segunda-feira, 18 de novembro de 2013

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
Neurosurg Focus. 2013;35(5):e1 
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


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.


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)

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