con la Salud , Evaluación de Resultado en la Atención de Salud/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Trastornos Relacionados con Sustancias/rehabilitación , Medicina Basada en la Evidencia , Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , Humanos , National Institute on Drug Abuse (U.S.) , Asunción de Riesgos , Índice de Severidad de la Enfermedad , Trastornos Relacionados con Sustancias/fisiopatología , Estados UnidosRESUMEN
The false-suffocation hypothesis of panic disorder (Klein, 1993) suggested δ-opioid receptors as a possible source of the respiratory dysfunction manifested in panic attacks occurring in panic disorder (Preter and Klein, 2008). This study sought to determine if a lack of δ-opioid receptors in a mouse model affects respiratory response to elevated CO2, and whether the response is modulated by benzodiazepines, which are widely used to treat panic disorder. In a whole-body plethysmograph, respiratory responses to 5% CO2 were compared between δ-opioid receptor knockout mice and wild-type mice after saline, diazepam (1mg/kg), and alprazolam (0.3mg/kg) injections. The results show that lack of δ-opioid receptors does not affect normal response to elevated CO2, but does prevent benzodiazepines from modulating that response. Thus, in the presence of benzodiazepine agonists, respiratory responses to elevated CO2 were enhanced in δ-opioid receptor knockout mice compared to wild-type mice. This suggests an interplay between benzodiazepine receptors and δ-opioid receptors in regulating the respiratory effects of elevated CO2, which might be related to CO2 induced panic.
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Dióxido de Carbono/toxicidad , Trastorno de Pánico/fisiopatología , Receptores de GABA-A/fisiología , Receptores Opioides delta/fisiología , Insuficiencia Respiratoria/fisiopatología , Animales , Benzodiazepinas/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Dióxido de Carbono/sangre , Modelos Animales de Enfermedad , Hipercapnia/inducido químicamente , Hipercapnia/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Trastorno de Pánico/tratamiento farmacológico , Trastorno de Pánico/metabolismo , Pletismografía Total/métodos , Receptores de GABA-A/efectos de los fármacos , Receptores Opioides delta/deficiencia , Receptores Opioides delta/genética , Insuficiencia Respiratoria/tratamiento farmacológico , Insuficiencia Respiratoria/genética , Volumen de Ventilación Pulmonar/fisiologíaRESUMEN
Resting-state functional magnetic resonance imaging (fMRI) has provided a novel approach for examining interhemispheric interaction, demonstrating a high degree of functional connectivity between homotopic regions in opposite hemispheres. However, heterotopic resting-state functional connectivity (RSFC) remains relatively uncharacterized. In the present study, we examine non-homotopic regions, characterizing heterotopic RSFC and comparing it to intrahemispheric RSFC, to examine the impact of hemispheric separation on the integration and segregation of processing in the brain. Resting-state fMRI scans were acquired from 59 healthy participants to examine inter-regional correlations in spontaneous low frequency fluctuations in BOLD signal. Using a probabilistic atlas, we correlated probability-weighted time series from 112 regions (56 per hemisphere) distributed throughout the entire cerebrum. We compared RSFC for pairings of non-homologous regions located in different hemispheres (heterotopic connectivity) to RSFC for the same pairings when located within hemisphere (intrahemispheric connectivity). For positive connections, connectivity strength was greater within each hemisphere, consistent with integrated intrahemispheric processing. However, for negative connections, RSFC strength was greater between the hemispheres, consistent with segregated interhemispheric processing. These patterns were particularly notable for connections involving frontal and heteromodal regions. The distribution of positive and negative connectivity was nearly identical within and between the hemispheres, though we demonstrated detailed regional variation in distribution. We discuss implications for leading models of interhemispheric interaction. The future application of our analyses may provide important insight into impaired interhemispheric processing in clinical and aging populations.
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Mapeo Encefálico/métodos , Cerebro/fisiología , Imagen por Resonancia Magnética/métodos , Adulto , Cerebro/anatomía & histología , Femenino , Humanos , Aumento de la Imagen , Sistema Límbico/anatomía & histología , Sistema Límbico/fisiología , Masculino , Persona de Mediana Edad , Valores de Referencia , Adulto JovenRESUMEN
BACKGROUND: Similar patterns of vulnerability to carbon dioxide (CO(2)) inhalation have been reported in adults with panic disorder (PD) and children with separation anxiety disorder (SAD), suggesting a link between the adult and child conditions. This study examines the influence of familial risk for PD on CO(2) responses in children with SAD. We hypothesized that offspring with SAD of parents with PD would have distinct CO(2) responses. METHODS: Two hundred twelve 9- to 20-year-old offspring of parents with or without PD were exposed to maintained 5% CO(2) inhalation in the participants' homes. Anxiety symptoms, panic attacks, and respiratory physiology (respiratory frequency and tidal volume) were monitored during baseline and 15-min maintained CO(2) breathing. RESULTS: As hypothesized, significant offspring SAD x parent PD interactions were obtained for anxiety symptoms, respiratory frequency, tidal volume, and a panting index during CO(2) inhalation. Offspring with both SAD and parental PD exhibited more anxiety symptoms at termination of 5% CO(2) breathing than the other offspring groups and had the most extreme values on measures of respiratory physiology. CONCLUSIONS: Youth with both SAD and parental PD have respiratory responses to CO(2) similar to adult PD. They might be a subtype of SAD at particularly high risk for adult PD.
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Ansiedad de Separación/diagnóstico , Dióxido de Carbono/farmacología , Hijo de Padres Discapacitados/psicología , Trastorno de Pánico/diagnóstico , Adolescente , Adulto , Niño , Salud de la Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Frecuencia Respiratoria/efectos de los fármacos , Volumen de Ventilación Pulmonar/efectos de los fármacosRESUMEN
Functional connectivity analyses of resting-state fMRI data are rapidly emerging as highly efficient and powerful tools for in vivo mapping of functional networks in the brain, referred to as intrinsic connectivity networks (ICNs). Despite a burgeoning literature, researchers continue to struggle with the challenge of defining computationally efficient and reliable approaches for identifying and characterizing ICNs. Independent component analysis (ICA) has emerged as a powerful tool for exploring ICNs in both healthy and clinical populations. In particular, temporal concatenation group ICA (TC-GICA) coupled with a back-reconstruction step produces participant-level resting state functional connectivity maps for each group-level component. The present work systematically evaluated the test-retest reliability of TC-GICA derived RSFC measures over the short-term (<45 min) and long-term (5-16 months). Additionally, to investigate the degree to which the components revealed by TC-GICA are detectable via single-session ICA, we investigated the reproducibility of TC-GICA findings. First, we found moderate-to-high short- and long-term test-retest reliability for ICNs derived by combining TC-GICA and dual regression. Exceptions to this finding were limited to physiological- and imaging-related artifacts. Second, our reproducibility analyses revealed notable limitations for template matching procedures to accurately detect TC-GICA based components at the individual scan level. Third, we found that TC-GICA component's reliability and reproducibility ranks are highly consistent. In summary, TC-GICA combined with dual regression is an effective and reliable approach to exploratory analyses of resting state fMRI data.