Electroconvulsive therapy (ECT) is one of the oldest and most effective treatments for depression; however, its biological underpinnings are poorly understood. Brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis are two chemical messenger systems implicated in the antidepressant action and cognitive side effects of ECT. The Wistar-Kyoto (WKY) strain is a genetic model of depression that shows biological, cognitive, behavioural, and treatment-response abnormalities, making it potentially a useful model in which to investigate the underpinnings of the action of electroconvulsive stimulus (ECS: the amimal model of ECT). In addition, the WKY presents a potentially useful model for translational research on depression. The WKY strain is particularly valuable for the measurement of serum BDNF protein, for which the association with antidepressant treatments is much less clear (mostly stemming from investigations in humans) than that between brain BDNF and antidepressant treatments in rodent studies. The three studies presented add insight into the biological and behavioural effects of ECS. The first study (chapter 2) found no evidence of increased (R)-[11C]rolipram binding (an indirect marker of cyclic-adenosine monophosphate, cAMP) in the brain, despite significant increases of brain BDNF protein expression after repeated ECS. The second study (chapter 3) demonstrated the validity of the WKY strain in the investigation of ECS. Relative to Wistar controls, WKY showed similar antidepressant and cognitive effects (despite some abnormal behavioural responses), immediate but not sustained increases in brain BDNF protein, and a novel finding of increased extra-hypothalamic CRF after 5 daily ECS. The final study (chapter 4) demonstrated baseline strain differences in serum (WKY < Wistar) but not brain BDNF and, in both strains, no change in serum BDNF despite significant changes in brain BDNF after repeated ECS treatment. Preliminary results from a human pilot study investigating similar measures in a small group of people receiving ECT for depression are also presented. The results of this body of work advance our understanding of the activation and role of brain and serum measures of BDNF and the HPA axis in ECS/ECT, and raise important issues in the translation of research from basic science to the human condition of depression.

Electroconvulsive therapy (ECT) is one of the oldest and most effective treatments for depression; however, its biological underpinnings are poorly understood. Brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis are two chemical messenger systems implicated in the antidepressant action and cognitive side effects of ECT. The Wistar-Kyoto (WKY) strain is a genetic model of depression that shows biological, cognitive, behavioural, and treatment-response abnormalities, making it potentially a useful model in which to investigate the underpinnings of the action of electroconvulsive stimulus (ECS: the amimal model of ECT). In addition, the WKY presents a potentially useful model for translational research on depression. The WKY strain is particularly valuable for the measurement of serum BDNF protein, for which the association with antidepressant treatments is much less clear (mostly stemming from investigations in humans) than that between brain BDNF and antidepressant treatments in rodent studies. The three studies presented add insight into the biological and behavioural effects of ECS. The first study (chapter 2) found no evidence of increased (R)-[11C]rolipram binding (an indirect marker of cyclic-adenosine monophosphate, cAMP) in the brain, despite significant increases of brain BDNF protein expression after repeated ECS. The second study (chapter 3) demonstrated the validity of the WKY strain in the investigation of ECS. Relative to Wistar controls, WKY showed similar antidepressant and cognitive effects (despite some abnormal behavioural responses), immediate but not sustained increases in brain BDNF protein, and a novel finding of increased extra-hypothalamic CRF after 5 daily ECS. The final study (chapter 4) demonstrated baseline strain differences in serum (WKY < Wistar) but not brain BDNF and, in both strains, no change in serum BDNF despite significant changes in brain BDNF after repeated ECS treatment. Preliminary results from a human pilot study investigating similar measures in a small group of people receiving ECT for depression are also presented. The results of this body of work advance our understanding of the activation and role of brain and serum measures of BDNF and the HPA axis in ECS/ECT, and raise important issues in the translation of research from basic science to the human condition of depression.

Electroconvulsive therapy (ECT) is one of the oldest and most effective treatments for depression; however, its biological underpinnings are poorly understood. Brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis are two chemical messenger systems implicated in the antidepressant action and cognitive side effects of ECT. The Wistar-Kyoto (WKY) strain is a genetic model of depression that shows biological, cognitive, behavioural, and treatment-response abnormalities, making it potentially a useful model in which to investigate the underpinnings of the action of electroconvulsive stimulus (ECS: the amimal model of ECT). In addition, the WKY presents a potentially useful model for translational research on depression. The WKY strain is particularly valuable for the measurement of serum BDNF protein, for which the association with antidepressant treatments is much less clear (mostly stemming from investigations in humans) than that between brain BDNF and antidepressant treatments in rodent studies. The three studies presented add insight into the biological and behavioural effects of ECS. The first study (chapter 2) found no evidence of increased (R)-[11C]rolipram binding (an indirect marker of cyclic-adenosine monophosphate, cAMP) in the brain, despite significant increases of brain BDNF protein expression after repeated ECS. The second study (chapter 3) demonstrated the validity of the WKY strain in the investigation of ECS. Relative to Wistar controls, WKY showed similar antidepressant and cognitive effects (despite some abnormal behavioural responses), immediate but not sustained increases in brain BDNF protein, and a novel finding of increased extra-hypothalamic CRF after 5 daily ECS. The final study (chapter 4) demonstrated baseline strain differences in serum (WKY < Wistar) but not brain BDNF and, in both strains, no change in serum BDNF despite significant changes in brain BDNF after repeated ECS treatment. Preliminary results from a human pilot study investigating similar measures in a small group of people receiving ECT for depression are also presented. The results of this body of work advance our understanding of the activation and role of brain and serum measures of BDNF and the HPA axis in ECS/ECT, and raise important issues in the translation of research from basic science to the human condition of depression.

Electroconvulsive therapy (ECT) is one of the oldest and most effective treatments for depression; however, its biological underpinnings are poorly understood. Brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis are two chemical messenger systems implicated in the antidepressant action and cognitive side effects of ECT. The Wistar-Kyoto (WKY) strain is a genetic model of depression that shows biological, cognitive, behavioural, and treatment-response abnormalities, making it potentially a useful model in which to investigate the underpinnings of the action of electroconvulsive stimulus (ECS: the amimal model of ECT). In addition, the WKY presents a potentially useful model for translational research on depression. The WKY strain is particularly valuable for the measurement of serum BDNF protein, for which the association with antidepressant treatments is much less clear (mostly stemming from investigations in humans) than that between brain BDNF and antidepressant treatments in rodent studies. The three studies presented add insight into the biological and behavioural effects of ECS. The first study (chapter 2) found no evidence of increased (R)-[11C]rolipram binding (an indirect marker of cyclic-adenosine monophosphate, cAMP) in the brain, despite significant increases of brain BDNF protein expression after repeated ECS. The second study (chapter 3) demonstrated the validity of the WKY strain in the investigation of ECS. Relative to Wistar controls, WKY showed similar antidepressant and cognitive effects (despite some abnormal behavioural responses), immediate but not sustained increases in brain BDNF protein, and a novel finding of increased extra-hypothalamic CRF after 5 daily ECS. The final study (chapter 4) demonstrated baseline strain differences in serum (WKY < Wistar) but not brain BDNF and, in both strains, no change in serum BDNF despite significant changes in brain BDNF after repeated ECS treatment. Preliminary results from a human pilot study investigating similar measures in a small group of people receiving ECT for depression are also presented. The results of this body of work advance our understanding of the activation and role of brain and serum measures of BDNF and the HPA axis in ECS/ECT, and raise important issues in the translation of research from basic science to the human condition of depression.

Os estudos publicados nos últimos anos sobre a utilização da estimulação magnética transcraniana de repetição (EMTr) têm sugerido significativas ações antidepressivas. Neste trabalho foi realizado um estudo comparativo da EMTr com a eletroconvulsoterapia (ECT) que é um método consagrado para o tratamento de transtornos depressivos. Foi feita, em primeiro lugar, uma extensa revisão a respeito destes dois métodos de tratamento não medicamentoso, expondo a sua história, a sua eficácia, as principais indicações, contra-indicações e efeitos colaterais, além dos possíveis mecanismos de ação, que ainda não estão completamente esclarecidos. A seguir foi realizado um ensaio clínico controlado, randomizado, simples-cego, comparando a eficácia de ambos para o tratamento da Depressão Maior unipolar refratária, sem sintomas psicóticos, com indicação de ECT. Também foi realizada uma avaliação dos efeitos cognitivos, especialmente da memória. Trinta e cinco pacientes foram incluídos. A eletroconvulsoterapia foi realizada com indução anestésica geral e relaxamento muscular. Foram feitas aplicações na posição unilateral direita com carga 4,5 vezes o limiar convulsígeno. A EMTr foi aplicada no córtex pré-frontal dorso-lateral esquerdo com intensidade de 100% do limiar motor. Os pacientes receberam 20 sessões (cinco dias por semana por quatro semanas), com 25 séries de estimulação por dia (com freqüência de 10 Hz por 10 segundos, com intervalos de 20 segundos). As escalas de avaliação foram aplicadas nos tempos basal, após duas semanas de tratamento e após quatro semanas de tratamento. Ambos os tratamentos tiveram eficácia equivalente, com uma taxa de redução média dos escores na escala de Hamilton para depressão de 42 %, uma resposta clínica de 46 % e uma taxa de remissão de 14%. A EMTr apresentou um perfil mais benigno de efeitos colaterais (cefaléia em 1 %). A ECT resultou em cefaléia (em 20 %) e náuseas (em 10%).Não houve diferença nos efeitos cognitivos entre os dois tratamentos, tendo ambos se mostrado bastante benignos. Este estudo é uma contribuição para a crescente literatura a respeito do assunto e sugere um efeito antidepressivo da EMTr, comparável ao da ECT em pacientes com depressão maior unipolar sem sintomas psicóticos / Studies published over the past few years suggest that repetitive transcranial magnetic stimulation (rTMS) may have significant antidepressant actions. This work performs a comparison between rTMS and electroconvulsive therapy (ECT), an established method to treat depression disorders. First there was an extensive review on the knowledge of both non pharmacological treatments including their history, efficacy, main indications, contraindications and side effects, in addition to the possible mechanisms of action, not yet fully understood. After that, a controlled randomized, single-blind clinical trial was conducted, comparing the efficacy to treat unipolar resistant nonpsychotic major depression that were referred to receive ECT. An evaluation of cognitive effects was also performed, specially memory effects. Thirty five patients were included. Electroconvulsive therapy was performed with general anesthesia and muscular relaxation. Right unilateral electrodes positioning was used, with a charge 4.5 times the convulsive threshold. rTMS was performed over the left dorsolateral prefrontal cortex at 100% motor threshold. Patients were treated with 20 sessions (five times per week for four weeks) with 25 trains a day (frequency of 10 Hz, duration of 10 seconds with 20 seconds intertrain interval). Patients were evaluated at baseline, after two weeks and after four weeks of either treatment. Both groups were equivalent in efficacy, showing a means of reduction on Hamilton depression rating scale of 42%, an overall clinical response of 46% and a remission rate of 14%. rTMS showed a more benign profile regarding side effects (headache on 1%). ECT induced headache (20%) and nausea (10%). No cognitive effects were observed on either treatments. This study adds to the growing literature supporting an antidepressant effect for rTMS, similar to ECT on patients with unipolar nonpsychotic major depression

Os estudos publicados nos últimos anos sobre a utilização da estimulação magnética transcraniana de repetição (EMTr) têm sugerido significativas ações antidepressivas. Neste trabalho foi realizado um estudo comparativo da EMTr com a eletroconvulsoterapia (ECT) que é um método consagrado para o tratamento de transtornos depressivos. Foi feita, em primeiro lugar, uma extensa revisão a respeito destes dois métodos de tratamento não medicamentoso, expondo a sua história, a sua eficácia, as principais indicações, contra-indicações e efeitos colaterais, além dos possíveis mecanismos de ação, que ainda não estão completamente esclarecidos. A seguir foi realizado um ensaio clínico controlado, randomizado, simples-cego, comparando a eficácia de ambos para o tratamento da Depressão Maior unipolar refratária, sem sintomas psicóticos, com indicação de ECT. Também foi realizada uma avaliação dos efeitos cognitivos, especialmente da memória. Trinta e cinco pacientes foram incluídos. A eletroconvulsoterapia foi realizada com indução anestésica geral e relaxamento muscular. Foram feitas aplicações na posição unilateral direita com carga 4,5 vezes o limiar convulsígeno. A EMTr foi aplicada no córtex pré-frontal dorso-lateral esquerdo com intensidade de 100% do limiar motor. Os pacientes receberam 20 sessões (cinco dias por semana por quatro semanas), com 25 séries de estimulação por dia (com freqüência de 10 Hz por 10 segundos, com intervalos de 20 segundos). As escalas de avaliação foram aplicadas nos tempos basal, após duas semanas de tratamento e após quatro semanas de tratamento. Ambos os tratamentos tiveram eficácia equivalente, com uma taxa de redução média dos escores na escala de Hamilton para depressão de 42 %, uma resposta clínica de 46 % e uma taxa de remissão de 14%. A EMTr apresentou um perfil mais benigno de efeitos colaterais (cefaléia em 1 %). A ECT resultou em cefaléia (em 20 %) e náuseas (em 10%).Não houve diferença nos efeitos cognitivos entre os dois tratamentos, tendo ambos se mostrado bastante benignos. Este estudo é uma contribuição para a crescente literatura a respeito do assunto e sugere um efeito antidepressivo da EMTr, comparável ao da ECT em pacientes com depressão maior unipolar sem sintomas psicóticos / Studies published over the past few years suggest that repetitive transcranial magnetic stimulation (rTMS) may have significant antidepressant actions. This work performs a comparison between rTMS and electroconvulsive therapy (ECT), an established method to treat depression disorders. First there was an extensive review on the knowledge of both non pharmacological treatments including their history, efficacy, main indications, contraindications and side effects, in addition to the possible mechanisms of action, not yet fully understood. After that, a controlled randomized, single-blind clinical trial was conducted, comparing the efficacy to treat unipolar resistant nonpsychotic major depression that were referred to receive ECT. An evaluation of cognitive effects was also performed, specially memory effects. Thirty five patients were included. Electroconvulsive therapy was performed with general anesthesia and muscular relaxation. Right unilateral electrodes positioning was used, with a charge 4.5 times the convulsive threshold. rTMS was performed over the left dorsolateral prefrontal cortex at 100% motor threshold. Patients were treated with 20 sessions (five times per week for four weeks) with 25 trains a day (frequency of 10 Hz, duration of 10 seconds with 20 seconds intertrain interval). Patients were evaluated at baseline, after two weeks and after four weeks of either treatment. Both groups were equivalent in efficacy, showing a means of reduction on Hamilton depression rating scale of 42%, an overall clinical response of 46% and a remission rate of 14%. rTMS showed a more benign profile regarding side effects (headache on 1%). ECT induced headache (20%) and nausea (10%). No cognitive effects were observed on either treatments. This study adds to the growing literature supporting an antidepressant effect for rTMS, similar to ECT on patients with unipolar nonpsychotic major depression

Bakgrund: ECT har funnits inom den psykiatriska vården sedan 40-talet och används fortfarande idag. Behandlingen är vanligast hos patienter med djup depression. Trots att behandlingen är vanlig finns det en begränsad kunskap om patienters erfarenheter inom området.  Sjuksköterskorna ansvarar för omvårdnad och ska identifiera patienternas behov.  Syfte: Syftet är att beskriva erfarenheter av ECT hos patienter som lever med depression. Metod: En kvalitativ innehållsanalys av 12 narrativa texter i form av bloggar har lyfts fram. Resultat: En hoppfullhet finns inför behandlingen, men patienterna är rädda för att biverkningar efteråt ska påverka deras liv negativt. ECT hjälper patienterna att bryta depression, men biverkningar i form av minnesstörningar och kognitiv påverkan förekommer. Patienterna anser att delaktigheten blir lidande då informationen för att kunna ta ett beslut om ECT är bristfällig. Konklusion: Patienterna ser en ljusare framtid då ECT har hjälpt dem att bryta depressionen och lidandet. Patienterna önskar att informationen om ECT:s  risker och biverkningar skulle ha lyfts fram tydligare då biverkningarna påverkar deras liv negativt så som minnesstörningar och kognitiv biverkan. Det är viktigt att sjuksköterskorna samspelar med patienten och gör patienten delaktig i den egna vården för att minska lidandet. / Background: ECT has been a part of psychiatric health care since the 1940’s and is still used today. The treatment is most commonly used with patients suffering from deep depression. Despite the treatment being common, there is little knowledge of the patients’ experiences thereof. The nurses are responsible for the nursing of the patient and for identifying the patients’ needs. Aim: The aim of the study is to describe the experiences of ECT for patients suffering from depression. Method: The study applies a qualitative content analysis in 12 narratives from blogs. Results: Patients are hopeful before the treatment, but at the same time anxious that the treatment will have side effects affecting their lives. ECT helps patients defeat depression, thus sideeffects such as memory disorders and cognitive loss may occur. The patients experience losses in involvement as the information needed to make a decision on ECT is flawed. Conclusion: Patients see a brighter future as ECT has helped them to defeat their depression and suffering. The patients wish that they had been given clearer information regarding the risks and side effects of ECT as the side effects affected their lives. It is therefore important that the nurses cooperate with the patients in order to support their needs and reduce suffering.

Bridging the fields of engineering and psychiatry, this dissertation proposes a novel framework for the rational dosing of electric and magnetic seizure therapy, including electroconvulsive therapy (ECT) and magnetic seizure therapy (MST), for the treatment of psychiatric disorders such as medication resistant major depression and schizophrenia. The objective of this dissertation is to develop computational modeling tools that allow ECT and MST stimulation paradigms to be biophysically optimized ex vivo, prior to testing safety and efficacy in preclinical and clinical trials. Despite therapeutic advances, treatment resistant depression (TRD) remains a largely unmet clinical need. ECT is highly effective for TRD, but its side effects limit its real-world clinical utility. Modifications of treatment technique (e.g., electrode placement, stimulus parameters, novel paradigms such as MST) significantly improve the tolerability of convulsive therapy. However, we know relatively little about the distribution of the electric field (E-field) induced in the brain to inform spatial targeting of ECT and MST. Lacking an understanding of biophysical and physiological mechanisms, refinements in ECT/MST technique rely exclusively on time-consuming and costly clinical trials. Consequently, key questions remain unanswered about how to position the ECT electrodes or MST coil for targeted brain stimulation. Addressing this knowledge gap, this dissertation proposes a new platform that will inform an improved spatial targeting of ECT and MST through state-of-the-art computer simulations of the E-field distribution in human and nonhuman primate (NHP) brain. Part I of this dissertation aims to develop anatomically realistic finite element models of transcranial electric and magnetic stimulation in human and NHPs incorporating tissue heterogeneity and anisotropy derived from structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) data. The NHP models of ECT and MST are created alongside the human model since NHPs are used in preclinical studies on the mechanisms of seizure therapy. Part II of this dissertation aims to apply the model developed in Part I to electric and magnetic seizure therapy. We compute the strength and spatial distributions of the E-field induced in the brain by various ECT and MST paradigms. The relative E-field strength among various regions of interest (ROIs) is examined to select electrode/coil configurations that produce most focal stimulation of target ROIs that are considered to mediate the therapeutic action of ECT and MST. Since E-field alone is insufficient to account for individual differences in neurophysiological response, we calibrate the E-field maps relative to the neural activation threshold via in vivo measurements of the corticospinal tract response to single pulses (motor threshold, MT). We derive an empirical estimate of the neural activation threshold by coupling simulated E-field strength with individually measured MT. The E-field strength relative to an empirical neural activation threshold and corresponding volume of suprathreshold stimulation (focality) is examined to inform the selection of ECT and MST stimulus pulse amplitude that will result in focal ROI stimulation. We contrast the ECT/MST stimulation strength and focality with conventional fixed and individually titrated pulse amplitude necessary to induce a seizure (seizure threshold, ST) to study pulse amplitude adjustment as a novel means of controlling stimulation strength and focality. This work provides a basis for rational dosing of seizure therapies that could help improve their risk/benefit ratio and guide the development of safer alternatives for patients with severe psychiatric disorders.

Electroconvulsive therapy (ECT) effectively treats depression by administration of repeated seizure-inducing electrical stimuli. Sprague-Dawley rats were administered 6 electroconvulsive shocks (ECS) over 2 weeks, and in vivo single unit extracellular electrophysiological activity was recorded after 48 hours. Overall firing activity in the locus coeruleus and ventral tegmental area was unchanged, suggesting the therapeutic efficacy of ECT may not be attributed to increased norepinephrine and dopamine release. There were more spontaneously active neurons in the substantia nigra pars compacta (SNc), indicating greater dopamine tone in the nigrostriatal motor pathway, which may contribute to alleviation of psychomotor retardation. In the facial motor nucleus (FMN), locally administered norepinephrine, but not serotonin, facilitated greater glutamate-induced firing, which may contribute to improved facial motricity. Current results indicate that repeated ECS enhances postsynaptic norepinephrine neurotransmission in the FMN and SNc dopamine neurotransmission, which could represent the mechanism behind the alleviation of depressive symptoms including psychomotor retardation.

Electroconvulsive therapy (ECT) effectively treats depression by administration of repeated seizure-inducing electrical stimuli. Sprague-Dawley rats were administered 6 electroconvulsive shocks (ECS) over 2 weeks, and in vivo single unit extracellular electrophysiological activity was recorded after 48 hours. Overall firing activity in the locus coeruleus and ventral tegmental area was unchanged, suggesting the therapeutic efficacy of ECT may not be attributed to increased norepinephrine and dopamine release. There were more spontaneously active neurons in the substantia nigra pars compacta (SNc), indicating greater dopamine tone in the nigrostriatal motor pathway, which may contribute to alleviation of psychomotor retardation. In the facial motor nucleus (FMN), locally administered norepinephrine, but not serotonin, facilitated greater glutamate-induced firing, which may contribute to improved facial motricity. Current results indicate that repeated ECS enhances postsynaptic norepinephrine neurotransmission in the FMN and SNc dopamine neurotransmission, which could represent the mechanism behind the alleviation of depressive symptoms including psychomotor retardation.