Esquizofrenia é uma severa doença neurobiológica com fatores genéticos e ambientais desempenhando um papel na fisiopatologia. Diversas regiões cerebrais têm sido implicadas no processo da doença e estão conectadas em complexos circuitos neuronais. Nos níveis molecular e celular, a conectividade afetada entre essas regiões, envolvendo mielinização disfuncional dos axônios neuronais, bem como as alterações no nível sináptico e metabolismo energético levando a distúrbios na plasticidade sináptica, são os maiores achados em estudos post-mortem. Estudos de microarranjos investigando a expressão gênica contribuíram para os achados de alterações em vias complexas em regiões cerebrais relevantes na esquizofrenia. Além disso, estudos utilizando microdissecção e captura a laser permitiram a investigação da expressão gênica em grupos específicos de neurônios. Entretanto, deve ser mantido em mente que em estudos post-mortem, confusos efeitos de medicação, qualidade de RNAm, bem como capacidade de mecanismos regenerativos neuroplásticos do cérebro em indivíduos com história de vida de esquizofrenia, podem influenciar o complexo padrão de alterações no nível molecular. Apesar dessas limitações, estudos transcriptômicos livres de hipóteses em tecido cerebral de pacientes esquizofrênicos oferecem uma possibilidade única para aprender mais sobre os mecanismos subjacentes, levando a novas ópticas da fisiopatologia da doença.

Schizophrenia is a severe neurobiological disease with genetic and environmental factors playing a role in the pathophysiology. Several brain regions have been implicated in the disease process and are connected in complex neuronal circuits. On the cellular and molecular level, affected connectivity between these regions, involving dysfunctional myelination of neuronal axons, as well as alterations on the synaptic level and energy metabolism of neurons leading to disturbances in synaptic plasticity are major findings in post-mortem studies. Microarray studies investigating genome-wide gene expression have contributed to the findings of alterations in complex pathways in relevant brain regions in schizophrenia. Moreover, first Laser-capture Microdissection studies allowed the investigation of gene expression in specific groups of neurons. However, it must be kept in mind that in post-mortem studies confounding effects of medication, mRNA quality as well as the capability of the brain for neuroplastic regenerative mechanisms in individuals with a lifetime history of schizophrenia may influence the complex pattern of alterations on the molecular level. Despite these limitations, hypothesis-free transcriptome studies in brain tissue from schizophrenia patients offer a unique possibility to learn more about underlying mechanisms, leading to new insights in the pathophysiology of the disease.

Indigenous workers are migrating to Washington State in increasing numbers. These workers often speak little or no Spanish or English, and instead speak pre-Hispanic languages such as Mixteco (spoken in southern Mexico) and Mam (spoken in Guatemala). Mam and Mixteco workers migrate to the U.S. due to a number of social, political and economic pressures in their countries. Once they are in the U.S., Mixteco workers generally perform difficult and poorly paid work in agriculture, while Mam workers work long days harvestingfloral greens, often for less than the minimum wage. Indigenous workers face numerous legal needs, often involving immigration, wage payment, workers' compensation, housing, health care and language access, but addressing these needs is complicated by language barriers, cultural differences, and a general distrust of outsiders fostered by the history of violence and oppression in the workers' home countries. Case studies of litigation on behalf of Mam and Mixteco workers illustrate these dynamics. To address the legal needs of indigenous workers in Washington State, lawyers' associations in the home countries and in the U.S. should establish a transnational project to develop pro bono services for workers; law schools should train lawyers and students, in conjunction with community groups, to enforce workers' rights; and advocates should develop a pilot partnership project to match medical services in the U.S. with corresponding services in Mexico or Guatemala to cooperate in providing treatment and compensation to deserving workers under the Washington State workers' compensation system.

Los trabajadores indígenas están migrando al estado de Washington en un número cada vez mayor. Estos trabajadores a menudo hablan poco o nada de español o inglés, y en su lugar hablan lenguas prehispánicas, como el mixteco (hablado en el sur de México) y mam (se habla en Guatemala). Los trabajadores mixtecos y man emigran a los Estados Unidos debido a una serie de presiones sociales, políticas y económicas en sus países. Una vez que están en los Estados Unidos, los trabajadores mixtecos en general realizan un trabajo difícil y mal pagado en la agricultura, mientras que los mam trabajan largas jornadas en la cosecha de las verduras florales, a menudo por menos del salario mínimo. Los trabajadores indígenas se enfrentan a numerosas necesidades legales, a menudo relacionadas con la inmigración, el pago de salarios, la compensación de trabajadores, la vivienda, la salud y el acceso al idioma, pero ello se complica debido a las barreras del idioma, diferencias culturales, y una desconfianza generalizada de los extranjeros promovida por la historia de violencia y opresión en los países de origen de estos trabajadores. Los estudios de casos de litigio en nombre de los trabajadores mam y mixtecos ilustran esta dinámica. Para atender las necesidades legales de los trabajadores indígenas en el estado de Washington, las asociaciones de abogados en los países de origen y en los Estados Unidos deberían establecer un proyecto trasnacional para desarrollar servicios pro bono para los trabajadores; las escuelas de derecho deben capacitar a los abogados y estudiantes, en colaboración con grupos comunitarios, para hacer cumplir los derechos, y los defensores deben desarrollar un proyecto piloto de colaboración para que los servicios médicos en los Estados Unidos coincidan con los servicios correspondientes en México o Guatemala; cooperar en el suministro de tratamiento y la compensación a los trabajadores que la merecen en el estado de Washington.

Beside its role in motor coordination, the cerebellum is involved in cognitive function such as attention, working memory, verbal learning, and sensory discrimination. In schizophrenia, a disturbed prefronto-thalamo-cerebellar circuit has been proposed to play a role in the pathophysiology. In addition, a deficit in the glutamatergic N-methyl-D-aspartate (NMDAf) receptor has been hypothesized. The risk gene neuregulin 1 may play a major role in this process. We demonstrated a higher expression of the NMDA receptor subunit 2D in the right cerebellar regions of schizophrenia patients, which may be a secondary upregulation due to a dysfunctional receptor. In contrast, the neuregulin 1 risk variant containing at least one C-allele was associated with decreased expression of NMDA receptor subunit 2C, leading to a dysfunction of the NMDA receptor, which in turn may lead to a dysfunction of the gamma amino butyric acid (GABA) system. Accordingly, from post-mortem studies, there is accumulating evidence that GABAergic signaling is decreased in the cerebellum of schizophrenia patients. As patients in these studies are treated with antipsychotics long term, we evaluated the effect of long-term haloperidol and clozapine treatment in an animal model. We showed that clozapine may be superior to haloperidol in restoring a deficit in NMDA receptor subunit 2C expression in the cerebellum. We discuss the molecular findings in the light of the role of the cerebellum in attention and cognitive deficits in schizophrenia.

Patients with schizophrenia have a two- to three-fold increased risk of premature death as compared to patients without this disease. It has been established that patients with schizophrenia are at a high risk of developing cardiovascular disease. Moreover, an important issue that has not yet been explored is a possible existence of a "cerebral" focus that could trigger sudden cardiac death in patients with schizophrenia. Along these lines, several structural and functional alterations in the thalamic complex are evident in patients with schizophrenia and have been correlated with the symptoms manifested by these patients. With regard to abnormalities on the cellular and molecular level, previous studies have shown that schizophrenic patients have fewer neuronal projections from the thalamus to the prefrontal cortex as well as a reduced number of neurons, a reduced volume of either the entire thalamus or its subnuclei, and abnormal glutamate signaling. According to the glutamate hypothesis of schizophrenia, hypofunctional corticostriatal and striatothalamic projections are directly involved in the pathophysiology of the disease. Animal and post-mortem studies have provided a large amount of evidence that links the sudden unexpected death in epilepsy (SUDEP) that occurs in patients with schizophrenia and epilepsy to thalamic changes. Based on the results of these prior studies, it is clear that further research regarding the relationship between the thalamus and sudden cardiac death is of vital importance.

OBJECTIVES: The aim of our study was to investigate the impact of typical and atypical antipsychotic drugs on leptin concentration in blood and changes in the receptor expression in the hypothalamus of male Wistar rats. METHODS: From the age of 13 to 18 weeks, three groups of 20 animals were fed an average dose of 3.5 + 0.03 mg/ kg body weight (BW) haloperidol; 30.6 + 0.22 mg/kg BW clozapine; or 14.9 + 0.13 mg/kg BW ziprasidone in ground food pellets containing 15% fat. Twenty control animals received no drugs. Blood samples were taken at week 14, 16, and 19. Locomotor activity and exploratory behavior were measured using the alcove test at weeks 15 and 17. The expression of the hypothalamic leptin receptor in rat brains was determined by using a Western blot. RESULTS: Rats medicated with haloperidol and ziprasidone showed a significantly decreased percentage weight gain and food consumption. We observed no differences in the alcove test, but locomotor activity was significantly reduced in the haloperidol group. Except for rats in the clozapine and ziprasidone groups, after 2 weeks of drug application, we found no changes in the leptin blood concentrations among the four groups or animals within each group. Moreover, we did not find specific differences in hypothalamic leptin receptor expression among the groups. CONCLUSION: We concluded that in male Wistar rats during this treatment period, the tested drugs did not act directly on the leptin regulatory system. We recommend further studies using long-term treatment of different rat strains.

OBJECTIVES: Although schizophrenia affects both human genders, there are gender-dependent differences with respect to age of onset, clinical characteristics, course and prognosis of the disease. METHODS: To investigate sex-dependent differences in motor coordination and activity as well as in cognitive and social behavior, we repeatedly tested female (n = 14) and male (n = 12) Fisher rats (postnatal days, PD 56-174) that had received intracerebroventricular injections of kainic acid as well as female (n = 15) and male (n = 16) control animals. The hippocampus was examined histologically. RESULTS: Compared to male controls, in the alcove test both female controls and female animals with prenatal intervention spent less time in a dark box before entering an unknown illuminated area. Again, animals that received prenatal injection (particularly females) made more perseveration errors in the T-maze alternation task compared to controls. Female rats exhibited a higher degree of activity than males, suggesting these effects to be sex-dependent. Finally, animals that received prenatal intervention maintained longer lasting social contacts. Histological analyses showed pyramidal cells in the hippocampal area CA3 (in both hemispheres) of control animals to be longer than those found in treated animals. Sex-dependent differences were found in the left hippocampi of control animals and animals after prenatal intervention. CONCLUSION: These results demonstrate important differences between males and females in terms of weight gain, response to fear, working memory and social behavior. We also found sex-dependent differences in the lengths of hippocampal neurons. Further studies on larger sample sets with more detailed analyses of morphological changes are required to confirm our data.

OBJETIVOS: Em pacientes com primeiro episódio de esquizofrenia, estudos com ressonância magnética funcional (RMf) têm demonstrado disfunção pré-frontoparietal durante estimulação acústica e visual. O objetivo do presente estudo foi investigar a rede pré-frontoparietal em pacientes idosos com esquizofrenia utilizando o mesmo paradigma. Adicionalmente, foram presumidos efeitos favoráveis na ativação cerebral pelo antipsicótico atípico clozapina em comparação a neurolépticos típicos. MÉTODOS: Foram investigados 18 pacientes com esquizofrenia crônica e 21 controles saudáveis idosos. Nove pacientes com esquizofrenia haviam sido medicados com clozapina e nove haviam recebido neurolépticos típicos por décadas. Concomitantemente às avaliações com escalas psicopatológicas e neuropsicológicas foi utilizado um paradigma de estimulação auditiva e visual em um aparelho de ressonância magnética de 1,5 Tesla para investigar a resposta BOLD em diferentes áreas cerebrais. RESULTADOS: Comparados a controles saudáveis, os pacientes com esquizofrenia apresentaram diminuição na ativação cerebral nos córtices pré-frontal e parietal, assim como no giro do cíngulo anterior medial. Nessas regiões, os pacientes medicados com clozapina apresentaram resposta BOLD aumentada em comparação aos pacientes tratados com neurolépticos típicos. DISCUSSÃO: O presente estudo confirmou a presença de distúrbios na rede pré-frontoparietal em pacientes idosos com esquizofrenia, apontando assim para a preservação de déficits de ativação cerebrais e a influência de distúrbios do desenvolvimento neural em esquizofrenia crônica até a velhice. CONCLUSÃO: O antipsicótico atípico clozapina parece facilitar a ativação de áreas cerebrais mesmo em pacientes idosos com esquizofrenia crônica.

OBJECTIVES: In first-episode schizophrenia patients, functional magnetic resonance imaging (fMRI) has shown prefronto-parietal dysfunction during acoustic and visual stimulation. The aim of this study was to investigate the prefronto-parietal network in elderly schizophrenia patients using the same paradigm. Additionally, we hypothesized favourable effects on brain activation by the atypical antipsychotic clozapine compared to typical neuroleptics. METHODS: We investigated 18 elderly, chronic schizophrenia patients and 21 elderly healthy controls. Nine schizophrenia patients had been medicated with clozapine and 9 had been receiving typical neuroleptics over decades. In addition to assessments with psychopathological and neuropsychological rating scales we used an acoustic and visual stimulation paradigm in a 1.5 Tesla MRI scanner to investigate BOLD-response in different brain areas. RESULTS: Compared to healthy controls schizophrenia patients showed decreased brain activation in the prefrontal and parietal cortex as well as medial anterior cingulate gyrus compared to healthy controls. In these regions, patients medicated with clozapine showed increased BOLD-response compared to patients treated with typical neuroleptics. DISCUSSION: Our study confirmed prefronto-parietal network disturbances in elderly schizophrenia patients thus pointing to the preservation of brain activation deficits and the influence of neurodevelopmental disturbances in chronic schizophrenia until old-age. CONCLUSION: The atypical antipsychotic clozapine seems to facilitate brain activation even in elderly, chronic schizophrenia patients.

It is widely accepted that neurobiological abnormalities underlie the symptoms of psychiatric disorders such as schizophrenia and unipolar or bipolar affective disorders. New molecular methods, computer-assisted quantification techniques and neurobiological investigation methods that can be applied to the human brain are all used in post-mortem investigations of psychiatric disorders. The following article describes modern quantitative methods and recent post-mortem findings in schizophrenia and affective disorders. Using our brain bank as an example, necessary considerations of modern brain banking are addressed such as ethical considerations, clinical work-up, preparation techniques and the organization of a brain bank, the value of modern brain banking for investigations of psychiatric disorders is summarized.