Deep Brain Stimulation for Epilepsy

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CHAPTER 69 Deep Brain Stimulation for Epilepsy

Robert S. Fisher, Brian Litt, William C. Stacey

Epilepsy is a highly prevalent, serious neurological and sometimes neurosurgical disorder that affects approximately 1% of the world’s population. In the majority of people, epilepsy can be controlled adequately with antiepileptic medications, but some continue to experience breakthrough seizures or unacceptable side effects of medications. For this highly needy population, new treatment strategies are required. Deep brain stimulation (DBS) is one such new modality of treatment and at the time of this writing is just on the verge of probable admission into the mainstream of epilepsy therapies. Although palliative, DBS has the advantage of tissue preservation and also the potential ability to favorably influence multifocal epilepsy.

Electrical stimulation of the nervous system has a very long history. Legend holds that a freed slave of Emperor Tiberius in 15 AD accidentally stepped on a torpedo electric fish. After recovering from the shock, he noted improvement in his gout. A local physician consequently recommended torpedo fish treatment of pain.^1,² From early times, electrical stimulation therapies were prone to adoption by charlatans. The grand electrical machine of Francis Lowndes produced static electricity with impressive effects on the subject’s hairstyle and purported benefits for a wide list of maladies.³ In the 1700s, a Leyden jar, an early form of a battery, was used to generate sparks claimed to be beneficial for paralysis, blindness, warts, toothache, St. Vitus’ chorea, and death by drowning. A theatrical high point of DBS was accomplished by Dr. José Delgado, who stopped a charging bull with handheld radio control of brain electrodes implanted in the animal’s internal capsule and basal ganglia.

The first legitimate scientific use of electrical brain stimulation in a live patient was probably performed by Dr. Roberts Bartholow.² The patient had an infected scalp ulcer and osteomyelitis. Débridement led to exposure of the brain. During the procedure, Dr. Bartholow stimulated the exposed cortex with a sporadic current source and noted muscle contractions. Intraoperative electrical brain stimulation came into mainstream medicine through the efforts of the neurosurgeon Wilder Penfield and the neurologist Herbert Jasper at the Montréal Neurological Institute in the 1940s and 1950s. Their use of stimulation was diagnostic rather than explicitly therapeutic, and the information gained from electrical stimulation mapping was used to aid tailored resections of the brain for lesions and seizures.

Many innovators used depth wires to record deep in the brain in the late 1940s and early 1950s, but therapeutic stimulation via implanted wires was probably first performed by Heath in the early 1950s, with stimulation of the posterior frontal/septal region being used to alleviate pain and psychosis. In a 1963 article, R. G. Heath refers to work begun in 1952 with electrodes implanted into the centromedian nucleus, septal region, and mesencephalic tegmentum in a patient with psychomotor epilepsy.⁴ Stimulation was set at 100 Hz, 3 to 5 mA for 15 minutes and could be triggered by the patient. A variety of subjective symptoms were produced by stimulation, some of which were sufficiently positive that patients would initiate stimulation up to 300 times per hour. At one point the patient’s acute psychotic symptoms were interrupted with septal stimulation.

Cerebellar Stimulation

Irving Cooper, working from Valhalla, New York, pioneered the use of DBS as chronic therapy for epilepsy.⁵ His first therapeutic target of DBS for epilepsy was the cerebellum based on previous animal work. Sherrington showed in 1897 that the cerebellar cortex provoked inhibitory activity in various structures. In 1941, Moruzzi demonstrated that motor twitches in cats from strychnine on the cortex could be attenuated by cerebellar stimulation.⁶ In 1955, Cooke and Snider demonstrated that 60-Hz stimulation of the cerebellar cortex could modify seizures provoked by electrical stimulation of the cat cerebral cortex.⁷ Cooper and colleagues used a silicon mesh with four to eight pairs of bipolar platinum electrodes applied to the midline cerebellum or neocerebellum to stimulate the cerebellar cortex chronically in patients.⁸ Electrodes were stimulated through a subcutaneous antenna on the chest by inductive coupling through the skin. Their 1973 article reported cerebellar stimulation in seven patients with intractable seizures, three with psychomotor seizures, three with grand mal seizures, two with petit mal seizures, and one with focal seizures involving the left side of the face, arm, and leg. Six of the seven were said to improve over a period of 8 months, and virtually complete control of seizures was achieved in four of them.

The original article by Cooper and coworkers in 1973 stimulated a small series of cerebellar implantation in people with epilepsy. As summarized by Krauss and Fisher, 11 uncontrolled studies showed benefit of cerebellar stimulation.⁹ Two blinded controlled studies, one by Wright and colleagures¹⁰ and the other by Van Buren and associates,¹¹ were, however, negative. The Wright study was performed in 12 patients with treatment lasting 6 months. The Van Buren study included 5 patients. Neither showed efficacy over sham stimulation. Even though these two controlled studies were criticized methodologically and totaled just 17 patients, they served to place cerebellar stimulation for epilepsy on the back burner for many years. Certain practitioners, notably the neurosurgeon Ross Davis, continued arguments that cerebellar stimulation could be effective in selected people with epilepsy.¹²^–¹⁶ At a mean follow-up of 17 years, 19 patients with cerebellar stimulators were contacted by Davis, and 53% indicated that that they were seizure free and 32% had reduced seizures.¹² Generalized tonic-clonic seizures appeared to show the best response.

Velasco and colleagues performed a small double-blind, randomized trial of bilateral stimulation of the superomedial surface of the cerebellum in five patients with refractory motor seizures.¹⁷ The parameters of the stimulation consisted of 10 pulses per second, 4 minutes on and 4 minutes off adjusted to a current density of 2 microcoulombs (µC) per square centimeter per pulse. Statistical analysis indicated a beneficial effect of stimulation. The three patients who completed the protocol for 2 years showed a reduction in generalized tonic-clonic seizures to a mean of 24% of baseline levels. Definitive documentation of the efficacy of cerebellar stimulation will probably be provided only by a large, controlled clinical trial.

Stimulation Sites for Treating Epilepsy

Figure 69-1 illustrates various regions of the nervous system that have been stimulated in humans to treat seizures. Direct cortical stimulation is discussed separately in this text. Exemplary studies at the different sites are tabulated in Table 69-1. No attempt is made to list all DBS studies in the literature. Only stimulation of the peripheral vagus nerve is licensed in the United States for epilepsy therapy. Vagus nerve stimulation is not discussed in this chapter.

FIGURE 69-1 Sites in the brain (and vagus nerve) that have been subjected to deep brain stimulation to treat seizures. CM, centromedian thalamus. Except for direct focus and vagus, black lines indicate the approximate areus superficial to the deep brain stimulation sites.

TABLE 69-1 Studies of Stimulation Sites

The literature on DBS for neurological disorders is difficult to interpret. Reports usually consist of small, uncontrolled studies. Particularly in the early phases of DBS, descriptions of seizure types, specific seizure frequencies, and concurrent therapies were lacking. Most articles reported various degrees of improvement in seizure frequency after stimulation, but it remains unclear how much of this was due to stimulation. An important alternative explanation would involve either a placebo effect or regression to the mean, by which patients would return to their baseline seizure frequency after entering a clinical trial at a particularly bad point in their disorder. Early studies were done without the benefit of magnetic resonance imaging (MRI) to accurately localize placement of the stimulating electrodes. Stimulation parameters often varied widely among patients in a particular series. The actual number of patients treated is difficult to estimate because authors frequently published different reports with overlapping patients. Nevertheless, we briefly review each of the brain sites (other than direct stimulation of the cortex) stimulated to treat seizures. Cerebellar simulation was discussed earlier in its historical context.

Brainstem

The brainstem is the source of the reticular activating system classically described by Moruzzi and Magoun.⁶ Activation of the reticular activating system would be expected to result in electroencephalographic (EEG) desynchronization and make the formation of seizures, which consist of highly synchronous rhythms, more difficult. Only two studies have evaluated brainstem stimulation for epilepsy in patients. In these studies,^19,²⁰ the locus caeruleus was stimulated in a total of three patients. Benefit was reported in the form of a reduction in seizures and prolongation of auras, but the benefit was mild and sustained for only a few days.

Posterior Hypothalamus

The mammillary bodies of the posterior hypothalamus are on the classic circuit of Papez, which links hippocampal outflow to the mammillary bodies and anterior thalamus, to the cingulate, and then back to the entorhinal cortex and hippocampus. Interruption of the mammillothalamic tract prevents pentylenetetrazol-induced seizures in guinea pigs.⁵⁵ Stimulation of the mammillary nuclei at high frequency with depth electrodes similarly increases the pentylenetetrazol seizure threshold in rats.⁵⁶ Activation of the histamine system mediated by the mammillary nucleus was hypothesized to be involved in the mechanism of action of mammillary body DBS.⁵⁷ With these experimental data as background, van Rijckevorsel and colleagues in Brussels implanted DBS electrodes in three patients with refractory epilepsy.²¹ They observed paroxysmal epileptiform discharges in the mammillary bodies. Although potentially beneficial for seizures, stimulation and further implantations were not continued because of the potential risk for hemorrhage.

Corpus Callosum

Marino Junior and Gronich in São Paulo implanted DBS electrodes in 10 patients with disabling convulsive disorders.²² Preliminary evaluation suggested that such implantation was better tolerated than corpus callosotomy and possibly beneficial against the seizures.

Caudate

A long history of animal experimentation suggests the possible utility of DBS in the caudate for controlling seizures. The caudate has been shown to exert inhibitory control over propagation of seizures. In 1982, Oakley and Ojemann showed that caudate stimulation attenuated seizures produced by placing alumina cream on the cortex of monkeys.⁵⁸ After continuous caudate stimulation, five of the six monkeys exhibited a rebound in increased seizure activity. Psatta showed that caudate stimulation at 5 Hz, 0.3 msec, 1- to 5-V pulses for 1 to 3 seconds reduced interictal spiking in freely moving cats made epileptic by cobalt on the neocortex.⁵⁹ La Grutta and Sabatino placed bipolar stimulating electrodes bilaterally in the caudate of cats, followed by hippocampal injection of penicillin. Hippocampal spiking decreased by 55% with stimulation.⁶⁰

Clinical application of caudate stimulation was first performed by Sramka and associates. In a study of various DBS sites for epilepsy, six patients underwent unilateral or bilateral caudate stimulation. Over a period of 4 to 6 days of treatment, two were said to be without seizures and four improved.²³ Further studies by Sramka and the Chkhenkelis of low-frequency (4 to 8 Hz) stimulation of the head of the caudate reduced the frequency of mesial temporal neocortical seizures, often to 10% to 30% of baseline levels.²⁴^–²⁶

Centromedian Thalamus

The centromedian thalamus (CM) is part of the so-called nonspecific thalamic activating system that interacts with diffuse regions of the cortex and, in the case of the CM, also with the basal ganglia and brainstem. In 1987, the Velasco brothers and colleagues implanted electrodes in five patients with multifocal or primary generalized refractory seizures.²⁷ Stimulation parameters were bipolar square pulses 0.1 msec in duration, 60 to 100 Hz, and 0.8 to 2.0 mA in trains of 1 minute every 5 minutes, alternating on the right and left side for 2 hours daily. The stimulator wires were external. Generalized tonic-clonic seizures were reduced 80% to 100% and complex partial seizures 60% to 100%. One patient with myoclonic seizures had the seizures abolished completely with stimulation.

Fisher and associates tested this protocol in a double-blind, randomized crossover trial in seven patients.²⁸ Stimulation was on or off for 3 months, then off in all patients for a 3-month “wash-out,” and then off or on as the opposite treatment of the first 3 months for an additional 3 months. Patients could not tell whether the stimulator was on or off. Overall seizure frequency improved 30% but the difference was not statistically significant. The patient with the greatest improvement could not be analyzed because the family did not wish the stimulator settings to be changed from the apparently beneficial effects in the first 3 months (stimulator on). The degree of carryover effect from stimulation in the first cycle could not be estimated but may have influenced the frequency of seizures during the control months. Subsequently, Velasco and colleagues implanted deep brain stimulators into the centromedian nucleus in 50 to 100 patients.³⁰^–³³ ^,61 ^,62 Further experience suggested that generalized tonic-clonic seizures improved the most and atypical absence seizures in part, but complex partial seizures and focal EEG spiking improved little. Patients with the otherwise highly intractable Lennox-Gastaut syndrome had up to an 80% reduction in seizures. The only controlled study of CM stimulation has been that of Fisher and associates,²⁸ and no definitive large randomized trial has been performed.

Hippocampus

Most brain regions subjected to DBS for seizures are synaptically connected to but remote from the seizure focus or foci. Hippocampal stimulation provides an exception to this rule in that the hippocampus is often the primary site of the seizure focus. Direct hippocampal stimulation in humans to treat epilepsy was again pioneered by the Velasco brothers. In 2000, Velasco and colleagues published a study of 16 patients with complex partial and secondarily generalized tonic-clonic seizures.³⁴ Hippocampal stimulation was delivered at high frequency, low amplitude continuously with 130 pulses per second, 450-µsec pulse duration, and an amplitude of 200 to 400 µA. In 7 patients, seizures were abolished after 6 days of stimulation. Long-term follow-up by Velasco and associates of 9 patients for 18 months to 7 years showed that the reduction in seizures was greater than 95% with hippocampal stimulation, provided that the baseline MRI findings were normal, versus a 50% to 70% reduction in the presence of mesial temporal sclerosis.⁴¹

Vonck, Boon, and colleagues extended the findings of Velasco for hippocampal stimulation.^37,³⁸ In an initial study of 3 patients with complex partial seizures, all had greater than 50% improvement in their seizures. In a later study of 7 patients implanted with bilateral hippocampal electrodes, seizures were reduced by half or better. Boon and coworkers evaluated 10 patients with long-term hippocampal stimulation: 1 became seizure free, 1 had a 90% reduction, 5 had at least a 50% reduction, 2 had a 30% to 49% reduction, and 1 was not helped.⁴² A paradigm of seizure detection and hippocampal stimulation in response was used by Osorio and colleagues in 4 patients.³⁹ With this paradigm, seizures were reduced by 56%. A small, randomized crossover trial involving 4 patients was performed by Tellez-Zenteno and associates.⁴⁰ Left hippocampal stimulation at 190 Hz was on for a month and off for a month or in the reverse order. Seizure frequency decreased a median of 15%, which was not statistically significant. No large, randomized trial of hippocampal stimulation has been completed as of the time of this writing, but such a trial is under development.

Subthalamic Nucleus

The subthalamic nucleus (STN) is a target for the treatment of certain movement disorders.⁶³ In 1998, Vercueil, Benabid, and colleagues demonstrated that high-frequency stimulation of the STN suppressed absence seizures in a genetic absence seizure strain of rats.⁶⁴ In the clinic of Benabid, this was carried forward to patients.⁴³ DBS electrodes were inserted bilaterally into the STN of five patients. Stimulation was mostly continuous at 130 pulses per second, a duration of 90 µsec, and an amplitude 1.5 to 5.2 V. Mean reductions in seizure frequency for each patient were 81%, 42%, 68%, 67%, and 0%. Neme and colleagues implanted electrodes in the STN in four patients with partial epilepsy.⁴⁵ Two of the patients had a reduction in seizures in the range of 42% to 75%. No benefit occurred in the other two. Handforth and coworkers showed a 33% to 50% reduction during the time of STN stimulation in two patients with partial seizures.⁴⁶ Vesper reported 50% improvement with STN stimulation in a patient with progressive myoclonic epilepsy.⁴⁷

Anterior Nucleus of the Thalamus

The anterior nucleus of the thalamus (AN) was an original target of Cooper in his early studies of DBS for epilepsy. His rationale for implanting in this particular nucleus was not clearly expressed in his publications, except that it was considered to be part of the nonspecific thalamus. The AN can influence EEG activity in regions of the frontal cortex. Cooper, Upton, and associates published several case series reporting the beneficial effects of AN stimulation on seizures,⁶⁵^–⁶⁸ but the results were not quantifiable from the publications. In 1988, a group from the Medical College of Pennsylvania published two abstracts on 5 patients who underwent AN stimulation.⁴⁹ Seizures were reduced to 23% of baseline. A pilot study was then initiated by Fisher and colleagues to develop parameters and methodology for a controlled trial of AN stimulation.²⁸ The results in the 10 patients in the pilot study were published in two separate reports. The group from Toronto reported on 5 of the patients.⁵⁰ Seizures were reduced to a mean of 47% of baseline. Interestingly, benefit appeared to occur mainly after implantation, before turning on the stimulator. The second cohort of 5 different patients in the pilot trial was reported from the Barrow Neurological Institute and the University of Pennsylvania.⁵¹ Seizures were reduced to 33% of baseline. There appeared to be particular benefit against seizures of a type that could produce falls and injuries. In South Korea, Lee and associates showed seizures to be reduced to 44% of baseline with AN stimulation in 6 patients.⁵² Lim and colleagues in Taiwan showed a reduction to 49% of baseline in 4 patients.⁵³ Osorio and colleagues in Kansas reported a reduction to 25% of baseline in 4 patients with AN stimulation.³⁹ A per-patient analysis of the six studies demonstrated a mean reduction in seizures to 47% of baseline levels at approximately 12 months after implantation.

Recently, a multicenter, randomized, double-blind parallel-group study of AN stimulation for epilepsy was published.54a,69 The study, sponsored by Medtronic, is abbreviated SANTE for “stimulation of the anterior nucleus of the thalamus for epilepsy.” The protocol admitted patients with partial and secondarily generalized seizures at a frequency of six or more per month and refractory to at least three antiepileptic drugs. Patients could not be candidates for conventional resective surgery. Stimulators were implanted bilaterally in the AN and connected to a Medtronic (Santa Rosa, CA) model 7428 Kinetra neurostimulator using DBS model 3387 leads. A 3-month baseline seizure frequency was recorded before implantation of the stimulator, and randomization was performed 1 month later. Patients randomized to the treatment group received 5-V stimulation at 145 pulses per second, 90-µsec pulse duration, on for 11 minutes and off for 5 minutes, synchronously to the left and right. Those randomized to the control group underwent stimulation with the same settings, but at 0 V. After a 3-month double-blind phase, the stimulation parameters were set open-label to 5 V in all patients and then allowed to vary systematically. A total of 158 patients were entered into the study and 110 underwent implantation. During the 3-month blinded phase, the stimulated group experienced a 40.5% median reduction in seizures compared with baseline versus a 14.5% reduction in the control group (p = 0.038). Improvement was maintained during a 2-year open-label phase. No symptomatic hemorrhages or deaths attributable to stimulation occurred. Stimulated subjects reported more adverse events linked to depression or memory problems.

Complications

Complications of DBS can be categorized as tissue reactions, hemorrhage, abnormal sensations, memory impairment, infection, or an adverse impact on seizures. Tissue reactions to chronic cerebellar stimulation in monkeys were examined by Brown and coworkers.⁷⁰ After 2 months of stimulation of the cerebellum, light and electron microscopic analysis was performed on the monkey brains. The electrode array produced meningeal thickening and loss of Purkinje cells. An estimated charge density of 7.4 µC/cm² per pulse, which is approximately 5 times the usual clinical intensity, did not result in any morphologic changes in tissue. In contrast, Henderson and coauthors reported a case in which an electrode migrated from the thalamic ventral intermediate nucleus to the centromedian nucleus and produced cell loss in that region.⁷¹ Cell loss in the cerebellum may not always be a consequence of neurostimulation. Salcman and colleagues showed significant Purkinje cell loss in five patients in whom the cerebellar cortex was biopsied at the time of electrode implantation.⁷² Very little information is known about tissue loss as a result of thalamic stimulation to treat epilepsy. One patient treated by AN stimulation for seizures died of “sudden unexplained death in epilepsy” 8 months after implantation. Examination by microscopy and immunohistochemistry showed no significant changes other than mild inflammation along the electrode track.⁷³

Hemorrhage is perhaps the most feared complication of DBS. It usually occurs at the time of electrode implantation or immediately thereafter. Improvements in imaging technology, surgical technique, and the flexibility of electrodes have reduced the likelihood of a hemorrhagic complication. In addition, it is important to note that not all implantation-related hemorrhage is symptomatic; some hemorrhages are detectable only with neuroimaging. Little information is available about the risk for hemorrhage with implantation in the hippocampus, CM, or AN for epilepsy. One patient in an early trial of AN stimulation suffered a symptomatic hemorrhage resulting in prolonged hemiparesis, although that result was not documented in a scientific publication. Much more information is known about the complications of DBS for treating movement disorders because the number of patients is much larger and the experience over time much greater. In the pivotal trial of STN stimulation for Parkinson’s disease reported in the New England Journal of Medicine by the Deep-Brain Stimulation for Parkinson’s Disease Study Group, 3 of 102 (3%) patients experienced intracranial hemorrhage related to the implantation procedure.⁷⁴ Hemiparesis as a result of the hemorrhage developed in all 3. Three patients had seizures and 4 had infections. Beric and colleagues reported the complications of DBS for Parkinson’s disease, tremor, and dystonia after 149 implants in 86 patients.⁷⁵ Two patients (2.3%) experienced clinically significant hemorrhage. A third patient had a delayed chronic subdural hematoma discovered 2 months after implantation. Other complications included seizures in 2 patients (1 with hemorrhage), confusion in 4, and behavioral changes in 2, along with other occasional complications. Overall, 26 of 86 patients experienced some adverse event, and in 6 the effects were lasting. Sansur and coauthors specifically reported on the incidence of symptomatic hemorrhage after stereotactic electrode placement.⁷⁶ Between 1991 and 2005, two neurosurgeons placed 567 electrodes in 259 patients for DBS, radiofrequency lesioning, or recording of seizure foci. The overall risk for symptomatic hemorrhage was 1.2%, and 0.7% of the patients had lasting symptoms. Poor prognostic factors included old age, male sex, hypertension, and the diagnosis of Parkinson’s disease. This suggests that the incidence of symptomatic hemorrhage might be expected to be lower in a cohort of younger patients with epilepsy.

Hamani and Lozano reviewed hardware-related complications of DBS.⁷⁷ Adverse events were identified in 922 patients. The most common was infection in 6.1%, with the next most common being misplacement or migration of the leads in 5.1%, lead fractures in 5%, and skin erosion in 1.3%. Hariz and associates evaluated complications at 4 years in 69 patients participating in DBS implantation in the STN and globus pallidus pars interna (GPi).⁷⁸ Seven of the patients required additional surgery because of device-related complications such as infection, lead fracture, or skin erosion. Non–device-related complications included cognitive or memory decline or psychiatric disturbances in 18.8% of the STN patients and 12.5% of the GPi stimulation patients. A total of 4.7% of the STN patients exhibited depression. Speech difficulties were present in about 14% of the patients, disequilibrium or falls in 12.5%, and gait disorders in 14%. Numerous other side effects occurred at lower percentages.

DBS can produce untoward changes in cognition. Hippocampal stimulation with subdural strips or electrodes inserted into the hippocampus at 2 Hz, 3 V, and a pulse duration of 2.5 msec produced measurable deterioration in memory performance.⁷⁹ It is notable that this low-frequency stimulation of the hippocampus is distinct from the typical 130-Hz stimulation used in more recent clinical trials. However, memory deficits were also observed in an 11-year-old child undergoing 60-Hz, 1-msec, 1.0- to 7.5-mA stimulation, which is closer to the currently used parameters.⁸⁰

Stimulation of the thalamus can produce paresthesias and other abnormal sensations. Dostrovsky and Lozano studied more than 150 patients undergoing stereotactic thalamotomy for relief of tremor.⁸¹ Stimulation of the central thalamus produced paresthesias, illusions of movements, and occasionally other sensations. Stimulation of the centromedian nucleus is usually asymptomatic, but if the current spreads beyond the nucleus, paresthesias and ocular convergence could sometimes occur.²⁸

A few patients have had seizures with the implantation of electrodes for DBS, mostly as a consequence of hemorrhage or trauma. Reports of epilepsy secondary to stimulation-induced “kindling” have not emerged to date.

Mechanisms of Deep Brain Stimulation

The mechanisms of DBS as a therapy for epilepsy have largely been unexplored. Several studies have, however, evaluated the effects of brain stimulation in simple model systems or in the STN as a treatment of movement disorders. Theories of action tend to fall into three general categories: neuronal blockade; synaptic blockade by increased inhibition, decreased excitation, or both; disruption of neuronal networks; or some combination of these mechanisms.

At the level of an individual fiber, the effects of stimulation can be inferred from information about orientation of the current (longitudinal versus transverse), resistance of the membrane, extracellular and intracellular tissue, the presence of myelin and nodes of Ranvier, and action potentials and active membrane properties. At the level of a neuronal network, the effects are not predictable. Stimulation can excite inhibitory neurons and change the sign of the effect. Few brain nuclei are round and isotropic, so real-life stimulation probably spreads beyond the target nuclei, with unknown effects on other nuclei and nearby fibers of passage. In the immediate region of the stimulation, neurons may be depolarized to the point of inactivity, but excitatory effects may prevail at a distance.⁸² The effects of stimulation are well known to depend on the stimulus parameters, such that stimulation at one frequency or intensity may be inhibitory and at others, excitatory. Complex neuronal functions can be disrupted, but not replicated, by stimulation.

Mechanisms have been elucidated by studies involving hippocampal slices by Durand and colleagues ⁸³^–⁹¹ and by Schiff and associates.⁹²^–⁹⁴ Direct or alternating electric fields applied to hippocampal slices that have been made hyper-synchronous by various manipulations appear to be able to disrupt epileptiform activity in the slice. Stimulation produces direct current negative shifts accompanied by marked release of potassium from the intracellular space into the extracellular space. The elevation in extracellular potassium levels produces a depolarization block that causes the neurons to fail to fire because of inactivation of sodium channels. It is not known whether axons may still be able to fire in such circumstances.

At the gross level, stimulation of the STN or ventral intermediate nucleus for tremor or Parkinson’s disease imitates the effects of lesions, thus implying an inhibitory action of stimulation,⁹⁵ but the mechanisms of DBS are probably not just inhibitory. In live animals and humans, the effects of DBS appear to be more complex than simple depolarization block or neuronal inactivation. Stimulation of the rat STN with adjacent intracellular recording showed that neuronal firing is inhibited after stimulation but that action potentials can still be made to fire during the time of inhibition, which rules out depolarization block.⁹⁶ Furthermore, stimulation produces sequences of excitation followed by inhibition in some neurons. Unit recordings in patients undergoing implantation for Parkinson’s disease have shown similar inhibition of neurons after stimulation.⁸¹ In monkeys made Parkinson-like with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), stimulation of the STN excited neurons in the GPi, a target of outgoing STN neurons.⁹⁷ This suggests a functional stimulatory effect of DBS, even though local STN neurons show inhibition. Metabolic imaging with thalamic ventralis intermedius stimulation for tremor showed increased blood flow in the thalamus and ipsilateral frontal cortex.⁹⁸

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