Neuromodulação em esquizofrenia : estimulação elétrica cerebral e neurofeedback hemoencefalográfico
Arquivos
Data
2017-12-01
Autores
Gomes, July Silveira 
Orientadores
Dias, Álvaro Machado
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A esquizofrenia é um transtorno heterogêneo cujos sintomas podem ser distribuídos em 5 fatores: sintomas positivos, sintomas negativos, desorganização, déficits cognitivos e sintomas de humor. Dentre os sintomas refratários incluem-se os sintomas negativos e os déficits cognitivos, que estão associados a prejuízos na funcionalidade e a baixas taxas de superação. O lobo frontal está fortemente implicado nos prejuízos associados ao transtorno e diferenças no funcionamento em diversas regiões do cérebro são observadas entre pessoas com esquizofrenia e controles saudáveis. Até o momento nenhuma medicação é considerada efetiva para o tratamento dos sintomas negativos e déficits cognitivos, abrindo campo para investigações de técnicas não-farmacológicas, como a neuromodulação. Nessa tese, apresento 4 estudos investigando os efeitos de 3 técnicas de neuromodulação em esquizofrenia. OBJETIVOS: Estudo 1 – Analisar os efeitos da estimulação transcraniana por corrente contínua nos sintomas negativos em esquizofrenia; Estudo 2 – Analisar os efeitos da estimulação transcraniana por corrente contínua nos déficits cognitivos (desfecho primário) e sintomas negativos (desfecho secundário) em esquizofrenia; Estudo 3 – Analisar os efeitos da estimulação do nervo trigêmeo na alucinação olfativa em esquizofrenia: estudo de caso; Estudo 4: Analisar os efeitos do treinamento de autorregulação por neurofeedback hemoencefalográfico na cognição e sintomas em esquizofrenia. MÉTODO: Estudo 1: Foram realizadas 10 sessões de estimulação transcraniana por corrente contínua com os seguintes parâmetros: ânodo em F3, cátodo em F4, 2 mA, 20 minutos, eletrodos 25 cm2. Quinze pacientes foram randomizados em 2 grupos (ativo ou placebo) e os sintomas negativos foram avaliados através da PANSS antes e após a estimulação. Estudo 2: Foram usados os mesmos parâmetros de estimulação do estudo 1. Vinte e quatro pacientes foram randomizados em 2 grupos (ativo ou placebo) e avaliados antes, após a estimulação e follow-up de 3 meses utilizando-se subteste de memória de trabalho da Matrics e para sintomas negativos, através da PANSS. Outras medidas neuropsicológicas e dados clínicos foram coletados para análises exploratórias. Estudo 3 – Foram realizadas 10 sessões de estimulação do nervo trigêmeo em 01 paciente com alucinação olfatória. Dados eletroencefalográficos foram coletados antes e ao final da estimulação; Estudo 4: Foram realizadas 10 sessões de treinamento com neurofeedback hemoencefalográfico com 8 pacientes com esquizofrenia e 12 controles saudáveis, em 4 regiões separadamente: F7, Fp1, Fp2 e F8. Realizou-se avaliação cognitiva utilizando a bateria MATRICS e avaliação clínica através da PANSS. RESULTADOS: Estudo 1 – O grupo ativo apresentou redução nos sintomas negativos, com interação tempo*grupo significante (p=0.004). Estudo 2 – não foi observada interação tempo*grupo para memória de trabalho (p = 0.720) nem para as outras variáveis cognitivas (p > 0.05). Observou-se interação tempo*grupo significante para o escore negativo da PANSS (p < 0.001, d = 0.23, CI.95 = -0.59 – 1.02), escore geral (p = 0.011) e PANSS total (p<0.001). A análise exploratória dos 5 fatores da PANSS sugere efeitos para o fator negativo (p = 0.012), cognitivo (p =0.016) e depressão (p = 0.029). Estudo 3 – De acordo com a escala analógica visual, a intensidade da alucinação reduziu de 9.4 para 0.3. A potência de alfa apresentou a maior inibição em PZ, reduzindo de 19.68 µV2 para 8.22 µV2 (t=-11.41, p<0.001). Também observamos redução em beta e aumento em gama em diferentes regiões. Estudo 4 – Observou-se interação tempo*grupo para a perfusão no hemisfério esquerdo (F7 e Fp1) e quase significante na região frontotemporal à direita (F8). A maioria das funções cognitivas avaliadas apresentou melhora após o treinamento em ambos os grupos. CONCLUSÃO: Estudo 1 – O aumento na excitabilidade do córtex pré-frontal dorsolateral esquerdo parece contribuir para a redução dos sintomas negativos em pessoas com esquizofrenia. Estudo 2 – Os resultados sugerem efeitos terapêuticos da estimulação transcraniana por corrente continua em esquizofrenia, com redução dos sintomas negativos. No entanto, não foi possível confirmar a superioridade da estimulação ativa sobre o placebo para melhora da memória de trabalho. Estudo 3 – A melhora clínica da paciente com alucinação olfativa pode estar relacionada com a indução da neuromodulação do nervo trigêmeo, através da regulação cortiço-subcortical, envolvendo o tálamo. Estudo 4 – Esse foi o primeiro estudo demonstrando possíveis efeitos cognitivos do treinamento por neurofeedback hemoencefalográfico em pacientes com esquizofrenia.
Schizophrenia is a heterogeneous disorder with symptoms classified in 5 factors: negative, disorganization/ cognitive, excitement, positive and depressive/ anxiety. Among the refractory symptoms, the negative and cognitive deficits are associated to functionality impairments and low recovery. The frontal lobe is implicated in those deficits and differences on brain functioning are observed in diverse regions, when comparing people with schizophrenia and healthy controls. By now, no pharmacological treatments are recommended for improvement of the negative symptoms neither of the cognitive deficits. On this thesis, I present 4 studies investigating the effects of 3 neuromodulation technique on schizophrenia. OBJECTIVE: Study 1 – to investigate the effects of transcranial direct current stimulation on negative symptoms in schizophrenia. Study 2 - to investigate the effects of transcranial direct current stimulation on working memory (primary outcome and negative symptoms (secondary outcomes) in schizophrenia. Study 3 – to evaluate the effects of trigeminal nerve stimulation on olfactory hallucination of 1 patient with schizophrenia. Study 4 – to evaluate the effects of the self-regulation neurofeedback training based on hemoencephalography on cognition and symptoms in schizophrenia. METHOD: We applied 10 sessions of tDCS in schizophrenia subjects. Stimulation used the following parameters: 2mA, for 20 minutes, with electrodes of 25cm2 wrapped in cotton material soaked in saline solution. Anode at F3 and cathode at F4. Fifteen patients were enrolled in a double-blinded, randomized, sham-controlled clinical trial. Negative symptoms were evaluated using PANSS scale, before and after the stimulation. Study 2 – The same parameters described in study 1 were applied. Twenty-four participants were assessed at baseline, after intervention and in a 3-months follow-up. For assessment, we evaluated the working memory score from MATRICS (primary outcome) and the negative score from PANSS (secondary outcome). Study 3 – We applied 10 sessions of trigeminal nerve stimulation in a patient with olfactory hallucination. Electroencephalographic data were obtained before and after stimulation. Study 4 – Hemoencephalography neurofeedback training were done along 10 session for 8 people with schizophrenia and 12 health controls in 4 brain sites (F7, Fp1, Fp2 and F8). Cognitive performance were assessed using MATRICS and symptoms with PANSS. RESULTS: Study 1 - patients who received active stimulation showed greater reduction on PANSS negative score, compared to controls (p=0.004). Study 2 - We did not find group*time interaction for the working memory (p = 0.720) score or any other cognitive variable (p > 0.05). We found a significant group*time interaction for PANSS negative (p < 0.001, d = 0.23, CI.95 = -0.59 – 1.02), general (p = 0.011) and total scores (p<0.001). Exploratory analysis of PANSS 5 factors suggests tDCS effect on PANSS negative (p = 0.012), cognitive (p =0.016) and depression factors (p = 0.029). Study 3 - According to a visual analog scale rated from 0-10, the hallucinations intensity varied from 9.4 to 0.3. Alpha power showed the greatest reduction at Pz, changing from 19.68 µV2 to 8.22 µV2 (t=-11.41, p<0.001). We also observed reduction in beta in some regions and increasing in gamma powers. Study 4 - We found a group*time interaction for HEG-NFBK performance in the left hemisphere sites (F7 an Fp1) and a near-to-significant in the right frontotemporal region (F8). Most of cognitive domains improved after intervention for both groups. CONCLUSION: Study 1 - Our findings suggest that increases in the excitability at the left dorsolateral prefrontal cortex may contribute to the transient diminishing of negative symptoms, possibly due to regulatory effects on brain circuits related to motivation. Study 2 - The results from this trial highlight the therapeutic effects of tDCS for treatment of persistent symptoms in schizophrenia, with reduction of negative symptoms. We were not able to confirm the superiority of active tDCS over sham to improve working memory performance. Larger sample size studies are needed to confirm these findings. Study 3 – The observed clinical amelioration may relate to TNS-induced cortical-subcortical regulation involving the interaction of the trigeminal nerve and the olfactory related-neurons, which is suggested to occur on the thalamus. Study 4 - To our knowledge, this is the first controlled trial showing effects of NFBK on cognitive performance improvement in schizophrenia. Further research investigating the effects of HEG-NFBK training in schizophrenia should be performed.
Schizophrenia is a heterogeneous disorder with symptoms classified in 5 factors: negative, disorganization/ cognitive, excitement, positive and depressive/ anxiety. Among the refractory symptoms, the negative and cognitive deficits are associated to functionality impairments and low recovery. The frontal lobe is implicated in those deficits and differences on brain functioning are observed in diverse regions, when comparing people with schizophrenia and healthy controls. By now, no pharmacological treatments are recommended for improvement of the negative symptoms neither of the cognitive deficits. On this thesis, I present 4 studies investigating the effects of 3 neuromodulation technique on schizophrenia. OBJECTIVE: Study 1 – to investigate the effects of transcranial direct current stimulation on negative symptoms in schizophrenia. Study 2 - to investigate the effects of transcranial direct current stimulation on working memory (primary outcome and negative symptoms (secondary outcomes) in schizophrenia. Study 3 – to evaluate the effects of trigeminal nerve stimulation on olfactory hallucination of 1 patient with schizophrenia. Study 4 – to evaluate the effects of the self-regulation neurofeedback training based on hemoencephalography on cognition and symptoms in schizophrenia. METHOD: We applied 10 sessions of tDCS in schizophrenia subjects. Stimulation used the following parameters: 2mA, for 20 minutes, with electrodes of 25cm2 wrapped in cotton material soaked in saline solution. Anode at F3 and cathode at F4. Fifteen patients were enrolled in a double-blinded, randomized, sham-controlled clinical trial. Negative symptoms were evaluated using PANSS scale, before and after the stimulation. Study 2 – The same parameters described in study 1 were applied. Twenty-four participants were assessed at baseline, after intervention and in a 3-months follow-up. For assessment, we evaluated the working memory score from MATRICS (primary outcome) and the negative score from PANSS (secondary outcome). Study 3 – We applied 10 sessions of trigeminal nerve stimulation in a patient with olfactory hallucination. Electroencephalographic data were obtained before and after stimulation. Study 4 – Hemoencephalography neurofeedback training were done along 10 session for 8 people with schizophrenia and 12 health controls in 4 brain sites (F7, Fp1, Fp2 and F8). Cognitive performance were assessed using MATRICS and symptoms with PANSS. RESULTS: Study 1 - patients who received active stimulation showed greater reduction on PANSS negative score, compared to controls (p=0.004). Study 2 - We did not find group*time interaction for the working memory (p = 0.720) score or any other cognitive variable (p > 0.05). We found a significant group*time interaction for PANSS negative (p < 0.001, d = 0.23, CI.95 = -0.59 – 1.02), general (p = 0.011) and total scores (p<0.001). Exploratory analysis of PANSS 5 factors suggests tDCS effect on PANSS negative (p = 0.012), cognitive (p =0.016) and depression factors (p = 0.029). Study 3 - According to a visual analog scale rated from 0-10, the hallucinations intensity varied from 9.4 to 0.3. Alpha power showed the greatest reduction at Pz, changing from 19.68 µV2 to 8.22 µV2 (t=-11.41, p<0.001). We also observed reduction in beta in some regions and increasing in gamma powers. Study 4 - We found a group*time interaction for HEG-NFBK performance in the left hemisphere sites (F7 an Fp1) and a near-to-significant in the right frontotemporal region (F8). Most of cognitive domains improved after intervention for both groups. CONCLUSION: Study 1 - Our findings suggest that increases in the excitability at the left dorsolateral prefrontal cortex may contribute to the transient diminishing of negative symptoms, possibly due to regulatory effects on brain circuits related to motivation. Study 2 - The results from this trial highlight the therapeutic effects of tDCS for treatment of persistent symptoms in schizophrenia, with reduction of negative symptoms. We were not able to confirm the superiority of active tDCS over sham to improve working memory performance. Larger sample size studies are needed to confirm these findings. Study 3 – The observed clinical amelioration may relate to TNS-induced cortical-subcortical regulation involving the interaction of the trigeminal nerve and the olfactory related-neurons, which is suggested to occur on the thalamus. Study 4 - To our knowledge, this is the first controlled trial showing effects of NFBK on cognitive performance improvement in schizophrenia. Further research investigating the effects of HEG-NFBK training in schizophrenia should be performed.
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Citação
GOMES, July Silveira. Neuromodulação em esquizofrenia : estimulação elétrica cerebral e neurofeedback hemoencefalográfico. 2017. São Paulo. Tese (Doutorado em Psiquiatria e psicologia médica) - Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, 2017