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
Sumário:
- 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)
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)
