The modulating impact of cigarette smoking on brain structure in panic disorder: a voxel-based morphometry study.

Cigarette smoking increases the likelihood of developing anxiety disorders, among them panic disorder (PD). While brain structures altered by smoking partly overlap with morphological changes identified in PD, the modulating impact of smoking as a potential confounder on structural alterations in PD has not yet been addressed. In total, 143 PD patients (71 smokers) and 178 healthy controls (62 smokers) participated in a multicenter magnetic resonance imaging (MRI) study. T1-weighted images were used to examine brain structural alterations using voxel-based morphometry in a priori defined regions of the defensive system network. PD was associated with gray matter volume reductions in the amygdala and hippocampus. This difference was driven by non-smokers and absent in smoking subjects. Bilateral amygdala volumes were reduced with increasing health burden (neither PD nor smoking > either PD or smoking > both PD and smoking). As smoking can narrow or diminish commonly observed structural abnormalities in PD, the effect of smoking should be considered in MRI studies focusing on patients with pathological forms of fear and anxiety. Future studies are needed to determine if smoking may increase the risk for subsequent psychopathology via brain functional or structural alterations.

The Rodent-versus-wild Snake Paradigm as a Model for Studying Anxiety- and Panic-like Behaviors: Face, Construct and Predictive Validities.

Using an innovative approach to study the neural bases of psychiatric disorders, this study investigated the behavioral, morphological and pharmacological bases of panic attack-induced responses in a prey-versus-coral snake paradigm. Mesocricetus auratus was chronically treated with intraperitoneal administration of the selective serotonin uptake inhibitor paroxetine or the gamma aminobutyric acid (GABA)/benzodiazepine receptor agonist alprazolam at three different doses and were then confronted with a venomous coral snake (Micrurus frontalis, Reptilia, Elapidae). The threatened rodents exhibited defensive attention, flat back approaches, defensive immobility, and escape defensive responses in the presence of the venomous snake, followed by increases in Fos protein in limbic structure neurons. Chronic administration of both paroxetine and alprazolam decreased these responses with morphological correlates between the panicolytic effect of both drugs administered at the highest dose and decreases in Fos protein-immunolabeled perikarya found in the amygdaloid complex, hypothalamus and periaqueductal gray matter columns, which are structures that make up the encephalic aversion system. These findings provide face, construct and predictive validities of this new experimental model of anxiety- and panic attack-like behavioral responses displayed by threatened prey confronted with venomous coral snakes.

Mobilization of Peripheral Blood Stem Cells and Changes in the Concentration of Plasma Factors Influencing their Movement in Patients with Panic Disorder.

In this paper we examined whether stem cells and factors responsible for their movement may serve as new biological markers of anxiety disorders. The study was carried out on a group of 30 patients diagnosed with panic disorder (examined before and after treatment), compared to 30 healthy individuals forming the control group. We examined the number of circulating HSCs (hematopoetic stem cells) (Lin-/CD45 +/CD34 +) and HSCs (Lin-/CD45 +/AC133 +), the number of circulating VSELs (very small embryonic-like stem cells) (Lin-/CD45-/CD34 +) and VSELs (Lin-/CD45-/AC133 +), as well as the concentration of complement components: C3a, C5a and C5b-9, SDF-1 (stromal derived factor) and S1P (sphingosine-1-phosphate). Significantly lower levels of HSCs (Lin-/CD45 +/AC133 +) have been demonstrated in the patient group compared to the control group both before and after treatment. The level of VSELs (Lin-/CD45-/CD133 +) was significantly lower in the patient group before treatment as compared to the patient group after treatment.The levels of factors responsible for stem cell movement were significantly lower in the patient group compared to the control group before and after treatment. It was concluded that the study of stem cells and factors associated with their movement can be useful in the diagnostics of panic disorder, as well as differentiating between psychotic and anxiety disorders.

Sex determinants of experimental panic attacks.

Panic disorder is twice a common in women than in men. In women, susceptibility to panic increases during the late luteal (premenstrual) phase of the menstrual cycle, when progesterone secretion is in rapid decline. This article considers the evidence for the midbrain periaqueductal grey (PAG) as a locus for panic and for the use of PAG stimulation as an animal model of panic in both sexes. We show in females how a rapid fall in progesterone secretion, such as occurs during the late dioestrus phase of the ovarian cycle in rats (similar to the late luteal phase in women), triggers a neuronal withdrawal response during which the excitability of the midbrain panic circuitry increases as a result of upregulation of extrasynaptic GABAA receptors on inhibitory interneurones in the PAG. The withdrawal effect is due not to the native hormone but to its neuroactive metabolite allopregnanolone. Differences in the kinetics of allopregnanolone metabolism may contribute to individual differences in susceptibility to panic in women.

Differentiating ictal panic with low-grade temporal lobe tumors from psychogenic panic attacks.

OBJECTIVE: Indolent low-grade temporal lobe tumors may present with ictal panic that may be difficult to differentiate from psychogenic panic attacks. The current study aims to demonstrate the differences between the two disorders and help physicians generate a diagnostic paradigm. METHOD: This was a retrospective study of 43 patients who underwent a temporal lobectomy between 1981 and 2008 for the treatment of intractable temporal lobe epilepsy secondary to low-grade neoplasms at Rush University Medical Center. A total of 10 patients in this group presented with ictal panic who were previously being treated for psychogenic panic attacks. Medical records were reviewed for age at seizure onset, duration of symptoms, lateralization of the epileptogenic zone, pathological diagnosis, and postsurgical seizure outcome according to the modified Engel classification. RESULTS: Neuropathologic findings of the 10 tumors were pleomorphic xanthoastrocytoma, ganglioglioma, oligodendroglioma, and dysembryoplastic neuroepithelial. The mean age of the patients undergoing surgery was 28 years (range, 15-49). The mean duration of panic symptoms prior to surgery was 9.8 years (range, 3-23). All patients had unprovoked ictal panic. None had symptoms suggestive of a brain tumor, such as signs of increased intracranial pressure or any focal neurologic deficit. In 5 of the patients, other symptoms associated with the ictal panic, including unusual sounds, nausea, automatism, uprising gastric sensation, and déjà vu were identified. Gross total resection of the lesion resulted in improved seizure outcome in all patients undergoing surgery. Patient follow-up was, on average, 7.4 years (range, 2-14) from time of surgery. CONCLUSIONS: Although similar, ictal panic from epilepsy and classic panic attacks are clinically distinguishable entities with different modalities of treatment. A careful history may help differentiate patients with ictal panic from those with psychogenic panic attacks and determine for which patients to obtain neuroimaging studies.

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)

Hippocampal hyperexcitability underlies enhanced fear memories in TgNTRK3, a panic disorder mouse model.

Panic attacks are a hallmark in panic disorder (PAND). During the panic attack, a strong association with the surrounding context is established suggesting that the hippocampus may be critically involved in the pathophysiology of PAND, given its role in contextual processing. We previously showed that variation in the expression of the neurotrophin tyrosine kinase receptor type 3 (NTRK3) in both PAND patients and a transgenic mouse model (TgNTRK3) may have a role in PAND pathophysiology. Our study examines hippocampal function and activation of the brain fear network in TgNTRK3 mice. TgNTRK3 mice showed increased fear memories accompanied by impaired extinction, congruent with an altered activation pattern of the amygdala-hippocampus-medial prefrontal cortex fear circuit. Moreover, TgNTRK3 mice also showed an unbalanced excitation-to-inhibition ratio in the hippocampal cornu ammonis 3 (CA3)-CA1 subcircuit toward hyperexcitability. The resulting hippocampal hyperexcitability underlies the enhanced fear memories, as supported by the efficacy of tiagabine, a GABA reuptake inhibitor, to rescue fear response. The fearful phenotype appears to be the result of hippocampal hyperexcitability and aberrant fear circuit activation. We conclude that NTRK3 plays a role in PAND by regulating hippocampus-dependent fear memories.

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.

Damage to the right dorsal anterior cingulate cortex induces panic disorder.

Brain imaging studies suggest that panic disorder (PD) is mediated by several brain regions, including the anterior cingulate cortex (ACC). In the present report we describe a patient who experienced a panic attack during awake surgery (case 1) and another patient who developed PD after surgery and radiotherapy (case 2). In case 1, the patient experienced repeated panic attacks when the tumor at the upper border of right dorsal ACC was removed during awake surgery. In case 2, the patient developed PD at six months after surgery and Cyberknife radiotherapy. MRI examination revealed that the dorsal ACC size was reduced at six months after surgery and that the dorsal ACC was absent at two years after surgery, possibly due to radiotherapy-induced damage by radiotherapy. Profile of mood states (POMS) testing characterized the presence of tension-anxiety as the common abnormal symptom in cases 1 and 2. In conclusion, these results suggest that damage to the right dorsal ACC can induce PD and that this structure likely plays a pathophysiologic role in PD.

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 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.

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.