Thesis (Ph. D.)--University of Missouri-Columbia, 2006. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. "December 2006" Includes bibliographical references.

Complex regional pain syndrome (CRPS) is a chronic neuropathic pain disorder characterized by both central and peripheral symptoms that can be debilitating in children. CRPS treatment typically consists of intensive physical, occupational, and psychological therapy with evidence supporting the efficacy of this approach. Among these outcomes, some patients report significant improvements in pain while others report no change. Identifying baseline predictors of treatment resistance would refine our treatment approach and provide additional targets for intervention. The current study examined baseline brain structure via cortical thickness and gray matter volume (GMV) in 29 pediatric CRPS patients enrolled in an intensive pain rehabilitation program. All participants underwent MRI using a high-resolution T1-weighted sequence. Patients were categorized as pain treatment “responders” (n=19) or “non-responders” (n=10) based on change in reported pain levels from admission to follow up. Compared to treatment responders, non-responders demonstrated significantly less GMV in the bilateral nucleus accumbens p<0.05 and right: putamen p<0.01, pallidum p<0.05, and amygdala p<0.05. Furthermore, treatment non-responders exhibited significant cortical thickening in the left anterior insular cortex and medial frontal gyrus, and cortical thinning in the bilateral precentral gyrus and superior frontal gyrus; right: middle frontal gyrus, fusiform gyrus, inferior temporal gyrus, middle temporal gyrus, and anterior prefrontal cortex; and left: parahippocampal gyrus. Though we did see significant thinning of the primary motor cortex in treatment non-responders compared to responders, the majority of our findings were localized to regions associated with reward, motivation, learning, and emotion. We, therefore, postulate that treatment non-responders, when compared to responders, likely have an intrinsically reduced reward responsiveness, diminished motivation, and impaired learning, overall contributing to their negative treatment outcomes and chronification of pain. In conclusion, these baseline differences overall suggest these regional morphometric alterations may potentially serve as predictors of treatment response in pediatric CRPS. Furthermore, these areas may also indicate possible targets for future treatment.

Transtornos mentais graves são doenças crônicas altamente incapacitantes que geram um alto custo para a sociedade. Indivíduos acometidos por essas doenças apresentam maior morbidade e mortalidade. Dentre elas, a esquizofrenia parece possuir os piores desfechos. Portanto, estudar a esquizofrenia pode trazer contribuições importantes para o entendimento e manejo de transtornos mentais graves como a depressão maior e o transtorno bipolar. Esse trabalho buscou compreender mecanismos fisiopatológicos da esquizofrenia ao longo de quatro artigos que exploram aspectos de funcionamento cognitivo, funcionamento intelectual, de biomarcadores e de estrutura cerebral. O primeiro artigo investigou as alterações de performance de memória em indivíduos com esquizofrenia em estágios iniciais e tardios da doença comparadas ao transtorno bipolar e a sujeitos saudáveis. Os resultados mostraram que indivíduos com esquizofrenia apresentaram precoces prejuízos cognitivos de memória, diferentemente de indivíduos com transtorno bipolar quando comparados a controles. O segundo artigo investigou as influências das performances cognitiva e intelectual em estruturas cerebrais de indivíduos com esquizofrenia comparados a controles saudáveis. Os resultados indicaram que o funcionamento intelectual pré-morbido estava relacionado ao volume de estruturas globais, enquanto o funcionamento cognitivo estava relacionado ao volume e espessura de massa cinzenta cortical, sugerindo influências diferentes e complementares relacionadas a neurodesenvolvimento e neurodegeneração. O terceiro artigo investigou um biomarcador de envelhecimento precoce, um possível mecanismo para a neuroprogressão na esquizofrenia. Os resultados monstraram que indivíduos com esquizofrenia apresentaram encurtamento de telômero quando comparados a controles, mas não houveram diferenças entre o tamanho de telômero de pacientes e seus irmãos não afetados pela doença. Por fim, o quarto artigo buscou investigar a teoria do envelhecimentoa patológico acelerado na esquizofrenia, integrando os achados dos artigos anteriores. Os resultados demonstraram correlações entre comprimento de telômero, níveis de CCL11, performance de memória, volume de massa cinzenta e tempo de doença em indivíduos com esquizofrenia. Esses achados sugerem que a esquizofrenia seria uma doença do neurodesenvolvimento associada a uma carga adicional ao longo do curso da doença que levaria a um envelhecimento patológico precoce. A partir dos achados em esquizofrenia, pode-se ampliar a compreensão de alterações percebidas nas trajetórias de outras psicopatologias. Com adequado entendimento desses mecanismos, será possível o desenvolvimento de novos tratamentos e intervenções mais efetivas e eficazes. / Severe mental disorders are debilitating chronic diseases that have a high cost to society. Individuals affected by these diseases have increased morbidity and mortality. Among them, schizophrenia seems to have the worst outcomes. Therefore, studying schizophrenia may provide important contributions to the understanding and management of severe mental disorders such as major depression and bipolar disorder. The present study aimed to understand the pathophysiological mechanisms of schizophrenia over four articles that explore aspects of cognitive functioning, intellectual functioning, biomarkers and brain structure. The first article investigated changes in memory performance in individuals with schizophrenia in early and late stages of disease compared to bipolar disorder and healthy subjects. The results showed that subjects with schizophrenia had early cognitive deficits of memory, unlike individuals with bipolar disorder compared to controls. The second article investigated influences of cognitive and intellectual performances on brain structures of individuals with schizophrenia compared to healthy controls. The results indicated that premorbid intellectual functioning was related to volume of global structures, while cognitive functioning was related to volume and thickness of cortical gray matter, suggesting different and complementary influences related to neurodevelopment and neurodegeneration. The third article investigated an early aging biomarker, a possible mechanism of neuroprogression in schizophrenia. The results showed that individuals with schizophrenia had shortened telomeres when compared to controls, but there were no differences between the telometer length of patients and their siblings not affected by the disease. Finally, the fourth article sought to investigate the theory of pathological accelerated aging in schizophrenia, integrating the findings of the previous articles. The results demonstrated correlations between telometer length, CCL11 levels, memory performance, gray matter volume and illness duration in individuals with schizophrenia. These findings suggest that schizophrenia is a neurodevelopmental disorder associated with an additional burden over the course of the disease that leads to a pathological accelerated agig.

Transtornos mentais graves são doenças crônicas altamente incapacitantes que geram um alto custo para a sociedade. Indivíduos acometidos por essas doenças apresentam maior morbidade e mortalidade. Dentre elas, a esquizofrenia parece possuir os piores desfechos. Portanto, estudar a esquizofrenia pode trazer contribuições importantes para o entendimento e manejo de transtornos mentais graves como a depressão maior e o transtorno bipolar. Esse trabalho buscou compreender mecanismos fisiopatológicos da esquizofrenia ao longo de quatro artigos que exploram aspectos de funcionamento cognitivo, funcionamento intelectual, de biomarcadores e de estrutura cerebral. O primeiro artigo investigou as alterações de performance de memória em indivíduos com esquizofrenia em estágios iniciais e tardios da doença comparadas ao transtorno bipolar e a sujeitos saudáveis. Os resultados mostraram que indivíduos com esquizofrenia apresentaram precoces prejuízos cognitivos de memória, diferentemente de indivíduos com transtorno bipolar quando comparados a controles. O segundo artigo investigou as influências das performances cognitiva e intelectual em estruturas cerebrais de indivíduos com esquizofrenia comparados a controles saudáveis. Os resultados indicaram que o funcionamento intelectual pré-morbido estava relacionado ao volume de estruturas globais, enquanto o funcionamento cognitivo estava relacionado ao volume e espessura de massa cinzenta cortical, sugerindo influências diferentes e complementares relacionadas a neurodesenvolvimento e neurodegeneração. O terceiro artigo investigou um biomarcador de envelhecimento precoce, um possível mecanismo para a neuroprogressão na esquizofrenia. Os resultados monstraram que indivíduos com esquizofrenia apresentaram encurtamento de telômero quando comparados a controles, mas não houveram diferenças entre o tamanho de telômero de pacientes e seus irmãos não afetados pela doença. Por fim, o quarto artigo buscou investigar a teoria do envelhecimentoa patológico acelerado na esquizofrenia, integrando os achados dos artigos anteriores. Os resultados demonstraram correlações entre comprimento de telômero, níveis de CCL11, performance de memória, volume de massa cinzenta e tempo de doença em indivíduos com esquizofrenia. Esses achados sugerem que a esquizofrenia seria uma doença do neurodesenvolvimento associada a uma carga adicional ao longo do curso da doença que levaria a um envelhecimento patológico precoce. A partir dos achados em esquizofrenia, pode-se ampliar a compreensão de alterações percebidas nas trajetórias de outras psicopatologias. Com adequado entendimento desses mecanismos, será possível o desenvolvimento de novos tratamentos e intervenções mais efetivas e eficazes. / Severe mental disorders are debilitating chronic diseases that have a high cost to society. Individuals affected by these diseases have increased morbidity and mortality. Among them, schizophrenia seems to have the worst outcomes. Therefore, studying schizophrenia may provide important contributions to the understanding and management of severe mental disorders such as major depression and bipolar disorder. The present study aimed to understand the pathophysiological mechanisms of schizophrenia over four articles that explore aspects of cognitive functioning, intellectual functioning, biomarkers and brain structure. The first article investigated changes in memory performance in individuals with schizophrenia in early and late stages of disease compared to bipolar disorder and healthy subjects. The results showed that subjects with schizophrenia had early cognitive deficits of memory, unlike individuals with bipolar disorder compared to controls. The second article investigated influences of cognitive and intellectual performances on brain structures of individuals with schizophrenia compared to healthy controls. The results indicated that premorbid intellectual functioning was related to volume of global structures, while cognitive functioning was related to volume and thickness of cortical gray matter, suggesting different and complementary influences related to neurodevelopment and neurodegeneration. The third article investigated an early aging biomarker, a possible mechanism of neuroprogression in schizophrenia. The results showed that individuals with schizophrenia had shortened telomeres when compared to controls, but there were no differences between the telometer length of patients and their siblings not affected by the disease. Finally, the fourth article sought to investigate the theory of pathological accelerated aging in schizophrenia, integrating the findings of the previous articles. The results demonstrated correlations between telometer length, CCL11 levels, memory performance, gray matter volume and illness duration in individuals with schizophrenia. These findings suggest that schizophrenia is a neurodevelopmental disorder associated with an additional burden over the course of the disease that leads to a pathological accelerated agig.

As reações incondicionadas de defesa observadas em mamíferos são organizadas pelo Sistema Encefálico de Aversão (SEA), composto, entre outras estruturas, pela substância cinzenta periaquedutal dorsal (SCPd) e o colículo inferior (CI). Tem sido proposto que o CI seja parte do circuito sensoriomotor para os estímulos auditivos de natureza aversiva e a SCPd como a principal via de saída (output) do SEA para a elaboração de comportamentos defensivos. Ambas as estruturas são reguladas tonicamente pelo neurotransmissor inibitório ácido gama-aminobutírico (GABA). Este trabalho aborda a mediação química GABA/Benzodiazepínica (BZD) do processamento da informação aversiva no CI e das respostas de medo elaboradas pela SCPd. Grupos independentes de animais submetidos ao implante de quimitrodos (eletrodos acoplados a cânulas-guia para injeção de drogas) foram usados para avaliar no CI e SCPd os efeitos de injeções locais de muscimol (agonista de receptores GABA-A), semicarbazida (inibidor da síntese da enzima precursora do GABA descarboxilase do ácido glutâmico) ou midazolam (agonista BZD). Foram registrados potenciais evocados auditivos (PEA) no CI como medida eletrofisiológica da ativação neuronial, além da determinação dos limiares de congelamento e fuga, com o procedimento de estimulação elétrica (EE), tanto do CI quanto da SCPd. A mesma abordagem farmacológica com injeções de drogas intra-CI foi empregada em animais submetidos ao teste do Labirinto em Cruz Elevado (LCE), um modelo animal tradicional de ansiedade. Adicionalmente, investigou-se a participação de ambas as estruturas na expressão do comportamento de desligar uma luz de intensidade aversiva em um novo teste de medo incondicionado (Light Switch Off Test; LSOT) recentemente proposto pelo nosso grupo. Encontramos uma clara segregação funcional entre a porção dorsal e ventral do CI, sendo a última envolvida nos comportamentos defensivos. Mecanismos GABAérgicos em ambas as estruturas influenciam a amplitude do PEA e o congelamento pós-fuga da EE, sugerindo uma relação funcional entre as duas estruturas. Já no LSOT, os resultados indicam o envolvimento de mecanismos GABAérgicos do vCI, mas não da SCPd, na modulação da resposta incondicionada à luz em ratos. Os resultados obtidos permitem ampliar o conhecimento atual sobre a neurobiologia dos estados de medo e ansiedade, em uma abordagem integrada dos mecanismos de processamento das informações sensoriais e da expressão de reações de defesa. / Unconditioned defense reactions observed in mammals are organized by the Brain Aversive System, comprising, among other structures, the dorsal periaqueductal gray matter (dPAG) and the inferior colliculus (IC). It has been proposed that the IC is part of the sensorimotor circuitry that processes aversive auditory information and the dPAG is considered the main neural substrate for the expression of defensive behaviors. Both structures are tonically regulated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This work addresses the chemical mediation of GABA/Benzodiazepine (BZD) on aversive information processing in the IC and the elaboration of fear responses by dPAG. Independent groups of animals implanted with chemitrodes (electrodes attached to a guide cannula for drug injection) have been used to evaluate the IC and dPAG regarding the effects of local injections of GABAergic agents (muscimol, semicarbazide, and midazolam). Auditory evoked potentials (AEP) have been recorded in the IC as a measure of electrophysiological neuronal activation, in addition to determining the thresholds of defensive freezing and flight behaviors, using the electrical stimulation (EE) procedure in both IC and dPAG. The same pharmacological regimen of drug injections intra-dPAG and intra-CI have been applied to animals subjected to the elevated plus maze (EPM), a well-known animal model of anxiety, and also to a novel animal test for innate fear (Light Switch Off Test, LSOT) that has been developed and proposed by our group. We found a clear functional segregation between the dorsal and ventral portions of the IC, the latter being the specific collicular substrate of defensive behaviors. GABAergic mechanisms in both structures influence the amplitude of the AEP and post-stimulation freezing of EE, suggesting a functional link between the two structures. In the LSOT, our data indicate the involvement of GABAergic mechanisms of the ICv, but not the dPAG, in the modulation of the unconditioned response to light in rats. These original findings presented here contribute to broaden the current knowledge on the neurobiology of fear and anxiety, in an integrative approach of the mechanisms underlying sensory processing and the expression of defensive behaviors.

The midbrain periaqueductal gray matter (PAG) is an important brain region for the coordination of μ-opioid-induced pharmacological actions. The present study was designed to determine whether newly isolated μ-opioid peptide endomorphins can activate G proteins through μ-opioid receptors in the PAG by monitoring the binding to membranes of the non-hydrolyzable analog of GTP, guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPγS). An autoradiographic [35S]GTPγS binding study showed that both endomorphin-1 and -2 produced similar anatomical distributions of activated G proteins in the mouse midbrain region. In the mouse PAG, endomorphin-1 and -2 at concentrations from 0.001 to 10 μM increased [35S]GTPγS binding in a concentration-dependent manner and reached a maximal stimulation of 74.6 ± 3.8 and 72.3 ± 4.0%, respectively, at 10 μM. In contrast, the synthetic selective μ-opioid receptor agonist [D-Ala2,NHPhe4,Gly-ol]enkephalin (DAMGO) had a much greater efficacy and produced a 112.6 ± 5.1% increase of the maximal stimulation. The receptor specificity of endomorphin-stimulated [35S]GTPγS binding was verified by coincubating membranes with endomorphins in the presence of specific μ-, δ- or κ-opioid receptor antagonists. Coincubation with selective μ-opioid receptor antagonists β- funaltrexamine or D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 (CTOP) blocked both endomorphin-1 and-2-stimulated [35S]GTPγS binding. In contrast, neither δ- nor κ-opioid receptor antagonist had any effect on the [35S]GTPγS binding stimulated by either endomorphin-1 or -2. These findings indicate that both endomorphin-1 and -2 increase [35S]GTPγS binding by selectively stimulating μ-opioid receptors with intrinsic activity less than that of DAMGO and suggest that these new endogenous ligands might be partial agonists for μ-opioid receptors in the mouse PAG.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20803号 / 医博第4303号 / 新制||医||1025(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 平井 豊博, 教授 今中 雄一, 教授 伊達 洋至 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

This systematic review aims to investigate the alterations in gray matter volume (GMV) observed in the brains of individuals diagnosed with post-traumatic stress disorder (PTSD) through the Clinical Administered PTSD scale (CAPS) using Voxel-Based Morphometry (VBM) as a method. PTSD is diagnosed when an individual meets all the criteria for PTSD as defined by the DSM, which includes having experienced or witnessed a traumatic event, experiencing intrusive symptoms such as flashbacks or nightmares, avoiding triggers related to the trauma, experiencing negative changes in mood and cognition, and experiencing changes in arousal and reactivity. Previous research investigating gray matter alterations in patients with PTSD has yielded heterogeneous findings. The review incorporates a comprehensive search and analysis of pertinent studies conducted between 1995 and the present. Diverse databases were scrutinized to identify articles that fulfilled the inclusion criteria. Ultimately, a total of seven articles meeting our inclusion criteria were included in this systematic review. The sample sizes ranged from 30 to 75 participants. The control groups in the chosen articles varied, some only had healthy controls (HC), while some had trauma-exposed controls (TC) or included both. The results consistently revealed a reduction in GMV predominantly in the hippocampus, with additional areas exhibiting decreased GMV such as the bilateral hypothalamus and left inferior parietal lobule, right middle temporal gyrus, right inferior temporal gyrus, and right fusiform gyrus, as well as the bilateral calcarine cortex, left dorsal anterior cingulate cortex, left anterior cingulate cortex, and bilateral insula.

No description available.

Alcohol Use Disorder (AUD) is a pervasive and intricate public health challenge, with significant health and psychosocial consequences. Among the most frequently used substances, alcohol provokes diverse neurochemical and neurophysiological changes within the brain and is in long-term excessive use associated with severe cognitive dysfunctions such as memory, decision-making, and problem-solving abilities. This systematic review aims to compare gray matter volume in healthy individuals and those diagnosed with AUD, with the goal of identifying structural differences between the two groups. The six studies, identified from Scopus, Web of Science, and Medline EBSCO, included in this systematic review were written in English, published within the last 20 years, employed magnetic resonance imaging (MRI) to quantify volume, involved human participants over the age of 18, and included both AUD and healthy comparison groups examining gray matter volume differences. The number of participants and gender distribution differed among all the included articles, with two studies exclusively including males. The studies employed either region of interest (ROI) or voxel-based morphometry (VBM) as their analysis method. The results revealed gray matter reductions between individuals with AUD and those without through out the whole brain, both cortical and subcortical, with the most prominent reductions observed in the putamen and thalamus. Future research should consider the limitations presented in this systematic review by conducting longitudinal investigations focusing on gray matter reductions and recovery over extended periods. Such studies could offer deeper insights into how the brain's gray matter volume behaves during longer periods of abstinence among individuals with AUD.