Lasting effects of ketamine and isoflurane administration on anxiety- and panic-like behavioral responses in Wistar rats.

In clinical and laboratory practice, the use of anesthetics is essential in order to perform surgeries. Anesthetics, besides causing sedation and muscle relaxation, promote several physiological outcomes, such as psychotomimetic alterations, increased heart rate, and blood pressure. However, studies depicting the behavioral effect induced by ketamine and isoflurane are conflicting. In the present study, we assessed the behavioral effects precipitated by ketamine and isoflurane administration. We have also evaluated the ketamine effect on cell cytotoxicity and viability in an amygdalar neuronal primary cell culture. Ketamine (80 mg/kg) caused an anxiogenic effect in rats exposed to the elevated T-maze test (ETM) 2 and 7 days after ketamine administration. Ketamine (40 and 80 mg/kg) administration also decreased panic-like behavior in the ETM. In the light/dark test, ketamine had an anxiogenic effect. Isoflurane did not change animal behavior on the ETM. Neither ketamine nor isoflurane changed the spontaneous locomotor activity in the open field test. However, isoflurane-treated animals explored less frequently the OF central area seven days after treatment. Neither anesthetic caused oxidative damage in the liver. Ketamine also reduced cellular metabolism and led to neuronal death in amygdalar primary cell cultures. Thus, our work provides evidence that ketamine and isoflurane induce pronounced long lasting anxiety-related behaviors in male rats.

Role of the endocannabinoid 2-arachidonoylglycerol in aversive responses mediated by the dorsolateral periaqueductal grey.

2-arachidonoylglycerol (2-AG) is an endogenous ligand of the cannabinoid CB1 receptor. This endocannabinoid and its hydrolyzing enzyme, monoacylglycerol lipase (MAGL), are present in encephalic regions related to psychiatric disorders, including the midbrain dorsolateral periaqueductal grey (dlPAG). The dlPAG is implicated in panic disorder and its stimulation results in defensive responses proposed as a model of panic attacks. The present work verified if facilitation of 2-AG signalling in the dlPAG counteracts panic-like responses induced by local chemical stimulation. Intra-dlPAG injection of 2-AG prevented panic-like response induced by the excitatory amino acid N-methyl-d-aspartate (NMDA). This effect was mimicked by the 2-AG hydrolysis inhibitor (MAGL preferring inhibitor) URB602. The anti-aversive effect of URB602 was reversed by the CB1 receptor antagonist, AM251. Additionally, a combination of sub-effective doses of 2-AG and URB602 also prevented NMDA-induced panic-like response. Finally, immunofluorescence assay showed a significant increase in c-Fos positive cells in the dlPAG after local administration of NMDA. This response was also prevented by URB602. These data support the hypothesis that 2-AG participates in anti-aversive mechanisms in the dlPAG and reinforce the proposal that facilitation of endocannabinoid signalling could be a putative target for developing additional treatments against panic and other anxiety-related disorders.

Electroencephalographic findings in panic disorder / Achados eletroencefalográficos no transtorno do pânico

Some studies have reported the importance of electroencephalography (EEG) as a method for investigating abnormal parameters in psychiatric disorders. Different findings in time and frequency domain analysis with regard to central nervous system arousal during acute panic states have already been obtained. This study aimed to systematically review the EEG findings in panic disorder (PD), discuss them having a currently accepted neuroanatomical hypothesis for this pathology as a basis, and identify limitations in the selected studies. Literature search was conducted in the databases PubMed and ISI Web of Knowledge, using the keywords electroencephalography and panic disorder; 16 articles were selected. Despite the inconsistency of EEG findings in PD, the major conclusions about the absolute power of alpha and beta bands point to a decreased alpha power, while beta power tends to increase. Different asymmetry patterns were found between studies. Coherence studies pointed to a lower degree of inter-hemispheric functional connectivity at the frontal region and intra-hemispheric at the bilateral temporal region. Studies on possible related events showed changes in memory processing in PD patients when exposed to aversive stimuli. It was noticed that most findings reflect the current neurobiological hypothesis of PD, where inhibitory deficits of the prefrontal cortex related to the modulation of amygdala activity, and the subsequent activation of subcortical regions, may be responsible to trigger anxiety responses. We approached some important issues that need to be considered in further researches, especially the use of different methods for analyzing EEG signals (AU)

Alguns estudos relataram a importância da eletroencefalografia (EEG) como método de investigação de parâmetros anormais em transtornos psiquiátricos. Achados diferentes na análise do domínio do tempo e da frequência em relação à excitabilidade do sistema nervoso central durante estados agudos de pânico já foram obtidos. O objetivo deste estudo foi revisar sistematicamente os achados de EEG no transtorno do pânico (TP), discuti-los com base em uma hipótese neuroanatômica atualmente aceita para essa patologia e identificar limitações nos estudos selecionados. A pesquisa bibliográfica foi realizada nas bases de dados PubMed e ISI Web of Knowledge, utilizando as palavras-chave eletroencefalografia e transtorno do pânico; 16 artigos foram selecionados. Apesar da inconsistência dos achados de EEG no TP, as principais conclusões sobre a potência absoluta das bandas alfa e beta apontam para uma diminuição da potência em alfa, enquanto em beta a potência tende a aumentar. Diferentes padrões de assimetria foram encontrados entre estudos. Os estudos de coerência apontaram para um menor grau de conectividade funcional inter-hemisférica na região frontal e intra-hemisférica na região temporal bilateral. Estudos de potenciais eventos relacionados demonstraram mudanças no processamento da memória em pacientes com TP quando expostos a estímulos aversivos. Notou-se que a maioria dos resultados reflete a atual hipótese neurobiológica do TP, nos quais déficits inibitórios do córtex pré-frontal em relação à modulação da atividade da amígdala, e a subsequente ativação de regiões subcorticais, podem ser responsáveis por desencadear respostas de ansiedade. Foram abordadas algumas questões importantes que precisam ser consideradas em futuras pesquisas, especialmente o uso de diferentes métodos de análise de sinais de EEG (AU)

Differential involvement of dorsal raphe subnuclei in the regulation of anxiety- and panic-related defensive behaviors.

A wealth of evidence indicates that the dorsal raphe nucleus (DR) is not a homogenous structure, but an aggregate of distinctive populations of neurons that may differ anatomically, neurochemically and functionally. Other findings suggest that serotonergic neurons within the mid-caudal and caudal part of the DR are involved in anxiety processing while those within the lateral wings (lwDR) and ventrolateral periaqueductal gray (vlPAG) are responsive to panic-evoking stimuli/situations. However, no study to date has directly compared the activity of 5-HT and non-5HT neurons within different subnuclei of the DR following the expression of anxiety- and panic-related defensive responses. In the present investigation, the number of doubly immunostained cells for Fos protein and tryptophan hydroxylase, a marker of serotonergic neurons, was assessed within the rat DR, median raphe nucleus (MRN) and PAG following inhibitory avoidance and escape performance in the elevated T-maze, behaviors associated with anxiety and panic, respectively. Inhibitory avoidance, but not escape, significantly increased the number of Fos-expressing serotonergic neurons within the mid-caudal part of the dorsal subnucleus, caudal and interfascicular subnuclei of the DR and in the MRN. Escape, on the other hand, caused a marked increase in the activity of non-5HT cells within the lwDR, vlPAG, dorsolateral and dorsomedial columns of the PAG. These results strongly corroborate the view that different subsets of neurons in the DR are activated by anxiety- and panic-relevant stimuli/situations, with important implications for the understanding of the pathophysiology of generalized anxiety and panic disorders.

Current findings of fMRI in panic disorder: contributions for the fear neurocircuitry and CBT effects.

Thanks to brain imaging great advances have been made concerning the comprehension of neural substrates related to panic disorder (PD). This article aims to: review the recent functional MRI (fMRI) studies concerning PD; correlate the PD fMRI neurobiological findings with the fear neurocircuitry hypothesis; discuss the fear neurocircuitry hypothesis and link it to cognitive-behavior therapy findings; and comment on fMRI study limitations and suggest methodological changes for future research. As a whole, there is increasing evidence that brain structures such as the prefrontal cortex, the anterior cingulate cortex and limbic areas (hippocampus and amygdala) might play a major role in the panic response.

Panic disorder: is the PAG involved?

Data from studies with humans have suggested that abnormalities of midbrain structures, including the periaqueductal gray matter (PAG), could be involved in the neurobiology of panic disorder (PD). The electrical stimulation of the PAG in neurosurgical patients induces panic-like symptoms and the effect of drugs that are effective in the treatment of PD in the simulation of public speaking model of anxiety is in agreement with data from animal models of PD. Structural neuroimaging studies have shown increases in gray matter volume of midbrain and pons of PD patients. There is also evidence of lower serotonin transporter and receptor binding, and increases of metabolism in the midbrain of PD patients. Nevertheless, these midbrain abnormalities can not be considered as specific findings, since neuroimaging data indicate that PD patients have abnormalities in other brain structures that process fear and anxiety.

Transtornos de ansiedade / Anxiety disorders

Sintomas ansiosos são extremamente frequentes na prática médica. O diagnóstico de um transtorno ansioso depende da intensidade e duração dos sintomas, assim como de sua conexão com estímulos ambientais. Os critérios diagnósticos atuais discriminam vários tipos de transtornos ansiosos de forma que a comorbidade entre eles é frequentemente encontrada. Este artigo revê o quadro clínico e as estratégias gerais de tratamento farmacológico e psicoterapêutico do transtorno de pânico, agorafobia, transtorno de ansiedade generalizada, fobia social, fobias específicas, transtorno de estresse pós-traumático e transtorno obsessivo-compulsivo.

Transtorno do pânico / Panic disorder

Objetivos: Revisar o transtorno do pânico (TP), considerando seus aspectos clínicos, epidemiológicos, diagnósticos e etiológicos, bem como os avanços no tratamento, uma vez que o TP é uma entidade nosológica acompanhada de importante prejuízo psíquico e funcional. Método: Foi realizada uma revisão narrativa da literatura nas principais bases de dados existentes (MEDLINE, PsychINFO e SciELO) e em livros textos atualizados. Resultados: Devido à sintomatologia predominantemente física desse transtorno, os pacientes geralmente procuram vários atendimentos clínicos até que o diagnóstico seja feito. Em função desses aspectos e da sua cronicidade, o TP está associado a elevados custos econômicos. O tratamento do TP pode ser feito com psicoterapia e/ou psicofármacos. As diversas abordagens terapêuticas são apresentadas com o nível de evidência de cada recomendação. Em virtude da cronicidade e morbidade do TP, pesquisas têm se voltado para o estudo de estratégias de prevenção já na infância. Conclusões: O TP é um transtorno crônico e com baixas taxas de remissão dos sintomas em longo prazo. Sendo assim, sugere-se que sejam delineados novos estudos para tratamento precoce dos transtornos de ansiedade ou mesmo para prevenção em crianças de risco.

Objective: To review panic disorder (PD) considering its clinical, epidemiological, diagnostic, and etiologic aspects, as well as the advances in its treatment, since PD is a nosologic entity characterized by important psychiatric and functional impairment. Method: A review of the literature was carried out using the main databases available (MEDLINE, PsychINFO and SciELO) and up-to-date textbooks. Results: Due to the prevalence of physical symptoms in this disorder, patients usually have to seek clinical care for several times before the diagnosis is established. As a result of these aspects and because of its chronicity, PD is associated with high economic costs. PD treatment may include psychotherapy and/or use of psychotropic drugs. In this review, we present several different therapeutic approaches, as well as the levels of evidence of each recommendation. Due to PD chronicity and morbidity, researches have been focused on the study of strategies to prevent PD since childhood. Conclusions: PD is a chronic disorder with low long-term remission rates. Therefore, we suggest that new studies should be designed concerning the early treatment of anxiety disorders or even the prevention of this disorder in children at risk.

Structural magnetic resonance imaging in anxiety disorders: an update of research findings.

OBJECTIVE: The aim of the present report is to present a systematic and critical review of the more recent literature data about structural abnormalities detected by magnetic resonance in anxiety disorders. METHOD: A review of the literature in the last five years was conducted by a search of the Medline, Lilacs and SciELO indexing services using the following key words: "anxiety", "panic", "agoraphobia", "social anxiety", "posttraumatic" and "obsessive-compulsive", crossed one by one with "magnetic resonance", "voxel-based", "ROI" and "morphometry". RESULTS: We selected 134 articles and 41 of them were included in our review. Recent studies have shown significant morphological abnormalities in various brain regions of patients with anxiety disorders and healthy controls. Despite some apparently contradictory findings, perhaps reflecting the variability and limitations of the methodologies used, certain brain regions appear to be altered in a consistent and relatively specific manner in some anxiety disorders. These include the hippocampus and the anterior cingulate cortex in posttraumatic stress disorder and the orbitofrontal cortex in obsessive-compulsive disorder. CONCLUSIONS: The present review indicates that structural neuroimaging has contributed to a better understanding of the neurobiology of anxiety disorders. Further development of neuroimaging techniques, better sample standardization and the integration of data across neuroimaging modalities may extend progress in this area.

Structural magnetic ressonance imaging in anxiety disorders: an update of research findings: [review] / Ressonância magnética estrutural em transtornos de ansiedade: atualização dos achados de pesquisa: [revisão]

OBJECTIVE: The aim of the present report is to present a systematic and critical review of the more recent literature data about structural abnormalities detected by magnetic ressonance in anxiety disorders. METHOD: A review of the literature in the last five years was conducted by a search of the Medline, Lilacs and SciELO indexing services using the following key words: "anxiety", "panic", "agoraphobia", "social anxiety", "posttraumatic" and "obsessive-compulsive", crossed one by one with "magnetic resonance", "voxel-based", "ROI" and "morphometry". RESULTS: We selected 134 articles and 41 of them were included in our review. Recent studies have shown significant morphological abnormalities in various brain regions of patients with anxiety disorders and healthy controls. Despite some apparently contradictory findings, perhaps reflecting the variability and limitations of the methodologies used, certain brain regions appear to be altered in a consistent and relatively specific manner in some anxiety disorders. These include the hippocampus and the anterior cingulate cortex in posttraumatic stress disorder and the orbitofrontal cortex in obsessive-compulsive disorder. CONCLUSIONS: The present review indicates that structural neuroimaging has contributed to a better understanding of the neurobiology of anxiety disorders. Further development of neuroimaging techniques, better sample standardization and the integration of data across neuroimaging modalities may extend progress in this area.

OBJETIVO: Apresentar uma revisão sistemática e crítica dos achados mais recentes da literatura em relação a alterações estruturais avaliados por ressonância magnética nos transtornos de ansiedade. MÉTODO: Uma revisão da literatura dos últimos cinco anos foi realizada utilizando uma busca nos indexadores Medline, Lilacs e SciELO utilizando as seguintes palavras-chave: "anxiety", "panic", "agoraphobia", "social anxiety", "posttraumatic" e "obsessive-compulsive" cruzadas uma a uma com "magnetic ressonance", "voxel-based", "ROI" e "morphometry". RESULTADOS: Foram selecionados 134 artigos, sendo 41 foram incluídos nesta revisão. Estudos recentes mostram alterações morfológicas significativas entre os pacientes com transtorno de ansiedade e os controles saudáveis em várias regiões cerebrais. Apesar de achados contraditórios, sobretudo devido à variabilidade e às limitações nas metodologias utilizadas, algumas estruturas aparecem alteradas de forma mais consistente e relativamente específica em alguns transtornos de ansiedade, como o hipocampo e o córtex cingulado anterior no transtorno de estresse pós-traumático e o córtex orbitofrontal no transtorno obsessivo-compulsivo. CONCLUSÕES: A presente revisão aponta que a neuroimagem estrutural pode ser utilizada na busca de uma maior compreensão da neurobiologia dos transtornos de ansiedade. É possível que o rápido avanço das técnicas de neuroimagem, uma maior padronização das amostras e a associação de dados de diferentes modalidades permitam um maior entendimento deste cenário.

Regional gray matter abnormalities in panic disorder: a voxel-based morphometry study.

Although abnormalities in brain structures involved in the neurobiology of fear and anxiety have been implicated in the pathophysiology of panic disorder (PD), relatively few studies have made use of voxel-based morphometry (VBM) magnetic resonance imaging (MRI) to determine structural brain abnormalities in PD. We have assessed gray matter volume in 19 PD patients and 20 healthy volunteers using VBM. Images were acquired using a 1.5 T MRI scanner, and were spatially normalized and segmented using optimized VBM. Statistical comparisons were performed using the general linear model. A relative increase in gray matter volume was found in the left insula of PD patients compared with controls. Additional structures showing differential increases were the left superior temporal gyrus, the midbrain, and the pons. A relative gray matter deficit was found in the right anterior cingulate cortex. The insula and anterior cingulate abnormalities may be relevant to the pathophysiology of PD, since these structures participate in the evaluation process that ascribes negative emotional meaning to potentially distressing cognitive and interoceptive sensory information. The abnormal brain stem structures may be involved in the generation of panic attacks.

Correlation between voxel based morphometry and manual volumetry in magnetic resonance images of the human brain.

This is a comparative study between manual volumetry (MV) and voxel based morphometry (VBM) as methods of evaluating the volume of brain structures in magnetic resonance images. The volumes of the hippocampus and the amygdala of 16 panic disorder patients and 16 healthy controls measured through MV were correlated with the volumes of gray matter estimated by optimized modulated VBM. The chosen structures are composed almost exclusively of gray matter. Using a 4 mm Gaussian filter, statistically significant clusters were found bilaterally in the hippocampus and in the right amygdala in the statistical parametric map correlating with the respective manual volume. With the conventional 12 mm filter,a significant correlation was found only for the right hippocampus. Therefore, narrow filters increase the sensitivity of the correlation procedure, especially when small brain structures are analyzed. The two techniques seem to consistently measure structural volume.

Correlation between voxel based morphometry and manual volumetry in magnetic resonance images of the human brain

This is a comparative study between manual volumetry (MV) and voxel based morphometry (VBM) as methods of evaluating the volume of brain structures in magnetic resonance images. The volumes of the hippocampus and the amygdala of 16 panic disorder patients and 16 healthy controls measured through MV were correlated with the volumes of gray matter estimated by optimized modulated VBM. The chosen structures are composed almost exclusively of gray matter. Using a 4 mm Gaussian filter, statistically significant clusters were found bilaterally in the hippocampus and in the right amygdala in the statistical parametric map correlating with the respective manual volume. With the conventional 12 mm filter,a significant correlation was found only for the right hippocampus. Therefore,narrowfilters increase the sensitivity of the correlation procedure, especially when small brain structures are analyzed. The two techniques seem to consistently measure structural volume.

Trata-se de estudo comparativo entre a volumetria manual(VM) e a morfometria baseada no vóxel (MBV), como métodos de avaliação do volume de estruturas cerebrais. Os volumes do hipocampo e da amídala de 16 pacientes de pânico e 16 controles sadios medidos através da VM foram correlacionados com os volumes de matéria cinzenta estimados pela MBV.As estruturas escolhidas são constituídas quase exclusivamente de matéria cinzenta. Utilizando um filtro Gaussiano de 4 mm, encontram-se, bilateralmente, aglomerados significativos de correlação nas duas estruturas no mapa estatístico paramétrico, correspondendo ao respectivo volume manual. Com o filtro convencional de 12 mm, apenas uma correlação significativa foi encontrada no hipocampo direito. Portanto, filtros estreitos aumentam a sensibilidade do procedimento de correlação,especialmente quando estruturas pequenas são analisadas. Ambas as técnicas parecem medir consistentemente o volume estrutural.

Neuroanatomia do transtorno de pânico / Neuroanatomy of panic disorder

OBJETIVOS: O Transtorno de Pânico (TP) é um transtorno de ansiedade que permite um estudo comparativo de modelos animais visando à elucidação dos circuitos cerebrais envolvidos na sua gênese, embora estes ainda tenham sido pouco discutidos. MÉTODOS: Os autores realizam uma revisão da literatura sobre neurobiologia e neuroanatomia do TP. RESULTADOS: Uma revisão de dados demonstra a existência de uma "rede de medo", que tem como ponto principal o núcleo central da amígdala e compreende o hipotálamo, o tálamo, o hipocampo, a substância cinzenta periaquedutal, o locus ceruleus e outras estruturas do tronco cerebral. Sua presença é evidenciada em estudos de modelos animais de estados emocionais e comportamentais, e sua presença e importância podem ser extrapoladas para o TP em humanos. CONCLUSÃO: Esta rede de medo pode permitir que novos avanços e estudos utilizando técnicas de neuroimagem e/ou psicofármacos possam auxiliar na maior elucidação da circuitos cerebrais do TP.

The size and prevalence of the cavum septum pellucidum are normal in subjects with panic disorder.

Panic disorder is thought to involve dysfunction in the septohippocampal system, and the presence of a cavum septum pellucidum might indicate the aberrant development of this system. We compared the prevalence and size of cavum septum pellucidum in 21 patients with panic disorder and in 21 healthy controls by magnetic resonance imaging. The length of the cavum septum pellucidum was measured by counting the number of consecutive 1-mm coronal slices in which it appeared. A cavum septum pellucidum of >6 mm in length was rated as large. There was no significant difference in the proportion of patients (16 of 21 or 76.2%) and controls (18 of 21 or 85.7%) with a cavum septum pellucidum (P=0.35, Fisher's exact test, one-tailed), and no members of either group had a large cavum septum pellucidum. The mean cavum septum pellucidum rating in the patient and control groups was 1.81 (SD=1.50) and 2.09 (SD=1.51), respectively. There were also no significant differences between groups when we analyzed cavum septum pellucidum ratings as a continuous variable (U=196.5; P=0.54). Across all subjects there was a trend towards a higher prevalence of cavum septum pellucidum in males (100%, 10 of 10) than females (75%, 24 of 32; P=0.09, Fisher's exact test, one-tailed). Thus, we conclude that, while panic disorder may involve septo-hippocampal dysfunction, it is not associated with an increased prevalence or size of the cavum septum pellucidum.

[Neuroanatomy of panic disorder]. / Neuroanatomia do transtorno de pânico.

OBJECTIVES: Animal model studies may allow greater elucidation of the cerebral circuits involved in the genesis of panic disorder (PD), but these studies have not yet been fully analyzed. METHODS: The authors review recent literature on the neurobiology and neuroanatomy of PD. RESULTS: In this update, the authors present a revision of data that demonstrates the existence of a "fear network", which has as its main point the central nucleus of the amygdale and includes the hypothalamus, the thalamus, the hippocampus, the periaqueductal gray region, the locus ceruleus and other brainstem structures. Its existence is evidenced in animal studies of emotional and behavioral states, and its presence and importance can be extrapolated to the study of PD in humans. CONCLUSION: This fear network can allow new progresses and studies using neuroimaging techniques and/or psychopharmacological trials, further elucidating the cerebral circuits of PD.

Decreased left temporal lobe volume of panic patients measured by magnetic resonance imaging.

Reported neuroimaging studies have shown functional and morphological changes of temporal lobe structures in panic patients, but only one used a volumetric method. The aim of the present study was to determine the volume of temporal lobe structures in patients with panic disorder, measured by magnetic resonance imaging. Eleven panic patients and eleven controls matched for age, sex, handedness, socioeconomic status and years of education participated in the study. The mean volume of the left temporal lobe of panic patients was 9% smaller than that of controls (t21 = 2.37, P = 0.028). In addition, there was a trend (P values between 0.05 and 0.10) to smaller volumes of the right temporal lobe (7%, t21 = 1.99, P = 0.06), right amygdala (8%, t21 = 1.83, P = 0.08), left amygdala (5%, t21 = 1.78, P = 0.09) and left hippocampus (9%, t21 = 1.93, P = 0.07) in panic patients compared to controls. There was a positive correlation between left hippocampal volume and duration of panic disorder (r = 0.67, P = 0.025), with recent cases showing more reduction than older cases. The present results show that panic patients have a decreased volume of the left temporal lobe and indicate the presence of volumetric abnormalities of temporal lobe structures.