Review
Deep brain stimulation for epilepsy in clinical practice and in animal models

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Abstract

Given the tremendous success of deep brain stimulation (DBS) for the treatment of movement and neuropsychiatric disorders, clinicians have begun to open up to the possible use of electrical stimulation for the treatment of patients with uncontrolled seizures. DBS of various neural targets has been investigated in clinical studies and animal studies, including the anterior nucleus of thalamus (ANT), cerebellum, hippocampus, subthalamic nucleus (STN), centromedian nucleus of the thalamus (CMT), caudate nucleus (CN). Recently, a large and multicenter trial (SANTE: Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy) was conducted and subsequently with encouraging results, making ANT the most well-established target for DBS in the treatment of epilepsy to date. Here, we endeavor to review mainly the animal studies and clinical studies of ANT DBS to further explore the more reliable target.

Highlights

► Clinicians have begun to open up to the possible use of DBS for refractory Epilepsy. ► DBS of various neural targets has been investigated in clinical studies and animal studies. ► ANT is a promising and preferable target in seizure control for intractable epilepsy. ► We review mainly the animal studies and clinical studies of ANT DBS for epilepsy.

Introduction

Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures [5]. About 50 million people worldwide have epilepsy, with almost 90% of these people being in developing countries [105]. If seizures cannot be controlled, the patient may experience major disruptions in family, social, educational, and vocational activities that can have profound impacts on the quality of life [31].

Despite chronic medication therapy, which is based on the modulation of cortical inhibition/excitation balance to prevent seizures, up to 30% of patients with epilepsy will suffer from persistent seizures [77], [84]. A subset of these patients will be candidates for anterior temporal lobectomy, which in reported series has resulted in 80–90% seizure freedom [94]. In addition, stereotactic radiosurgery (RS) is currently under evaluation as an alternative to open surgery for mesial temporal lobe epilepsy (MTLE) [10]. However, both open surgery and stereotactic radiosurgery can be limited by anticipated functional deficits such as memory loss or cognitive impairment [41]. Moreover, patients who have seizures arising from eloquent cortex, or which are multiple focal, bilateral, or generalized, are not candidates for resective surgery [45]. Such intractable epilepsy, both resistant to drug treatment and unsuitable for surgery, is a significant public health problem so that other alternative therapeutic approaches are needed.

For these patients, neurostimulation has a potential for benefit. Different approaches exist for treatment, depending on the brain region that is targeted and the way the stimulation is applied [27], [41], [65], [76], [86]. The aim is to reduce the probability of seizure occurrence and/or propagation, either by manipulating remote control systems (vagus nerve stimulation, deep brain stimulation) or by interfering with the epileptogenic zone itself (direct cortex stimulation).

Vagal nerve stimulation has already been a success in intractable epilepsy and suggests that neuronal excitability can be significantly altered by electrical currents [6]. Nevertheless, most of these patients will not be seizure-free. Thus, due to the remarkable success of deep brain stimulation (DBS) for movement disorders [34], [48], combined with its advantages of programmability, reversibility, and low risk of complications [19], [81], there has been an explosion of research into implantable deep brain devices for treating refractory epilepsy [54], [55]. DBS of various neural targets has been investigated in clinical studies and animal studies, including the anterior nucleus of thalamus (ANT), cerebellum, hippocampus, subthalamic nucleus (STN), Centromedian nucleus of the thalamus (CMT), caudate nucleus (CN) (Table 1, Table 2). Recently, a multicenter and randomized trial (SANTE) of 110 patients was conducted to demonstrate the effectiveness of bilateral stimulation of ANT and had already provided encouraging data, added with its close connection to the mesial temporal structures via the fornix, mamilllothalamic tracts, and thalamocortico radiations, making ANT the most well-established target for DBS in the treatment of epilepsy to date.

Section snippets

Deep brain stimulation of ANT

Relevant circuits and advantages of targeting ANT: There is a concept that disorders of treated with DBS are fundamentally disorders of a specific brain network, as opposed to a specific neuron type, ion channel, or molecule [18], [56], which appears to hold true with epilepsy. Radiologic imaging and animal studies have confirmed the enhancement of metabolic activity in structures of neuroanatomic circuits described later, which supports the hypothesis that the neuroanatomic circuits may be

Hippocampus

Stimulation of the seizure onset zone is another attempt to control seizures by brain stimulation. Velasco et al. pioneered stimulation in the hippocampus with continuous stimulation, and reported exceedingly good outcomes in nine patients [101]. Boon implanted ten patients in the hippocampus and reported a good outcome in seven of the ten patients [7]. Another study with five patients reported less successful outcomes [90]. Stimulation of hippocampus could potentially avoid memory loss

Mechanisms of action of DBS

The mechanisms of action of DBS in reducing seizures remain unclear. Studies showed that both stimulation parameters and relevant modulators work together to take part in the potential mechanisms of DBS to influence stimulation outcomes [1] (Fig. 1). Some authors support the hypothesis that actual stimulation is not necessary to achieve efficacy and claim that efficacy is based on the lesion provoked by the insertion of the electrode (the so-called microthalamotomy effect) in animal and in

Optimizing stimulation to avoid DBS failures

Optimizing stimulation parameters: Most protocols that have evaluated DBS for epilepsy have used stimulation parameters derived from the literature on DBS for movement disorders. In DBS for movement disorders, continuous stimulation during therapy is standard [4], [42]. Recent experimental data suggest that continuous stimulation may fail to control the occurrence of seizures for a refractory period of about 60 s exists during which any stimulation is ineffective [24], [78]. Continuous

Conclusion

The momentum for DBS in the treatment of epilepsy is quickly building with the recent SANTE trial and the FDA's review of potential approval, making ANT a promising and preferable target in seizure control for intractable epilepsy. However, SANTE trial excluded the seizure types such as Lenox-Gastaut or generalized onset epilepsy in patient selection. In addition, only the patients with seizures of temporal lobe origin had a significant decrease in seizure frequency with ANT stimulation and

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (30870884) and the Shandong Provincial Outstanding Medical Academic Professional Program.

References (107)

  • M.A. Goldstein et al.

    Epilepsy and anxiety

    Epilepsy Behav.

    (2000)
  • F. Guo et al.

    Abnormal expressions of glutamate transporters and metabotropic glutamate receptor 1 in the spontaneously epileptic rat hippocampus

    Brain Res. Bull.

    (2010)
  • J.J. Hablitz

    Intramuscular penicillin epilepsy in the cat: effects of chronic cerebellar stimulation

    Exp. Neurol.

    (1976)
  • C. Halpern et al.

    Deep brain stimulation in neurologic disorders

    Parkinsonism Relat. Disord.

    (2007)
  • C. Hamani et al.

    Deep brain stimulation of the anterior nucleus of the thalamus: effects of electrical stimulation on pilocarpine-induced seizures and status epilepticus

    Epilepsy Res.

    (2008)
  • H.H. Jasper

    Current evaluation of the concepts of centrencephalic and cortico-reticular seizures

    Electroencephalogr. Clin. Neurophysiol.

    (1991)
  • B.C. Jobst

    Brain stimulation for surgical epilepsy

    Epilepsy Res.

    (2010)
  • M.D. Johnson et al.

    Mechanisms and targets of deep brain stimulation in movement disorders

    Neurotherapeutics

    (2008)
  • B.C. Lega et al.

    Deep brain stimulation in the treatment of refractory epilepsy: update on current data and future directions

    Neurobiol. Dis.

    (2010)
  • B. Litt et al.

    Brain stimulation for epilepsy

    Epilepsy Behav.

    (2001)
  • A.M. Lozano et al.

    How does DBS work?

    Suppl. Clin. Neurophysiol.

    (2004)
  • C.C. McIntyre et al.

    Uncovering the mechanism(s) of action of deep brain stimulation: activation, inhibition, or both

    Clin. Neurophysiol.

    (2004)
  • M.A. Mirski et al.

    Anticonvulsant effect of anterior thalamic high frequency electrical stimulation in the rat

    Epilepsy Res.

    (1997)
  • S.J. Nagel et al.

    Deep brain stimulation for epilepsy

    Neuromodulation

    (2009)
  • W.J. Nauta et al.

    Projections of the lentiform nucleus in the monkey

    Brain Res.

    (1966)
  • D. O'Sullivan et al.

    Long-term follow-up of thalamus for tremor and STN for Parkinson's disease

    Brain Res. Bull.

    (2009)
  • J.B. Ranck

    Which elements are excited in electrical stimulation of mammalian central nervous system: a review

    Brain Res.

    (1975)
  • A. Represa et al.

    Hippocampal plasticity in childhood epilepsy

    Neurosci. Lett.

    (1989)
  • G.J. Royce

    Cells of origin of subcortical afferents to the caudate nucleus: a horseradish peroxidase study in the cat

    Brain Res.

    (1978)
  • G.J. Royce

    Single thalamic neurons which project to both the rostral cortex and caudate nucleus studied with the fluorescent double labeling method

    Exp. Neurol.

    (1983)
  • C. Rubio et al.

    Stimulation of the superior cerebellar peduncle during the development of amygdaloid kindling in rats

    Brain Res.

    (2004)
  • A Stefani et al.

    Multi-target strategy for Parkinsonian patients: the role of deep brain stimulation in the centromedian-parafascicularis complex

    Brain Res. Bull.

    (2009)
  • F.T. Sun et al.

    Responsive cortical stimulation for the treatment of epilepsy

    Neurotherapeutics

    (2008)
  • A.L. Velasco et al.

    Absolute and relative predictor values of some non-invasive and invasive studies for the outcome of anterior temporal lobectomy

    Arch. Med. Res.

    (2000)
  • D.M. Andrade et al.

    Long-term follow-up of patients with thalamic deep brain stimulation for epilepsy

    Neurology

    (2006)
  • A.L. Benabid et al.

    Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders

    J. Neurosurg.

    (1996)
  • W. Blume et al.

    Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology

    Epilepsia

    (2001)
  • P. Boon et al.

    Deep brain stimulation in patients with refractory temporal lobe epilepsy

    Epilepsia

    (2007)
  • S. Chabardes et al.

    Deep brain stimulation in epilepsy with particular reference to the subthalamic nucleus

    Epileptic Disord.

    (2002)
  • E.F. Chang et al.

    Predictors of efficacy after stereotactic radiosurgery for medial temporal lobe epilepsy

    Neurology

    (2010)
  • S.A. Chkhenkeli et al.

    Effects of therapeutic stimulation of nucleus caudatus on epileptic electrical activity of brain in patients with intractable epilepsy

    Stereotact. Funct. Neurosurg.

    (1997)
  • I.S. Cooper et al.

    The effect of chronic cerebellar stimulation upon epilepsy in man

    Trans. Am. Neurol. Assoc.

    (1973)
  • I.S. Cooper et al.

    Chronic cerebellar stimulation in epilepsy. Clinical and anatomical studies

    Arch. Neurol.

    (1976)
  • W.M. Cowan et al.

    The origin of the mammillary peduncle and other hypothalamic connexions from the midbrain

    J. Anat.

    (1964)
  • J.A. Cruce

    An autoradiographic study of the descending connections of the mammillary nuclei of the rat

    J. Comp. Neurol.

    (1977)
  • R. Davis et al.

    Cerebellar stimulation for seizure control: 17-year study

    Stereotact. Funct. Neurosurg.

    (1992)
  • M.R. DeLong et al.

    Circuits and circuit disorders of the basal ganglia

    Arch. Neurol.

    (2007)
  • M. Deogaonkar et al.

    Surgical complications in 800 consecutive DBS implants, Abstract

  • J.O. Dostrovsky et al.

    Mechanisms of deep brain stimulation

    Mov. Disord.

    (2002)
  • R. Fisher et al.

    Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy

    Epilepsia

    (2010)
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