The authors evaluated the extent to which the Subdural Pharmacotherapy Device (SPD), chronically implanted over the frontal cortex to perform periodic, localized muscimol-delivery/CSF removal cycles, affects overall behavior, motor performance, electroencephalography (EEG) activity, and blood and CSF neurochemistry in macaque monkeys.
Two monkeys were used to adjust methodology and 4 monkeys were subjected to comprehensive testing. Prior to surgery, the animals' behavior in a large test chamber was monitored, and the motor skills required to remove food pellets from food ports located on the walls of the chamber were determined. The monkeys underwent implantation of the subdural and extracranial SPD units. The subdural unit, a silicone strip integrating EEG electrodes and fluid-exchange ports, was positioned over the right frontal cortex. The control unit included a battery-powered, microprocessor-regulated dual minipump and radiofrequency module secured to the cranium. After implantation, the SPD automatically performed periodic saline or muscimol (1.0 mM) deliveries at 12-hour intervals, alternating with local CSF removals at 6-hour intervals. The antiepileptic efficacy of this muscimol concentration was verified by demonstrating its ability to prevent focal acetylcholine-induced seizures. During SPD treatment, the monkeys' behavior and motor performance were again monitored, and the power spectrum of their radiofrequency-transmitted EEG recordings was analyzed. Serum and CSF muscimol levels were measured with high-performance liquid chromatography electrochemical detection, and CSF protein levels were measured with turbidimetry.
The SPD was well tolerated in all monkeys for up to 11 months. The behavioral study revealed that during both saline and muscimol SPD treatment, the monkeys could achieve the maximum motor performance of 40 food-pellet removals per session, as before surgery. The EEG study showed that local EEG power spectra were not affected by muscimol treatment with SPD. The neurochemical study demonstrated that the administration of 1.0 mM muscimol into the neocortical subarachnoid space led to no detectable levels of this compound in the blood and cisternal CSF, as measured 1–125 minutes after delivery. Total protein levels were within the normal range in the cisternal CSF, but protein levels in the cortical-site CSF were significantly higher than normal: 361 ± 81.6 mg/dl. Abrupt discontinuation of 3-month, periodic, subdural muscimol treatments induced withdrawal seizures, which could be completely prevented by gradually tapering off the subdural muscimol concentration from 1.0 mM to 0.12–0.03 mM over a period of 2 weeks. The monkeys' general health and weight were maintained. Infection occurred only in one monkey 9 months after surgery.
Long-term, periodic, transmeningeal muscimol delivery with the SPD is essentially a safe procedure. If further improved and successfully adapted for use in humans, the SPD can be used for the treatment of intractable focal neocortical epilepsy affecting approximately 150,000 patients in the US.
Abbreviations used in this paper:ACh = acetylcholine; AED = antiepileptic drug; CCD = charged-coupled device; EEG = electroencephalography; HPLC-ED = high-performance liquid chromatography electrochemical detection; RF = radiofrequency; SPD = Subdural Pharmacotherapy Device.
BaptisteSLTangHMKuznieckyRIDevinskyOFrenchJALudvigN: Comparison of the antiepileptic properties of transmeningeally delivered muscimol, lidocaine, midazolam, pentobarbital and GABA, in rats. Neurosci Lett469:421–4242010
ClarkeGO'MahonySMaloneGDinanTG: An isocratic high performance liquid chromatography method for the determination of GABA and glutamate in discrete regions of the rodent brain. J Neurosci Methods160:223–2302007
HamiltonSELooseMDQiMLeveyAIHilleBMcKnightGS: Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice. Proc Natl Acad Sci U S A94:13311–133161997
Ludvig N Kovacs L inventors: Hybrid neuroprosthesis for the treatment of brain disorders. US Patent 6497699 2002
LudvigNKuznieckyRIBaptisteSLJohnJEvon GizyckiHDoyleWK: Epidural pentobarbital delivery can prevent locally induced neocortical seizures in rats: the prospect of transmeningeal pharmacotherapy for intractable focal epilepsy. Epilepsia47:1792–18022006
LudvigNMedveczkyGFrenchJACarlsonCDevinskyOKuznieckyRI: Evolution and prospects for intracranial pharmacotherapy for refractory epilepsies: the subdural hybrid neuroprosthesis. Epilepsy Res Treat2010. (http://www.hindawi.com/journals/ert/2010/725696.html) [Accessed April 12 2012]
LudvigNMedveczkyGRizzoloRTangHMBaptisteSLDoyleWK: An implantable triple-function device for local drug delivery, cerebrospinal fluid removal and EEG recording in the cranial subarachnoid space of primates. J Neurosci Methods203:275–2832012
Monge-AcuñaAAFornaguera-TríasJ: A high performance liquid chromatography method with electrochemical detection of gamma-aminobutyric acid, glutamate and glutamine in rat brain homogenates. J Neurosci Methods183:176–1812009