China entra no mercado do dbs para o tratamento da doença de Parkinson

December 11, 2013 - Cientistas chineses testaram com sucesso um "marcapasso cerebral" auto-desenvolvido, o que poderia melhorar radicalmente o tratamento da doença de Parkinson.

Ele está sendo visto como um grande avanço na tecnologia médica chinesa, em uma área dominada por muito tempo pelos EUA. Desenvolvido pela Universidade de Tsinghua, ele é projetado para corrigir os desequilíbrios elétricos no cérebro. Um elétrodo é implantado numa zona específica do cérebro, e fornece uma pequena corrente elétrica.

Pela “descoberta” por uma equipe de pesquisadores da Universidade de Tsinghua são esperados custos significativamente mais baixos de gastos para os pacientes. O dispositivo foi patenteado na China e os EUA. (original em inglês, tradução Hugo) Fonte: China.cn, com vídeo.

Problemas do dbs

O gráfico apresentado relaciona os problemas observados no dbs ao longo de períodos, após respectivamente, 1-12 meses, 13-24 meses, e 25 meses ou mais.

Os problemas são, na ordem  apresentada no gráfico:
- parâmetros de estimulação inadequados (regulagem insatisfatória)
- progressão da doença
- danos no "marca-passo"
- mau posicionamento dos eletrodos
- seleção de paciente inadequado
- resultados motores esperados com efeitos colaterais

(extrato de artigo original em inglês, tradução Hugo) Fonte: Center for Movement.

Estimulação cerebral profunda: a "decisão de mudar de vida"

Extrato de artigo, como acima entitulado, publicado pela The Michael J.Fox Foundation em 05/12/2013.

December 05, 2013 (...)

Um longo caminho para a otimização

Mesmo para aqueles que são bons candidatos, e quem toma a decisão não trivial de ter eletrodos implantados no cérebro, ainda há um longo caminho pela frente. O procedimento exige muitas vezes ao paciente retornar com freqüência a o seu médico para ajustar o aparelho. E depois de tudo isto, o benefício terapêutico pode variar amplamente.

O Sr Stark, por exemplo, notou um único e limitado benefício terapêutico nos primeiros seis meses após a cirurgia. Então ele mudou de médico e encontrou um que melhor compreendeu as configurações ideais para ele - levando a um período de vida quase sem sintomas por sete anos. Agora, oito anos depois, ele vai novamente ver o seu médico para ajustar o aparelho, já que ele tem notado que recentemente alguns sintomas retornaram. (...)

NOTA: As informações médicas contidas neste artigo são apenas para fins informativos gerais. A Michael J. Fox Foundation tem uma política de se abster de defender, endossar ou promover qualquer terapia medicamentosa, tratamento, empresa ou instituição específica. É fundamental que as decisões de cuidados e tratamentos relacionados com a doença de Parkinson ou qualquer outra condição médica sejam feitas em consulta com um médico ou outro profissional de saúde qualificado. Cada paciente é diferente, e as respostas a tratamentos como DBS podem variar. (original em inglês, tradução Hugo) Fonte: The Michael J.Fox Foundation.

Interleaving

Cada vez fico mais convencido da utilidade do "interleaving". Estive pesquisando sobre a disponibilidade de algum algoritmo de procedimentos para um ótimo ajuste dos parâmetros do dbs, particularmente para os modelos atuais da Medtronic (Activa PC, RC, SC;  atenção: modelos Kinetra e Soletra não dispõem desta opção de programação), que facultam essa opção de programação, melindrosa e trabalhosa, e bati com o mesmo algoritmo já postado aqui no passado (ver em Marcadores: algoritmo).

Espero que surja um expert no assunto para expandir o algoritmo acima (que está em corrente, o interleaving só usa voltagem) para o interleaving, o que certamente resultará num diagrama gigante (embora com o fator  frequência mais restrito), dadas as combinações possíveis.

A convicção da importância deste tipo de programação decorre de meu presente estado positivo, que atingiu o climax no sábado passado (23/11), após uma semana cheia, com cerca de 7 sessões de ajuste no consultório do Dr Telmo Reis, com idas e vindas, visão dupla, etc... Neste clímax cheguei a escrever um texto exageradamente eufórico, que não vou publicar porque foi muito precoce. A regulagem não se mostrou perene. É necessário um tempo mais longo para ser estabilizada. Na semana passada voltei a perturbar e, em que pese não manter a mesma euforia, estou bem.

Dentro deste quadro expresso outra convicção: Ser paciente. Não só o paciente, mas o médico também. Anotar todas as regulagens, seus efeitos positivos e negativos, pois a programação do dbs trata-se a princípio de um método de tentativa e erro, e claro, com o uso de um algoritmo, como acima. Ao extrapolar este algoritmo para o interleaving, ele será exponencial. Para ressaltar a importancia da regulagem, e o tempo que isto demandará, extraí da Medtronic o texto abaixo.

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Sessões de programação
Depois de ter se recuperado do procedimento de implante, o médico irá programar o dispositivo para melhor controlar os seus sintomas individuais, minimizando os efeitos colaterais. Você vai voltar para as sessões de acompanhamento para ajustar ainda mais as configurações. Ajustes periódicos fazem parte da rotina da terapia DBS.

Após a programação inicial, as pessoas com tremor podem sentir uma breve sensação de formigamento, e geralmente experimentam alívio de sintomas quase que imediatamente. No entanto, os resultados variam. Pessoas com outros sintomas da doença de Parkinson, muitas vezes não se sentem qualquer sensação, e o efeito total do tratamento pode não ser imediato. Você vai ter melhores resultados após o sistema ter sido afinado para as suas necessidades específicas de controle dos sintomas. Pode levar vários meses para atingir o efeito máximo.

Dependendo do sistema e suas necessidades de terapia, você pode ter um controlador que lhe permitirá ligar o sistema e desligar, ajustar o estímulo, e verificar a bateria. (original em inglês, tradução Hugo)

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A Novel Brain-Computer Interface Approach to Deep Brain Stimulation for Parkinson's Disease

S. Andrew Josephson, MD

AccessMedicine from McGraw-Hill 

• 
  

DRUG & REFERENCE INFORMATION

• Stereotactic Surgery in Parkinson Disease
• Parkinson Disease
• Deep Brain Stimulation for Parkinson Disease

Deep brain stimulation (DBS) is often used in refractory cases of Parkinson’s disease as well as in a number of other movement disorders. Electrodes are placed in deep nuclei of the brain, and continuous stimulation is typically used. The stimulation can be adjusted periodically by the physician in order to improve the efficacy of the treatment. Brain-computer interfaces are increasingly being explored in order to modulate stimulation in a variety of settings. In a recent exploratory study, Little and colleagues (2013) aimed to test whether such an interface could be used in DBS to control stimulation settings at an individual patient level on a moment-by-moment basis; this type of adaptive DBS would potentially stand as a major advance in the therapy of movement disorders.

The authors developed a system in which local field potentials from the DBS electrodes could be recorded and then used by a computer for feedback to quickly adjust the stimulation parameters of the electrode to finely control stimulation. Patients were tested, in a blind and random fashion, with the following paradigms: no stimulation, typical continuous DBS, adaptive DBS, and a random stimulation paradigm in which bursts of stimulation occurred and were not triggered by the local field potentials. Eight patients with advanced Parkinson’s disease were included in the study, and all underwent DBS implantation in the subthalamic nucleus. Clinical assessments were made by both unblinded raters and those blind to the stimulation paradigm (via videotaped assessments) using the standard Unified Parkinson’s Disease Rating Scale. Although DBS leads were implanted bilaterally, only unilateral stimulation was assessed.

The authors found that both routine and adaptive DBS improved the motor scores of the patients compared with baseline. However, in the blind assessments, the improvement with adaptive DBS was 30.5% greater than that seen with standard, continuous DBS (p = .005). This effect was maintained if rigidity was excluded from the scored assessments, as this examination finding can be difficult to judge via videotape. Random stimulation also was found to be significantly inferior to the adaptive DBS protocol.

Adaptive DBS also resulted in a significant energy savings, potentially extending battery life and reducing side effects of stimulation. The mean total energy delivered with adaptive DBS was significantly less than that needed for continuous DBS (p < .0001), and over the entire block of stimulation, adaptive DBS was only “on” for 44.2% of the time. As the paradigm progressed, less and less “on” stimulation time was needed.

This intriguing study follows a recent trend where brain-computer interfaces are being used to more finely tune settings of various types of interventions and tailor them to an individual patient’s physiology. The results in this very small proof-of-concept study are impressive. Improved motor outcomes were observed while at the same time the strategy used substantially less energy. Although other confirmatory studies are certainly needed, the future of DBS brain-computer interface for treatment of Parkinson’s disease appears to be bright. Fonte: MedScape.

Possíveis efeitos colaterais do dbs (tradução abaixo)

Fonte: Movement & Neuroperformance Center.

Tradução do texto acima (por Hugo, em 29/11/2013)

Efeitos colaterais do dbs

O dbs (estimulação profunda do cérebro) pode trazer significantes benefícios, mas como a medicação, também pode ser associado a efeitos colaterais. Os efeitos colaterais podem ocorrer mesmo com a perfeita colocação dos eletrodos no cérebro. Os efeitos colaterais variam dependendo da localização dos eletrodos e da intensidade da estimulação. Os efeitos colaterais da estimulação são reversíveis e podem ser evitados com o uso de parâmetros adequados. Os que seguem são os efeitos colaterais mais comuns quando a estimulação está próxima de típicos alvos cerebrais para Parkinson, tremor ou distonia.

• Super contração da musculação que causa fala arrastada, musculatura facial contraída, engasgamento ou problemas de deglutição, olhos piscando, contrações labiais, arrastar perna, postura anormal de braço e mão, desequilíbrio, marcha congelada (rígida), visão dupla.
• Estimular sensações que podem incluir dormência, formigamento, sentir a face pesada ou espessa, língua, mão, perna, calor e suor.
• Outros efeitos colaterais podem incluir lentidão de movimentos, cãibras ou dor, tonturas, visão borrada, ansiedade depressão, confusão mental, quedas, sonolência.

O importante é que os efeitos colaterais da estimulação são reversíveis. O ajuste adequado da estimulação pode evitar ou eliminar tais efeitos. Se os eletrodos estão mal posicionados, os efeitos colaterais podem persistir e causar problemas inexistentes que não estavam presentes antes da cirurgia de dbs. O equívoco mais comum após o dbs é a confusão entre os efeitos colaterais e a evolução da doença. A piora do andar, equilíbrio, fala e deglutição podem ocorrer com o progresso da doença mas também podem ser um efeito colateral da estimulação. Hábeis especialistas em dbs podem distinguir entre fatores atribuídos à doença e aqueles problemas induzidos pela estimulação. Procurar por uma segunda opinião sobre os efeitos colaterais do dbs pode trazer uma nova visão sobre o problema e solucioná-lo depois de tentativas frustradas para maximizar os benefícios da estimulação.

Interleaving DBS

06 Nov - A programação intercalada (aqui será chamado de “interleaving”) é um tipo de recurso disponível para programar os neuroestimuladores Medtronic modelos SC, PC ou RC. O “interleaving” ganhou algum interesse ao haver a liberação desses neuroestimuladores Medtronic para pacientes e prestadores de serviços médicos. Apesar do “interleaving” ser um novo recurso, as configurações padrão de estimulação sabe-se serem eficazes prioritariamente ao “interleaving” e não há nenhuma evidência de que o “interleaving” aumente o benefício já estabelecido e comprovado ao longo de muitos estudos de investigação. O "interleaving" é mostrado no diagrama abaixo (aqui ao lado) e ilustra os parâmetros de estimulação padrão usando dois e um “pólos” por eletrodo, contra dois programas que alternam entre os “pólos” de um único eletrodo. (nota do tradutor: no Brasil chamamos de eletrodo o que nos EUA chamam “lead wire”. Aqui chamaremos de pólo o que nos EUA chamam de "electrode". Lembro que cada eletrodo tem 4 pólos.) Os prós e contras do "Interleaving" estão nas notas abaixo:

PRÓS:

O "interleaving" pode fornecer terapia para quando os efeitos colaterais são inevitáveis ​​na estimulação utilizando protocolos padrão.

Pode ajudar a contornar situação de quando não for ideal a posição dos eletrodos (acerto do alvo) no cérebro, como um esforço para evitar a cirurgia de reposicionamento.

CONTRAS:

Dreno de energia rápida pode dobrar ou triplicar taxa de esgotamento da bateria encurtando assim a longevidade da bateria.

Ainda não foi provado ser tão eficaz como parâmetros de estimulação padrão.

Os pacientes podem não ser informados sobre o consumo excessivo da bateria.

Aumento significativo na cirurgia de substituição da bateria.

A frequência máxima possível é de 125 hertz, o que talvez possa não fornecer estimulação eficaz ou benefício duradouro. (original em inglês, tradução Hugo) Fonte: dbs programming.

Deep Brain Stimulation

A Mechanistic and Clinical Update

Patrick J. Karas, B.A, Charles B. Mikell, M.D, Eisha Christian, M.D, Mark A. Liker, M.D, Sameer A. Sheth, M.D., Ph.D

Disclosures

Neurosurg Focus. 2013;35(5):e1 

Sumário:

• Abstract and Introduction
• Mechanisms of DBS
• DBS in Parkinson Disease
• DBS for Essential Tremor (não incluso)
• DBS in Dystonia (não incluso)
• DBS in Major Depression (não incluso)
• DBS in OCD (não incluso)
• DBS for Other Emerging Indications (não incluso)
• The Future of Electrical Stimulation

Obs.: os trechos não inclusos não abordam o parkinson. Para acessá-los somente na fonte. Traduzi apenas o capítulo final: O futuro da estimulação elétrica, no fim, grifado em verde.

Abstract and Introduction

Abstract

Deep brain stimulation (DBS), the practice of placing electrodes deep into the brain to stimulate subcortical structures with electrical current, has been increasing as a neurosurgical procedure over the past 15 years. Originally a treatment for essential tremor, DBS is now used and under investigation across a wide spectrum of neurological and psychiatric disorders. In addition to applying electrical stimulation for clinical symptomatic relief, the electrodes implanted can also be used to record local electrical activity in the brain, making DBS a useful research tool. Human single-neuron recordings and local field potentials are now often recorded intraoperatively as electrodes are implanted. Thus, the increasing scope of DBS clinical applications is being matched by an increase in investigational use, leading to a rapidly evolving understanding of cortical and subcortical neurocircuitry. In this review, the authors discuss recent innovations in the clinical use of DBS, both in approved indications as well as in indications under investigation. Deep brain stimulation as an investigational tool is also reviewed, paying special attention to evolving models of basal ganglia and cortical function in health and disease. Finally, the authors look to the future across several indications, highlighting gaps in knowledge and possible future directions of DBS treatment.

Introduction

Since its approval by the FDA in 1997 for the treatment of essential tremor, deep brain stimulation (DBS) has revolutionized functional neurosurgery. Electrical current has been known to be critical for biological signal transduction since Luigi Galvani's work in the 18th century, and reports from the middle of the previous century detail first attempts to harness the effects of electrical stimulation of the CNS.[24]However, the use of chronic electrical stimulation to directly alter brain function was not shown to be safe or effective until pioneering publications by Alim Benabid.[17] Soon after the approval of DBS for essential tremor, approvals for applications in Parkinson disease (PD) and dystonia followed. The last decade has seen remarkable progress in the development of new applications for DBS. In the present review we aim to provide an overview of the current understanding of the mechanisms and applications of DBS. We then discuss emerging indications with a focus on psychiatric disease. Finally, we discuss future possibilities for DBS technology, including tandem stimulation and rational target development.

Mechanisms of DBS

It has become clear that the "reversible functional lesion" paradigm that inspired the development of DBS from lesion procedures is no longer adequate to describe its effects.[16]Early theories focused on depolarization block of efferent activity and local γ-aminobutyric acid (GABA)-mediated inhibitory effects.[21] These notions were supported by acute stimulation experiments in animals, but paired electrode recordings and other advanced techniques complicated this picture. Proposed mechanisms of DBS can be grouped into 4 main categories: 1) inhibition of the target, the classic reversible functional lesioning paradigm; 2) activation of the target; 3) combined inhibition and activation; and 4) disruption of pathological oscillations to restore rhythmic activity and synchronization, the "noisy signal hypothesis."[134,141] Recent findings have mostly supported the view that therapeutic effects are related to alterations in ongoing oscillations. In PD, subthalamic nucleus (STN) field potentials have been found to exhibit abnormal phase-amplitude coupling and spike–local field potential (LFP) coupling to primary motor cortex.[45,177] Furthermore, globus pallidus internus (GPi) neurons were found to entrain high-frequency stimulation at therapeutic parameters.[42] The "modulation of brain rhythms" hypothesis will likely provide a useful framework from which to make predictions about possible therapeutic targets for DBS.

Part of the difficulty in identifying a mechanism for the physiological effect of DBS is due to the incomplete understanding of the pathophysiology of the diverse array of movement, neuropsychiatric, and cognitive disorders currently under investigation for DBS intervention. In the following sections, we discuss recent findings in DBS research, with a focus on reviewing the evolving view of DBS target circuits.

DBS in Parkinson Disease

Mechanistic Understanding

The current understanding of PD pathophysiology centers around abnormal β band oscillations (13–30 Hz) in the basal ganglia–cortical loop.[30] These pathological oscillations are suppressed by movement, dopaminergic medications, and DBS[203] and are believed to be closely related to the bradykinesia characteristic of PD.

The antikinetic nature of β oscillations has led to investigations of how they affect the relationship between the STN and primary motor cortex. An animal model of the therapeutic effects of DBS using optogenetics technology has further supported the hypothesis that high-frequency stimulation affects this relationship.[67] Importantly, high-frequency stimulation to primary motor (M1) afferents in the STN decreased bradykinesia, while stimulation in the β range exacerbated symptomatology. However, the mechanism by which β synchrony interferes with voluntary movement continues to be an area of intense study.

Local field potential recordings of M1 in patients undergoing DBS for PD suggest increased phase-amplitude coupling of M1 β-phase (13–30 Hz) and γ-amplitude (50–200 Hz) in PD patients.[45]Moreover, phase-amplitude coupling between M1 and STN revealed M1 LFP γ-power peaks occurring at a specific phase of the STN β rhythm in PD at a much higher magnitude than that of the STN β–M1 β coherence. This M1 β phase-coupled M1 broadband γ activity actually precedes STN β troughs, suggesting the existence of a feedback loop between the structures. It appears that pathological M1 broadband γ activity may be an important driver in maintaining aberrant STN oscillations. In turn, excessively synchronized STN and GPi β oscillations reinforce the pathological cortical β-phase and broadband γ-amplitude coupling. Another publication by the same group showed that epochs of M1 phase-amplitude coupling predicted STN spikes.[177] This theory contrasts with older literature emphasizing the importance of intrastriatal β-synchrony as the driver of pathological oscillations.[19]

Oscillatory activity in the motor cortex is now also being studied with magnetoencephalography as a possible biomarker for PD. The planning, execution, and termination of movement are known to be associated with consistent within-subject patterns of M1, primary sensory, and supplementary motor area oscillatory activity. Movement is preceded by a strong β desynchronization, beginning 600 msec prior to movement and lasting roughly 400 msec after the onset of movement. After this initial desynchronization, there is a strong β resynchronization called the postmovement β rebound that begins 500–800 msec after initiation of movement and lasts for 1000 msec.[64] A brief period (100–200 msec) of increased γ band activity is also associated with movement onset. Beta desynchronization is believed to be associated with movement selection,[85] and therefore excess β synchrony may underlie difficulty with movement initiation. In addition to excess β, PD patients were found to have diminished γ response amplitude and peak frequency.[78]

Taken together, these data fit into the model proposed by Shimamoto and colleagues in which excess motor cortical β synchrony, manifesting clinically as hypokinesia, is a result of strong pathological β oscillations passed from the basal ganglia.[177] This increased cortical β synchronization, in turn, leads to reinforcement of the basal ganglia β oscillations through pathological M1 β-phase γ-amplitude coupling (Fig. 1). This aberrant coupling decreases the cortex's capacity for activation-related γ activity, leading to difficulty initiating movement. Subthalamic nucleus DBS may have its effect on β oscillations and therefore movement initiation by altering the timing of M1 firing via orthodromic stimulation of afferents, limiting aberrant phase-amplitude coupling.

Pathological phase-amplitude coupling in PD creates a self-reinforcing loop. 1: Motor cortex (M1) β-phase oscillations drive M1 γ-amplitude changes reflected by intracortical β-phase γ-amplitude coupling. 2: Changing M1 γ amplitude drives/reinforces STN β-phase oscillations via the glutamatergic hyperdirect pathway. 3: Beta-phase oscillations propagate throughout basal ganglia via glutamatergic STN-to-GPe, STN-to-GPi, and STN-to-substantia nigra pars reticulata neurons. 4: Beta-phase oscillations in the basal ganglia reinforce β-phase oscillations in M1. Reinforced β-phase oscillations in M1 prevent M1 β desynchronization necessary to initiate movement, leading to bradykinesia. M1 β-phase–M1 γ-amplitude coupling may also prevent the normal increase in γ band activity associated with initiation of movement.

The GPi remains a common target for stimulation, although the mechanism of action of GPi DBS is still debated. Cleary and colleagues found that therapeutic GPi stimulation reduced mean firing rate and increased firing regularity of local neurons during electrical stimulation, importantly decreasing burst firing for a short period of time after firing.[42] Because stimulation of both the GPi and STN increase the regularity of thalamic neuronal firing,[7,206] as well as create complex "entrained" firing patterns in local GPi neurons,[39,42,197] it is likely that stimulation of the two regions has a similar mechanism of action. Alternative models of GPi stimulation suggest therapeutic benefit derives from stimulation of adjacent axonal projections, such as the medial medullary lamina (bradykinesia) and the internal capsule (rigidity).[83]

Current Approach to Therapy

Deep brain stimulation is a well-accepted approach to managing PD in patients with inadequate control of symptoms or with significant side effects from levodopa.[149] Class 1 evidence supports the use of STN DBS when compared with best medical therapy,[102,198,202] and in trials comparing the stimulation-on state versus the stimulation-off state.[150] However, several aspects of this accepted standard are in flux. Stimulation of the GPi has achieved wide acceptance after it was found to cause less decline in visuomotor function and decreased depression while maintaining equivalent primary outcome compared with STN stimulation, although the latter allowed greater reduction in medication dose.[59]

In addition to the STN and GPi, several other nuclei are accepted or under investigation for stimulation. The nucleus ventralis intermedius (VIM) of the thalamus is a standard target for alleviating tremor in PD.[125] The pedunculopontine tegmental nucleus is a target for gait disorder[25,171] and sleep modulation,[159] sometimes in tandem with stimulation of other nuclei.[90,195] Other targets in early stages of exploration include the posterior subthalamic area, caudal zona incerta, prelemniscal radiation, thalamic centromedian-parafascicular complex, and cerebral cortex.[53] As the currently approved targets only address motor symptoms of PD, more work is needed to identify the appropriateness of DBS for nonmotor PD symptoms.[53]

Cognitive Effects of DBS in the PD Population

The cognitive or nonmotor effects of PD are not as well defined as the motor effects. Motor effects are more commonly associated with presentation and disease burden, as they occur early in the course of the disease when the patient is in the most active and productive years of life. Cognitive decline is observed in advanced PD, a time during which DBS has historically been offered to the patient. However, the deleterious effect of compounding the natural progression of cognitive changes with the effects of DBS may outweigh DBS-derived motor improvement.

Initial long-term studies suggested an absence of significant change in cognition 5 years after STN DBS,[98] suggesting the promise of the technology's neuroprotective effects. However, other early studies comparing STN and GPi DBS targets reveal increased adverse cognitive and behavioral effects after STN DBS.[8,196] Speculation as to the potential cause of cognitive decline in early versus more recent studies may stem from the close anatomical apposition of motor, associative, and limbic pathways in the STN. As targeting techniques have improved, side effects of stimulation of these nonmotor pathways may have decreased. Definitive conclusions may also have been elusive due to small sample size and the study design. Woods and colleagues evaluated 30 studies investigating cognitive changes after DBS and identified only 2 that had sufficient statistical power on which to base conclusions.[205] Another meta-analysis found STN DBS to be relatively safe from a cognitive standpoint, except for a measurable decline in verbal fluency.[158]

Recent investigations in the US have corroborated the persistent decline in verbal fluency in the STN cohort,[207] as well as worsened dementia rating scores.[199] However, a European randomized controlled study evaluating the effects of STN versus GPi DBS in 128 patients with PD found no significant difference in cognitive side effects (a composite of multiple factors such as depression, anxiety, psychosis) in either group.[148] In fact, the authors recommended STN DBS due to superior overall outcomes of secondary investigative endpoints.

Areas of Evolving Practice

Although DBS has traditionally been reserved for PD patients with intractable symptoms, dyskinesias, or severe levodopa side effects, a recent study in patients with early motor symptoms of PD showed promising results.[173] This randomized prospective trial compared DBS combined with medication against medication alone in patients with early motor signs of PD (average duration of disease of 7.5 years). The primary outcome, quality of life (assessed using the Parkinson Disease Questionnaire-39), improved by 7.8 points in patients receiving a combination of DBS and medication, compared with a decrease of 0.2 points in patients receiving medication only. Patients who underwent surgery also experienced improved secondary outcomes, including decreased motor disability, improvement in performing activities of daily living, and fewer levodopa side effects. There was also an average of 1.9 hours/day increase in time with good movement and no dyskinesia, along with an average of 1.8 hours/day decrease in poor mobility time. Although patients in the stimulation group had slightly higher rates of mild adverse events, the authors argued that neurostimulation can and should be used to optimize treatment early in PD, before significant disabling motor and cognitive symptoms arise. It is also likely that performing surgery in patients who are younger and likely healthier will afford better surgical outcomes and a decreased risk of operative morbidity and death.

Other future directions of DBS for PD include tailoring the selection of nuclei to the individual's exact symptomatology, although target selection remains an area of debate.[54] Different modes of stimulation are also being attempted, including constant stimulation[151] and interleaved stimulation.[14]

DBS for Essential Tremor

Mechanistic Understanding

The disease formerly known as senile tremor, or benign essential tremor, has traditionally been underestimated by physicians. As the shedding of misleading labels has progressed (there is general agreement that it is neither benign nor confined to the elderly), a new understanding of its true public health cost has come into focus. The best estimates place its prevalence in patients over age 60 at 13–50 cases per 1000 people,[124] roughly the same as epilepsy.[12] In view of the aging population, there is new urgency to understanding the pathogenesis of essential tremor (ET).

The origin of pathological oscillations in ET has been debated. It has been known since the 1970s from animal lesion models that interactions between the inferior olive and the cerebellum are capable of driving ET-like tremor.[46] The view that olivocerebellar fibers represent a key node in ET pathophysiology was later confirmed with PET,[26] although functional MRI studies have yielded poor evidence for intrinsic olivary dysfunction.[31] Recent evidence suggests that GABA-receptor downregulation and/or dysfunction in the dentate nucleus (downstream of the Purkinje cells to which the inferior olive's climbing fibers project) correlates with tremor progression in a postmortem histopathological study.[157] The circuit targeted by effective DBS in ET has been probed with diffusion tensor imaging; effective contacts had robust connectivity to a circuit comprising the superior cerebellar peduncle (and presumably the dentate) as well as the primary motor cortex, supplementary motor area, lateral premotor cortex, and pallidum.[91] Source analysis of electroencephalography-electromyography coherence has supported a similar circuit.[143]

Current Approach

Essential tremor was the original indication for DBS, resulting in FDA approval in 1997.[16] Two multicenter studies were subsequently conducted in Europe with good tremor control and acceptable side-effect profiles found at both 1-year and 6-year follow-up.[117,187] An early randomized trial compared thalamotomy with DBS and showed superiority of efficacy with thalamic DBS, although there was 1 fatal hemorrhage after DBS.[174] After approval, the question of whether to implant 1 or both sides simultaneously was somewhat controversial. A small experience supported a stepwise benefit to a second, contralateral electrode in ET but not PD,[152] supporting the frequent practice of staging placement, starting with either the dominant hand or the more symptomatic side. Microelectrode recording is also variably practiced for VIM surgery.

Areas of Evolving Practice

More recent DBS approaches have included intraoperative CT-guided surgery, which appears to be accurate in the VIM thalamus.[33] There is also some experience with intraoperative MRI in VIM DBS.[111]

Initial enthusiasm for Gamma Knife thalamotomy[93] was tempered by a blinded study showing modest efficacy and a serious side-effect profile.[115] Additionally, many surgeons are accustomed to immediate physiological verification of treatment effect with test stimulation.[51] A larger retrospective series suggested that Gamma Knife thalamotomy could yield clinically significant reductions in tremor with an acceptable side-effect profile.[95]

Two groups have recently reported the use of focused ultrasonography for thalamotomy, combining the benefits of intraoperative testing with minimally invasive surgery.[52,120] Its efficacy is difficult to compare directly with DBS, as there has not been a direct comparison, but the results appear comparable.[146]

DBS in Dystonia (...)

The Future of Electrical Stimulation

Deep brain stimulation serves as a prime example of how advances in systems neuroscience are being translated into novel therapies. Deep brain stimulation is also gaining increasing acceptance for use on a case-by-case basis in a number of investigational indications. As noted in a recent review,[127] 100 Phase I/II and 21 Phase II/III trials of DBS were underway at the end of 2012. Many of the indications under investigation, such as obesity, addiction, depression, and Alzheimer disease, are extremely prevalent and represent a significant healthcare burden worldwide. Although other indications such as TS, OCD, dystonia, and Huntington disease are less prevalent, DBS may be able to return quality of life to patients not effectively treated by current medical technology. Promising preliminary results for several of these indications suggest that DBS will likely continue to increase in prevalence as a neurosurgical intervention.

In addition to potentially providing relief for millions of patients, DBS is also providing researchers with a window into the function of the human brain. As discussed above, our understanding of normal motor neurocircuitry, as well as the pathophysiology of PD, has changed drastically, thanks to cortical and subcortical single-neuron and LFP recordings obtained during implantation of DBS electrodes. Our understanding of mood and decision-making has also been transformed with this technology, providing new insights into how signals from broad areas of cortex are funneled into subcortical structures enabling decision-making and subsequent selection of action. Insights into mechanisms gained from DBS studies have also informed novel experimental designs: tractography studies (tracer studies in primates, diffusion tensor imaging), optogenetic manipulation of select neuron populations, and functional imaging (magnetoencephalography and resting state functional MRI) are sure to continue revolutionizing our understanding of brain circuitry and functional anatomy.

Finally, technology for stimulation continues to evolve. We have illustrated examples of how DBS targets are refined and targeted, and as our understanding of brain physiology improves, rational selection of targets for stimulation is becoming a reality. New stimulation settings, such as interleaved stimulation, continue to develop and are tested against current standards. In the near future, real-time LFP recordings may also be used to modulate stimulation settings, creating feedback loops for continuous stimulator setting modulation. Such de vices may help to extend battery life, as well as allow for intermittent stimulation in cases in which constant stimulation may not be needed, such as for augmentation in forming memories. Other forms of stimulation, such as transcranial magnetic stimulation, focused ultrasound, and possibly optogenetic stimulation, can also play a role in modulating aberrant neurocircuitry. As clinical applications of electrical stimulation continue to expand in the future, so too will our understanding of the brain as a collection of highly connected regions, speaking to each other in a language of oscillations and burst firing patterns that we are just beginning to decode. Fonte: MedScape.

O Futuro da Estimulação Elétrica
A estimulação cerebral profunda serve como um excelente exemplo de como os avanços em sistemas de neurociência estão sendo traduzidos para novas terapias. A estimulação profunda do cérebro também está ganhando cada vez mais aceitação para uso, caso a caso, em uma série de indicações de investigação. Como observado em uma revisão recente, [ 127] 100 Fase I / II e 21 ensaios de Fase II / III de DBS estavam em andamento no final de 2012. Muitas das indicações sob investigação, tais como a obesidade, dependência, depressão e doença de Alzheimer, são extremamente prevalecentes e representam um fardo significativo de saúde em todo o mundo. Embora outras indicações, como TS, OCD, distonia e doença de Huntington sejam menos prevalentes, o DBS pode ser capaz de trazer qualidade de vida aos pacientes não tratados de forma eficaz através da tecnologia médica atual. Promissores resultados preliminares para várias dessas indicações sugerem que o DBS provavelmente vá continuar a aumentar em prevalência como uma intervenção neurocirúrgica.
Além de potencialmente proporcionar alívio para milhões de pacientes, o DBS também está oferecendo aos pesquisadores uma janela para o funcionamento do cérebro humano. Como discutido acima, a nossa compreensão dos neurocircuitos normais motores, bem como a fisiopatologia da DP, mudou drasticamente, graças às gravações LFP (local field potential) cortical e subcortical de único neurônio obtidas durante a implantação de eletrodos do DBS. Nossa compreensão do ânimo e de tomada de decisão também foi transformado com esta tecnologia, fornecendo novos insights sobre como os sinais de amplas áreas do córtex são canalizados para estruturas subcorticais, permitindo a seleção de tomada de decisão e posterior da ação. Insights sobre os mecanismos de adquisição a partir de estudos DBS também informaram novos desenhos experimentais: estudos de “tractography” (estudos de tensor de difusão em marcadores nos primatas), manipulação optogenética para selecionar populações de neurônios, e imagem funcional (magnetoencephalography por ressonância magnética funcional em estado de descanso) e a certeza de continuar revolucionando nossa compreensão dos circuitos cerebrais e anatomia funcional.

Finalmente, a tecnologia para a estimulação continua a evoluir. Nós ilustramos exemplos de como os alvos do DBS são refinados e direcionados, e, como a nossa compreensão da fisiologia do cérebro melhora, a seleção racional de metas para a estimulação está se tornando uma realidade. Novas configurações de estímulo, como a estimulação intercalada, continuam a se desenvolver e são testados em relação aos padrões atuais. No futuro próximo, gravações LFP em tempo real podem também ser utilizados para modular a estimulação das configurações, criando laços de realimentação para a modulação do estimulador em configuração contínua. Tais dispositivos podem ajudar a prolongar a vida da bateria, assim como permitir a estimulação intermitente em casos em que podem não serem necessárias estimulação constantes, como por exemplo para o aumento na formação de memórias. Outras formas de estimulação, tal como a estimulação transcraniana magnética, ultra-som focado, e estimulação optogenetica possivelmente, podem também desempenhar um papel na modulação de neurocircuitos aberrantes. Como aplicações clínicas da estimulação elétrica continuam a se expandir no futuro, assim também será a nossa compreensão do cérebro como uma coleção de regiões altamente conectadas, falando umas com as outros em uma linguagem de oscilações e disparar padrões explosivos que estamos apenas começando a decodificar. (tradução Hugo)

Activa® PC+S

New Medtronic Deep Brain Stimulation System the First to Sense and Record Brain Activity While Delivering Therapy

First Implant of Activa® PC+S Deep Brain Stimulation System Initiates Research That Could One Day Significantly Change How Neurological and Psychological Diseases are Treated MINNEAPOLIS AND MUNICH - August 7, 2013 - Medtronic, Inc. (NYSE: MDT) today announced the first implant of a novel deep brain stimulation (DBS) system that, for the first time, enables the sensing and recording of select brain activity while simultaneously providing targeted DBS therapy. This initiates research on how the brain responds to the therapy and could yield insights that one day significantly change the way people with devastating neurological and psychological disorders, such as Parkinson's disease, essential tremor, dystonia, and treatment-resistant obsessive-compulsive disorder, are treated. (Medtronic, Inc. (NYSE: MDT) anunciou hoje o primeiro implante de um novo sistema de estimulação profunda do cérebro (DBS), sistema que, pela primeira vez, permite a detecção e registro da atividade cerebral e ao mesmo tempo selecionar uma terapia DBS ao alvo. Isto inicia a pesquisa sobre como o cérebro responde à terapia e como pode produzir insights que um dia mudarão significativamente a forma como as pessoas com distúrbios neurológicos e psicológicos devastadores, como a doença de Parkinson, tremor essencial, distonia, e resistentes ao tratamento do distúrbio obsessivo -compulsivo, são tratadas.) The Activa® PC+S DBS system delivers proven Medtronic DBS Therapy while at the same time sensing and recording electrical activity in key areas of the brain using sensing technology and an adjustable algorithm, which enable the system to gather brain signals at various moments as selected by a physician.  Initially, this new technology will be made available to a select group of physicians worldwide for use in clinical studies. These physicians will use the system to map the brain's responses to Medtronic DBS Therapy and explore applications for the therapy across a range of neurological and psychological conditions. (O sistema + Activa ® PC S Medtronic DBS Therapy possibilita ao mesmo tempo a aplicação e monitoramento da atividade elétrica em áreas chave do cérebro que utilizam tecnologia de sensoriamento e um algoritmo ajustável​​, que permite ao sistema coletar os sinais do cérebro em vários momentos selecionados por um médico. Inicialmente, esta nova tecnologia estará disponível para um seleto grupo de médicos em todo o mundo para uso em estudos clínicos. Estes médicos usarão o sistema para mapear as respostas do cérebro à Medtronic DBS Terapia e explorar as aplicações para a terapia em uma variedade de condições neurológicas e psicológicas.) The Activa PC+S system, which delivers stimulation to targeted areas of the brain like existing Medtronic DBS systems, was implanted for the first time at Ludwig Maximilians University in Munich, Germany in a person with Parkinson's disease. This patient will be treated by a team that includes neurologist Kai Bötzel, department of neurology, Ludwig Maximilian University and neurosurgeon Jan Mehrkens, M.D., head of functional neurosurgery, Ludwig Maximilian University, who implanted the system. Dr. Bötzel will be the first to use data gathered by the Activa PC+S system to gain unprecedented insight into how the brain responds to DBS therapy. "DBS therapy works for people with Parkinson's disease and other movement disorders, but there is much to learn about how the brain responds to the therapy," said Dr. Bötzel. "This new system will allow us to treat patients with conventional DBS therapy, while at the same time opening the door for research that was not possible until now. We hope these insights will lead to the development of effective new treatments tailored to the needs of individuals." "Devastating conditions like Parkinson's disease and obsessive-compulsive disorder take a significant toll on countless people, as well as their loved ones," said Lothar Krinke, Ph.D., vice president and general manager of the Deep Brain Stimulation business in Medtronic's Neuromodulation division. "Medtronic is excited to provide this new system to researchers worldwide, and we expect that their respective studies will lead to accelerated understanding of how neurological and psychological conditions develop and progress. This represents a significant milestone for DBS therapy and the long-term journey toward a closed-loop DBS system, which could personalize therapy by using device data to automatically adjust to the needs of individual patients." Medtronic's Activa PC+S system received CE (Conformité Européenne) mark in January 2013. It is not approved by the U.S. Food and Drug Administration for commercial use in the United States, and will be made available to select physicians for investigational use only. Additional implants of the Activa PC+S system, including the first implant in the United States, will take place in the coming months. Multimedia Release A multimedia version of this release, with links to graphics, animation and additional background information can be found at: http://bit.ly/19C3FLc About Medtronic DBS Therapy DBS therapy uses a surgically implanted medical device, similar to a pacemaker, to deliver mild electrical pulses to precisely targeted areas of the brain. The stimulation can be programmed and adjusted non-invasively by a trained clinician to maximize symptom control and minimize side effects. More than 100,000 patients worldwide have received Medtronic DBS Therapy. The therapy is currently approved in many locations around the world, including Europe and the United States, for the treatment of the disabling symptoms of essential tremor, advanced Parkinson's disease and chronic intractable primary dystonia, for which approval in the United States is under a Humanitarian Device Exemption (HDE). In Europe, Canada and Australia, DBS therapy is approved for the treatment of refractory epilepsy. DBS therapy is also approved for the treatment of severe, treatment-resistant obsessive-compulsive disorder in the European Union and Australia, and in the United States under an HDE. Medtronic's Leadership in Neuromodulation Medtronic developed and leads the field of neuromodulation, the targeted and regulated delivery of electrical pulses and pharmaceuticals to specific sites in the nervous system. The company's Neuromodulation business includes implantable neurostimulation and targeted drug delivery systems for the management of chronic pain, common movement disorders, spasticity and urologic and gastrointestinal disorders. About Medtronic Medtronic, Inc. (www.medtronic.com), headquartered in Minneapolis, is the global leader in medical technology - alleviating pain, restoring health, and extending life for millions of people around the world. Any forward-looking statements are subject to risks and uncertainties such as those described in Medtronic's periodic reports on file with the Securities and Exchange Commission. Actual results may differ materially from anticipated results. Fonte: Medtronic. Em resumo: O novo sistema em testes utiliza eletrodos diferentes dos utilizados atualmente que possibilitam ao médico monitorar graficamente o formato do campo eletrodinâmico gerado no entorno dos núcleos cerebrais alvos possibilitando um feedback da estimulação, otimizando-a.