An epidemiological shift towards the elderly population has occurred in traumatic brain injury (TBI). Age is believed to be one of the strongest prognostic indicators following TBI. Diffuse axonal injury (DAI), a prevalent feature of TBI, is believed to be the primary cause for much of the morbidity and mortality associated with TBI. The pathobiology associated with DAI is believed to occur in response to the primary injury in a progressive, secondary fashion. Though the injury mechanisms behind DAI have been shown to occur at numerous sites along the axon, recent work suggests that the axon initial segment (AIS) may show specific vulnerability to DAI and be the primary site of axonal pathobiogenesis. Despite its established predilection for injury, the mechanisms responsible for the pathobiology remain largely unclear – particularly with regard to the age. The current study aims to shed light on the mechanisms responsible for injury by investigating structural alterations to the AIS following DAI in young and old mice. To address this question we have used a central fluid percussion injury (cFPI) model to induce mild DAI on 22-month old aged mice and 3-month old young mice at 3-hours and 24-hours survival time. Double-labeling fluorescent immunohistochemistry was used to demonstrate colocalization of ankG, an AIS domain marker, and APP, a marker used to establish traumatic axonal injury (TAI). Qualitative-quantitative observations based on confocal microscopy demonstrated an increase in APP accumulation associated with AIS over time, post-injury. Initial segments displaying APP association consistently showed a significant overall shortening in young and aged groups at both survival times. No significant difference in AIS length was detected between AIS populations of young and aged mice. Qualitative findings, however, suggest that AIS degradation could be more profound with age, which could have implications on neuronal outcome.

Traumatic axonal injury (TAI) is a consistent feature of (TBI) and is responsible for much of its associated morbidity. TAI is now recognized to result from progressive/secondary axonal injury, though much remains unknown in regards to the pathobiology and the long-term consequences of axonal injury. TAI has been described in the perisomatic domain, located within the neocortex following mild TBI, and within this domain has been linked to neuronal recovery, not neuronal cell death in the acute setting. Due to technical limitations, our understanding of the long-term fate of this neuronal population and the mechanisms responsible for permitting neuronal survival, recovery and axon regeneration following injury are unknown. The studies presented in this thesis are centered upon the hypothesis that injury within the perisomatic domain is unique, and may allow for enhanced neuronal recovery and axonal regeneration. To address many of these questions, we have utilized a novel model of diffuse brain injury in mice, allowing for the use of transgenic mice to overcome previous limitations in the study of TAI. To address this hypothesis, we first assessed the impact of genetic deletion of cyclophilin D (CypD), a regulator of the mitochondrial permeability transition pore (mPTP), upon TAI within the perisomatic domain. Via this approach it was determined that CypD deletion reduced the number of injured axons by ~50%, indicating that CypD and mPTP formation contribute to TAI in the perisomatic domain. Next, using a fluorescent-based approach, we assessed the temporospatial events associated with TAI, acutely. Here it was determined that the axon initial segment (AIS) is uniquely susceptible to TAI following mild TBI (mTBI) and injury within this domain progresses rapidly to axon disconnection. Last we assessed the long-term fate of axotomized neurons and their associated axonal processes. We report that over a chronic time frame, TAI induces no overt cell death, instead results in significant neuronal atrophy with the simultaneous activation of a somatic program of axon regeneration and recovery of the remaining axonal processes. Taken together, the findings of this work reveal that TAI results in a unique axonal injury that results in a persistent axon regenerative attempt.

National concern over traumatic brain injury (TBI) is growing rapidly. Recent focus is on mild TBI (mTBI), which is the most prevalent injury level in both civilian and military demographics. A preeminent sequelae of mTBI is cognitive network disruption. Advanced neuroimaging of mTBI victims supports this premise, revealing alterations in activation and structure-function of excitatory and inhibitory neuronal systems, which are essential for network processing. However, clinical neuroimaging cannot resolve the cellular and molecular substrates underlying such changes. Therefore, to understand the full scope of mTBI-induced alterations it is necessary to study cortical networks on the microscopic level, where neurons form local networks that are the fundamental computational modules supporting cognition. Recently, in a well-controlled animal model of mTBI, we demonstrated in the excitatory pyramidal neuron system, isolated diffuse axonal injury (DAI), in concert with electrophysiological abnormalities in nearby intact (non-DAI) neurons. These findings were consistent with altered axon initial segment (AIS) intrinsic activity functionally associated with structural plasticity, and/or disturbances in extrinsic systems related to parvalbumin (PV)-expressing interneurons that form GABAergic synapses along the pyramidal neuron perisomatic/AIS domains. The AIS and perisomatic GABAergic synapses are domains critical for regulating neuronal activity and E-I balance. In this dissertation, we focus on the neocortical excitatory pyramidal neuron/inhibitory PV+ interneuron local network following mTBI. Our central hypothesis is that mTBI disrupts neuronal network structure and function causing imbalance of excitatory and inhibitory systems. To address this hypothesis we exploited transgenic and cre/lox mouse models of mTBI, employing approaches that couple state-of-the-art bioimaging with electrophysiology to determine the structural- functional alterations of excitatory and inhibitory systems in the neocortex.

O traumatismo craniencefálico (TCE) fechado é, classicamente, um modelo de lesão neuronal e axonal monofásica, onde a destruição do parênquima, incluindo neurônios e células gliais, ocorre principalmente no momento do trauma, seguida pela degeneração Walleriana anterógrada e retrógrada nos dias subseqüentes. Há evidências de progressão da perda neuronal e axonal na fase tardia após o trauma, observada principalmente pela evolução da atrofia cerebral, secundária a vários fatores, incluindo a apoptose neuronal. Com o objetivo de testar a hipótese de que as técnicas quantitativas em ressonância magnética (RM) permitem identificar, de modo não invasivo, as variáveis biológicas que estimam a perda neuronal e axonal no cérebro relacionadas ao TCE moderado e grave e à lesão axonal difusa, na fase tardia, foram avaliados 9 pacientes, sendo 5 do sexo masculino e 4 do sexo feminino, com idades variando de 11 a 28 anos (média de 21,1 anos), que foram vítimas de TCE moderado ou grave (Escala de Coma de Glasgow menor que 12 na admissão hospitalar após o TCE) e que tiveram boa recuperação. O tempo médio entre o trauma e o exame de ressonância magnética foi de 3,1 anos (± 0,5 anos). Foram utilizados os índices ventrículo-cerebrais bifrontal (IVCF) e bicaudado (IVCC), a medida do tempo de relaxação T2, o índice de transferência de magnetização (MTR), o coeficiente de difusão aparente (ADC) e a espectroscopia de prótons multi-voxel, com o cálculo dos índices metabólicos N-acetilaspartato/creatina (NAA/Cre) e colina/creatina (Cho/Cre). Foram estudados a substância branca (SB) frontal e parietal bilateralmente, o joelho e o esplênio do corpo caloso (CC) e a substância cinzenta (SC). As médias dos valores medidos foram comparadas às de um grupo controle formado por 9 pessoas sadias, pareadas pela idade e sexo. Observou-se aumento estatisticamente significativo (p ≤ 0,05) do IVCF e do IVCC nos pacientes, devido ao aumento ventricular secundário à atrofia subcortical; aumento no tempo de relaxação T2 na SB e no CC, que reflete o aumento da concentração de água por provável perda axonal e gliose; aumento do ADC e redução do MTR na SB e no CC, que demonstram lesão das fibras axonais mielinizadas, e redução do índice NAA/Cre no CC, indicando perda axonal. Não houve diferença estatisticamente significativa nas medidas realizadas na SC e nem no índice Cho/Cre (p › 0,05). Os resultados encontrados mostram que as técnicas quantitativas em RM foram capazes de detectar, de modo não invasivo, o dano neuronal e axonal na substância branca e no corpo caloso de cérebros humanos, secundário ao TCE moderado e grave. / Closed traumatic brain injury (TBI) is a classic model of monophasic neuronal and axonal injury, where tissue damage mainly occurs at the moment of trauma, followed by anterograde and retrograde Wallerian degeneration in the subsequent days. There are some evidences of delayed progression of the neuronal and axonal loss after TBI, mainly shown by gradual development of cerebral atrophy, due to many factors, including neuronal apoptosis. For the purpose of testing the hypothesis that quantitative magnetic resonance techniques are able to assess the biological variables which estimate neuronal and axonal loss in brain, related to moderate or severe TBI and diffuse axonal injury, nine patients (age range 11 – 28 years; mean age 21,1 years; 5 male and 4 female), who sustained a moderate or severe TBI (initial Glasgow Coma Scale less than 12), with good recovery, were evaluated in a mean of 3,1 years after trauma (± 0,5 year). The following techniques were applied: bicaudate (CVIC) and bifrontal (CVIF) cerebroventricular indexes; T2 relaxation time measurement (T2 relaxometry); magnetization transfer ratio (MTR); apparent diffusion coefficient (ADC); multivoxel proton magnetic resonance spectroscopy, using N-acetylaspartate/creatine (NAA/Cre) and choline/creatine (Cho/Cre) ratios; measured in the frontal and parietal white matter (WM) of both cerebral hemispheres, in the genu and splenium of the corpus callosum (CC) and in the gray matter (GM). The results were compared with those of a control group constituted by 9 healthy volunteers with a matched age and sex distribution. The CVIC and CVIF mean values were significantly increased (p ≤ 0,05) in patients due to ventricular enlargement secondary to subcortical atrophy; an increase in T2 relaxation time was observed in the WM and CC, reflecting an enhancement in water concentration, probably secondary to axonal loss and gliosis; increased ADC mean values and reduced MTR mean values were found in the WM and CC, showing damage in the myelinated axonal fibers; and decreased NAA/Cre ratio mean values in the CC, indicating axonal loss. No significant differences were observed in the mean values measured at the GM or in the Cho/Cre ratio mean values (p › 0,05). These quantitative magnetic resonance techniques were able to non-invasively demonstrate the neuronal and axonal damage in the WM and CC of human brains, secondary to moderate or severe TBI.

O traumatismo craniencefálico (TCE) fechado é, classicamente, um modelo de lesão neuronal e axonal monofásica, onde a destruição do parênquima, incluindo neurônios e células gliais, ocorre principalmente no momento do trauma, seguida pela degeneração Walleriana anterógrada e retrógrada nos dias subseqüentes. Há evidências de progressão da perda neuronal e axonal na fase tardia após o trauma, observada principalmente pela evolução da atrofia cerebral, secundária a vários fatores, incluindo a apoptose neuronal. Com o objetivo de testar a hipótese de que as técnicas quantitativas em ressonância magnética (RM) permitem identificar, de modo não invasivo, as variáveis biológicas que estimam a perda neuronal e axonal no cérebro relacionadas ao TCE moderado e grave e à lesão axonal difusa, na fase tardia, foram avaliados 9 pacientes, sendo 5 do sexo masculino e 4 do sexo feminino, com idades variando de 11 a 28 anos (média de 21,1 anos), que foram vítimas de TCE moderado ou grave (Escala de Coma de Glasgow menor que 12 na admissão hospitalar após o TCE) e que tiveram boa recuperação. O tempo médio entre o trauma e o exame de ressonância magnética foi de 3,1 anos (± 0,5 anos). Foram utilizados os índices ventrículo-cerebrais bifrontal (IVCF) e bicaudado (IVCC), a medida do tempo de relaxação T2, o índice de transferência de magnetização (MTR), o coeficiente de difusão aparente (ADC) e a espectroscopia de prótons multi-voxel, com o cálculo dos índices metabólicos N-acetilaspartato/creatina (NAA/Cre) e colina/creatina (Cho/Cre). Foram estudados a substância branca (SB) frontal e parietal bilateralmente, o joelho e o esplênio do corpo caloso (CC) e a substância cinzenta (SC). As médias dos valores medidos foram comparadas às de um grupo controle formado por 9 pessoas sadias, pareadas pela idade e sexo. Observou-se aumento estatisticamente significativo (p ≤ 0,05) do IVCF e do IVCC nos pacientes, devido ao aumento ventricular secundário à atrofia subcortical; aumento no tempo de relaxação T2 na SB e no CC, que reflete o aumento da concentração de água por provável perda axonal e gliose; aumento do ADC e redução do MTR na SB e no CC, que demonstram lesão das fibras axonais mielinizadas, e redução do índice NAA/Cre no CC, indicando perda axonal. Não houve diferença estatisticamente significativa nas medidas realizadas na SC e nem no índice Cho/Cre (p › 0,05). Os resultados encontrados mostram que as técnicas quantitativas em RM foram capazes de detectar, de modo não invasivo, o dano neuronal e axonal na substância branca e no corpo caloso de cérebros humanos, secundário ao TCE moderado e grave. / Closed traumatic brain injury (TBI) is a classic model of monophasic neuronal and axonal injury, where tissue damage mainly occurs at the moment of trauma, followed by anterograde and retrograde Wallerian degeneration in the subsequent days. There are some evidences of delayed progression of the neuronal and axonal loss after TBI, mainly shown by gradual development of cerebral atrophy, due to many factors, including neuronal apoptosis. For the purpose of testing the hypothesis that quantitative magnetic resonance techniques are able to assess the biological variables which estimate neuronal and axonal loss in brain, related to moderate or severe TBI and diffuse axonal injury, nine patients (age range 11 – 28 years; mean age 21,1 years; 5 male and 4 female), who sustained a moderate or severe TBI (initial Glasgow Coma Scale less than 12), with good recovery, were evaluated in a mean of 3,1 years after trauma (± 0,5 year). The following techniques were applied: bicaudate (CVIC) and bifrontal (CVIF) cerebroventricular indexes; T2 relaxation time measurement (T2 relaxometry); magnetization transfer ratio (MTR); apparent diffusion coefficient (ADC); multivoxel proton magnetic resonance spectroscopy, using N-acetylaspartate/creatine (NAA/Cre) and choline/creatine (Cho/Cre) ratios; measured in the frontal and parietal white matter (WM) of both cerebral hemispheres, in the genu and splenium of the corpus callosum (CC) and in the gray matter (GM). The results were compared with those of a control group constituted by 9 healthy volunteers with a matched age and sex distribution. The CVIC and CVIF mean values were significantly increased (p ≤ 0,05) in patients due to ventricular enlargement secondary to subcortical atrophy; an increase in T2 relaxation time was observed in the WM and CC, reflecting an enhancement in water concentration, probably secondary to axonal loss and gliosis; increased ADC mean values and reduced MTR mean values were found in the WM and CC, showing damage in the myelinated axonal fibers; and decreased NAA/Cre ratio mean values in the CC, indicating axonal loss. No significant differences were observed in the mean values measured at the GM or in the Cho/Cre ratio mean values (p › 0,05). These quantitative magnetic resonance techniques were able to non-invasively demonstrate the neuronal and axonal damage in the WM and CC of human brains, secondary to moderate or severe TBI.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24797号 / 医博第4989号 / 新制||医||1066(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 花川 隆, 教授 髙橋 良輔, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Traumatic brain injury is a topic that in recent years has received increased scrutiny by the media and is viewed as a cause for public health concern in athletes that are participating in contact sports. There has been an apparent rise in the reported number of traumatic brain injuries over the last decade possibly due to a number of factors such as an increase in enrollment of sports and suspected better understanding of brain injury in the sports world. Direct or indirect impact forces applied involving acceleration/deceleration and linear/angular forces primarily cause trauma to the brain. This insult results in evident diffuse axonal and focal injuries to varying degrees in brain tissue. The spectrum of pathophysiology in traumatic brain injury involves structural, neurochemical, metabolic, vascular, inflammatory, immunologic, and ultimately cell death, which plays a hand directly in the nonspecific presentation of symptoms reported by athletes as well as the progression of recovery. Traumatic brain injury is typically associated with short- and long-term sequelae, however, inducing repetitive episodes of trauma over a career, as may happen in sports, may lead to a progressive neurodegenerative disease known as chronic traumatic encephalopathy. Chronic traumatic encephalopathy has been known to affect boxers previously, but in recent years the attention has shifted and found this disease in athletes from other sports. The spectrum of disease in chronic traumatic encephalopathy involves a progressive tauopathy that spreads across different regions of the brain in a classified four staged grading system. Several risk factors have been identified in placing athletes at risk for traumatic brain episodes, however no risk factors have been directly linked to chronic traumatic encephalopathy. Much information is lacking in a complete understanding of traumatic brain injury and chronic traumatic encephalopathy, therefore emphasizing the importance of further research and consistently improving modifications in the protocols for assessment, recognition, management, and return to play criteria for injured athletes. Furthermore, despite the gaps in knowledge, preventative measures should serve a particular role in reducing the incidence of detected traumatic brain injuries, which should include policy changes, sport rule changes, and especially changes to the accepted sports culture through mandatory education.

INTRODUÇÃO: O comprometimento cognitivo observado na lesão axonial difusa (LAD) é considerado uma das mais debilitantes sequelas neurológicas nesta população. A estimulação magnética transcraniana (EMT), uma técnica de estimulação encefálica não-invasiva, tem sido utilizada com sucesso no tratamento de doenças neuropsiquiátricas. Os resultados pouco satisfatórios dos tratamentos convencionais dos distúrbios cognitivos vistos no traumatismo cranioencefálico (TCE) motivaram a investigação por novas estratégias terapêuticas, dentre elas a EMT. Entretanto, até o presente momento, não há estudos Sham-controlados investigando os efeitos cognitivos induzidos pela EMT nessa população. Assim, o presente estudo avaliou a segurança, tolerabilidade e eficácia da EMT na reabilitação cognitiva de pacientes com LAD crônica. MÉTODOS: Trata-se de um ensaio clínico prospectivo aleatorizado, duplamente encoberto, que incluiu 37 participantes com o diagnóstico de LAD crônica, em dois grupos de intervenção: Ativo e Sham. A EMT repetitiva (EMTr) de alta frequência (10 Hz) foi aplicada no córtex pré-frontal dorsolateral (CPFDL) esquerdo em um total de 10 sessões, com intensidade de 110% do limiar motor de repouso. Todos os participantes realizaram avaliação neuropsicológica (ANP), composta por sete testes neuropsicológicos [1: TMT Partes A e B; 2: Brief Visuospatial Memory Test (BVMT); 3: Hopkins Verbal Learning Test (HVLT); 4: Grooved Pegboard Test; 5: teste de Fluência Verbal semântica e fonêmica; 6: teste dos Dígitos e 7: teste dos Cinco Pontos], e avaliação da excitabilidade cortical (AEC), por meio da EMT de pulsos simples e pareados, ambas realizadas em três momentos distintos: antes da intervenção (E1 - pré-intervenção), até uma semana (E2 - pós-intervenção precoce) e 90 dias (E3 - pós-intervenção tardio) após o término da EMTr. O participante desconhecia em qual grupo de intervenção havia sido alocado, assim como o avaliador que realizou as ANPs. A medida de desfecho primário foi o escore no Trail Making Test (TMT) Parte B, um teste robusto que avalia funções executivas e atenção. RESULTADOS: Trinta participantes foram submetidos à EMTr e concluíram o seguimento, sendo 17 deles presentes no grupo Ativo e 13 no grupo Sham. Os dados demográficos pesquisados na linha de base, bem como os escores da ANP e valores aferidos na AEC, não foram diferentes entre os grupos. Com relação à performance no TMT Parte B, os tempos medianos aferidos no grupo Ativo foram 141 (100 - 209,5), 85 (67 - 274) e 161 (73 - 223) segundos nos momentos E1, E2 e E3, respectivamente, enquanto que no grupo Sham foram 97 (83 - 269), 70 (60 - 212) e 96 (59,5 - 171,5) segundos. Não houve interação tempo x grupo significativa entre as condições testadas (Ativo vs. Sham) durante os três momentos de avaliação (análise de variância ANOVA; P = 0,450), denotando não ter havido diferença no desempenho do TMT Parte B antes e após o tratamento. Consoante aos resultados do TMT Parte B, as pontuações obtidas nos outros testes incluídos na ANP não demonstraram diferenças em relação aos grupos de intervenção. Não foram observadas mudanças significativas, ou interação entre os grupos nos parâmetros avaliados na AEC. Em uma análise exploratória, observou-se alteração da inibição intracortical de intervalo curto, um dos parâmetros medidos na AEC, na linha de base do estudo em comparação com dados disponíveis na literatura em indivíduos saudáveis, sugerindo a existência de um comprometimento de circuitos corticais inibitórios nos pacientes com LAD crônica. CONCLUSÃO: Apesar de a EMT repetitiva de alta frequência no CPFDL esquerdo ter sido segura e relativamente bem tolerada, os achados deste estudo não forneceram evidências de efeito terapêutico cognitivo desta técnica em pacientes com LAD crônica. A AEC na linha de base demonstrou a presença de alteração da inibição cortical, o que amplia o conhecimento sobre os processos neurofisiológicos envolvidos neste tipo de lesão encefálica. Registro do ensaio clínico no Clinicaltrials.gov - NCT02167971 / INTRODUCTION: Cognitive impairment typically observed in diffuse axonal injury (DAI) is considered one of the main causes of disability in this population. Transcranial magnetic stimulation (TMS), a noninvasive brain stimulation technique, has been successfully used in the treatment of various neuropsychiatric disorders. The mixed results of the conventional treatments used for cognitive rehabilitation motivated the investigation of new therapeutic strategies, such as TMS. However, to the best of our knowledge, there are no sham-controlled studies addressing the cognitive effects induced by TMS in these victims. Thus, the present study aimed to evaluate the safety, tolerability and efficacy of TMS for cognitive rehabilitation in chronic DAI. METHODS: This is a prospective double-blind clinical trial that randomly included 37 participants with the diagnosis of chronic DAI in two intervention groups: Active and Sham. High frequency (10 Hz) repetitive TMS (rTMS) was applied over the left dorsolateral prefrontal cortex (DLPFC) in a total of ten sessions, at 110% intensity of the resting motor threshold. All participants underwent neuropsychological evaluation (NPE) that included 7 different neuropsychological tests [1: TMT Parts A and B; 2: Brief Visuospatial Memory Test (BVMT); 3: Hopkins Verbal Learning Test (HVLT); 4: Grooved Pegboard Test, 5: Controlled Oral Word Association Test; 6: Digit Span Test e 7: Five-Point Test], and cortical excitability assessment (CEA) with single and paired-pulse TMS, both performed at three different times: before the intervention (E1 - preintervention) , up to one week (E2 - early post-intervention) and 90 days (E3 - late post-intervention) after rTMS completion. The participant was unaware of which intervention group had been allocated, as well as the evaluator who carried out the NPEs. The primary outcome measure was the Trail Making Test (TMT) Part B, a robust test that assesses executive functions and attention. RESULTS: Thirty participants underwent rTMS and completed follow-up, 17 of them in the Active group and 13 in the Sham group. The demographic data at the baseline (E1), as well as the NPE scores and CEA values were not different between the groups. Regarding the performance in TMT Part B, the median times measured in the Active group were 141 (100 - 209.5), 85 (67 - 274) and 161 (73 - 223) seconds at evaluations E1, E2 and E3 respectively, while in the Sham group the values were 97 (83 - 269), 70 (60 - 212) and 96 (59.5 - 171.5) seconds. There was no significant interaction between the conditions tested (Active vs Sham) during the three assessments (analysis of variance ANOVA; P = 0.450), indicating that there was no difference in the performance of TMT Part B before and after treatment. As observed in the TMT Part B, no significant differences between the groups were seen in other tests included in NPE. Regarding the CEA, the parameters evaluated showed no time x group interaction. An exploratory analysis at the baseline of the study revealed alteration of short interval intracortical inhibition, one of the variables measured in CEA, when compared with data available in the literature in healthy individuals, suggesting impairment of cortical inhibitory circuits in patients with chronic LAD. CONCLUSION: rTMS was safe and well tolerated in this study. Findings did not provide evidence of therapeutic effect of 10 Hz rTMS over the left DLPFC for cognitive rehabilitation in chronic DAI. Alteration of short interval intracortical inhibition was demonstrated in this population, which expands knowledge about the neurophysiological processes involved in this type of brain injury

Introdução: Entre as lesões encefálicas adquiridas (LEAs) causadas por processos degenerativos, destaca-se a doença de Alzheimer (DA), que é uma demência que acomete uma grande parcela da população idosa e caracteriza-se pela presença de emaranhados neurofibrilares e placas senis. Exames de ressonância magnética (RM) mostram atrofia do córtex entorrinal, hipocampo, amígdala e da região para-hipocampal. Já a tomografia por emissão de pósitrons (PET) aponta redução do metabolismo cerebral de glicose em regiões como o lobo temporal e cíngulo posterior. O alentecimento do eletroencefalograma (EEG) pelo aumento das ondas teta e a diminuição da frequência alfa são mais evidentes em indivíduos com algum tipo de lesão encefálica. O traumatismo cranioencefálico (TCE) caracteriza-se por ser uma LEA não degenerativa e não congênita e é provocado por uma força mecânica externa. Espera-se um prejuízo, permanente ou temporário, nas funções cognitiva, física e psicossocial, com diminuição ou alteração do estado de consciência. Uma das principais causas de TCE é a lesão axonial difusa (LAD), causada por mecanismos de aceleração-desaceleração. Frequentemente as regiões ventral e lateral dos lobos frontal e temporal são danificadas. Objetivo: Entender as diferenças dos mecanismos funcionais entre os grupos - DA e LAD - com queixa de memória, sob o ponto de vista eletroencefalográfico. Métodos: Participaram deste estudo 85 indivíduos adultos. Destes, 34 haviam recebido o diagnóstico de DA, 32 de LAD e 19 eram adultos saudáveis. Foram aplicados o Mini-Exame do Estado Mental (MEEM), o teste do desenho do relógio (TDR) e o teste de fluência verbal (FV) para a categoria animais. Os indivíduos foram submetidos ao EEG de alta resolução com 128 canais. As fontes corticais dos ritmos do EEG foram estimadas pela análise por tomografia eletromagnética exata de baixa resolução (eLORETA). Resultados: Observou-se que a média da frequência registrada no EEG está dentro da normalidade nos grupos DA e LAD. A análise por eLORETA mostrou que, em comparação ao grupo controle (CTL), o grupo DA apresentou aumento da atividade teta nos lobos parietal e frontal e diminuição da atividade alfa 2 nos lobos parietal, frontal, límbico e occipital. Em comparação ao grupo CTL, o grupo LAD apresentou aumento da atividade teta nas áreas límbica, occipital sub-lobar e temporal. Conclusão: Os resultados sugerem que os indivíduos com DA e com LAD apresentam comprometimento da atividade elétrica em áreas importantes para a memória e aprendizagem / Introduction: Acquired brain injuries (ABI) caused by degenerative processes include Alzheimer\'s disease (DA), which is a dementia that affects a large part of the elderly population and is characterized by the presence of neurofibrillary tangles and senile plaques. Magnetic resonance (MR) imaging shows atrophy of the entorhinal cortex, hippocampus, amygdala and para-hippocampal area. Positron emission tomography (PET) points to a reduction in the cerebral metabolism of glucose in regions such as the temporal lobe and posterior cingulate. Traumatic brain injury (TBI) is a non-degenerative and non-congenital ABI and is caused by an external mechanical force. Impairment, permanent or temporary, is expected in cognitive, physical and psychosocial functions, with a decrease or alteration of the state of consciousness. One of the main causes of TBI is diffuse axonal injury (DAI), caused by acceleration-deceleration mechanisms. Often the ventral and lateral regions of the frontal and temporal lobes are damaged. Objective: To understand the differences in the functional mechanisms between the AD and DAI groups - with memory complaints, from the electroencephalographic point of view. Methods: The study included 85 adult subjects. Of these, 34 had received the diagnosis of AD, 32 of DAI and 19 were healthy adults. The Mini-Mental State Examination (MMSE), the clock drawing test (CDT) and the verbal fluency test (VF) for the animals category were applied. Subjects were submitted to high resolution EEG with 128 channels. Cortical sources of EEG rhythms were estimated by exact low resolution electromagnetic tomography (eLORETA) analysis. Results: The eLORETA analysis showed that, in comparison to the control (CTL) group, the AD group presented increased theta activity in the parietal and frontal lobes and decreased alpha 2 activity in the parietal, frontal, limbic and occipital lobes. In comparison to the CTL group, the DAI group presented increased theta activity in the limbic, occipital sublobar and temporal areas. Conclusion: The results suggest that individuals with AD and DAI have impairment of electrical activity in areas important for memory and learning

Introdução: A lesão axonial difusa (LAD) se destaca entre os ferimentos traumáticos pela gravidade de suas consequências. Entretanto, são poucas as pesquisas que descrevem a recuperação das vítimas e os fatores associados às consequências dessa lesão. Ampliar o conhecimento nessa área e relevante para introduzir novas técnicas na assistência prestada, planejar tratamentos e monitorar a evolução das vítimas. Objetivo: Descrever a recuperação das vítimas com diagnóstico principal de LAD ate 6 meses após trauma e identificar fatores sociodemograficos e clínicos associados a óbito e dependência aos 6 meses após a lesão. Método: Estudo do tipo coorte prospectivo, com dados coletados na internação, alta hospitalar, 3 e 6 meses após a LAD. Fizeram parte do estudo vítimas de LAD com idade 18 anos e 60 anos, admitidas no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo no período de julho de 2013 a fevereiro de 2014, com escore na escala de coma de Glasgow (ECGl) 8. A recuperação das vítimas de LAD foi analisada pelas diferenças dos resultados da aplicação da escala de Katz e escala de resultados de Glasgow ampliada (ERGA) em 3 períodos de avaliação (alta, 3 e 6 meses após LAD). Foram testadas associações entre variáveis de interesse e óbito, além de dependência até avaliação final. A regressão logística múltipla foi utilizada para identificar modelos para esses desfechos. Resultados: A casuística compôs-se de 78 vítimas com idade média de 32 anos (dp=11,9), 83,3% envolvida em acidentes de transporte e 89,7% do sexo masculino. A média do Injury Severity Score foi de 35,0 (dp=11,9) e do New Injury Severity Score (NISS), 46,2 (dp=15,9). Para a Maximum Abbreviated Injury Scale/cabeça, a média foi de 4,6 (dp=0,5). LAD leve foi observada em 44,9% das vítimas e a grave em 35,9%. Até 6 meses, 30,8% das vítimas foram a óbito e a pontuação média na ERGA dos sobreviventes evoluiu de 3,8 (dp=1,2) na alta para 2,1 (dp=1,6) aos 3 meses e 1,2 (dp=1,6) na avaliação final. Para a escala de Katz, as médias foram de 8,5 (dp=5,5) na alta, de 3,2 (dp= 5,5) aos 3 meses e 1,8 (dp=4,5) aos 6 meses. Diferenças estatisticamente significativas foram observadas na comparação dos resultados de todos os tempos. Apresentaram significância estatística no modelo de regressão logística para óbito as variáveis de gravidade da LAD com hipóxia pela SpO2 e hipotensão com NISS; para dependência, a gravidade da LAD e tempo de internação hospitalar permaneceram no modelo isoladamente. Conclusões: Foi elevada a mortalidade; entretanto, a grande maioria dos sobreviventes alcançou condições condizentes com vida independente aos 6 meses. Nesse período, a recuperação das vítimas foi expressiva, ainda que mais acentuada nos 3 primeiros meses. A LAD grave destacou-se como fator de risco para óbito e dependência. A quase totalidade das vítimas com essa lesão morreu ou estava dependente aos 6 meses após trauma. Como fatores de risco para óbito, também foram identificados o NISS, a hipóxia pela SpO2 e a hipotensão e, para dependência, o tempo de internação hospitalar / Introduction: Diffuse axonal injury (DAI) stands out from other traumatic injuries because of the severity of its consequences. However, few studies describe outcome and the factors associated to outcome of this type of injury. Enhance knowledge in this area is important to introduce new techniques in the delivery of care, treatment planning and to monitor the recovery of DAI. Objective: Describe outcome of victims with primary diagnosis of DAI 6 months after trauma and identify sociodemographic and clinical factors associated to mortality and dependence 6 months after injury. Method: Prospective cohort study with data from admission, discharge, 3 and 6 months after DAI. Participants were DAI victims aged 18 years and 60 years old, admitted to the Hospital das Clínicas da Universidade de São Paulo from July 2013 to February 2014, with a Glasgow Coma Scale (GCS) 8. The outcome of victims was analyzed by the differences found between the results of the Katz scale and the Extended Glasgow Outcome scale (GOS-E) in three different periods (discharge, 3 and 6 months after DAI). Associations between variables of interest and mortality, and dependence to final evaluation were tested. Multiple logistic regression was applied to identify models of these outcomes. Results: The sample consisted of 78 victims with an average age of 32 years (SD=11.9), 83.3% involved in traffic accidents, and 89.7% were male. The mean Injury Severity Score was 35.0 (SD=11.9) and the New Injury Severity Score (NISS) was 46.2 (SD=15.9). For the Maximum Abbreviated Injury Scale/head, the average was 4.6 (SD=0.5). Mild DAI was observed in 44.9% of the victims and severe DAI was observed in 35.9%. Up to 6 months, 30.8% of the victims died and the average score in GOS-E survivors increased from 3.8 (SD=1.2) at discharge to 2.1 (SD=1.6) at 3 months and 1.2 (SD=1.6) at the final evaluation. According to Katz scale, the average was 8.5 (SD=5.5) at discharge, 3.2 (SD=5.5) at 3 months and 1.8 (SD=4.5) at 6 months. Statistically significant differences were observed comparing the results from all periods. In the regression model for mortality the variables of DAI severity with hypoxia by SpO2 and hypotension with NISS were statistically relevant; for dependence, the DAI severity and the hospitalization period remained in the model alone. Conclusions: Besides the high mortality, the vast majority of survivors reached conditions consistent with independent living at 6 months after injury. During this period, the recovery of victims was increased, although more pronounced in the first 3 months. Severe DAI stood out as a risk factor for mortality and dependence. Almost all the victims died or were dependent six months after trauma. NISS, hypoxia by SpO2 and hypotension were also identified as risk factors related to mortality; the length of hospitalization was identified as a risk factor related to dependence on outcome