Radiosurgery performed with the aid of a 3-mm collimator in the subthalamic nucleus and substantia nigra of the vervet monkey

Restricted access

Object. Radiosurgery for functional neurosurgery performed using a linear accelerator (LINAC) has not been extensively characterized in preclinical studies. In the present study, the properties of a newly designed 3-mm-diameter collimator were evaluated in a dedicated LINAC, which produced lesions in the basal ganglia of vervet monkeys. Lesion formation was determined in vivo in three animals by examining magnetic resonance (MR) images to show the dosedelivery precision of targeting and the geometry and extent of the lesions. Postmortem immunohistochemical studies were conducted to determine the extent of lesion-induced radiobiological effects.

Methods. In three male vervet monkeys, the subthalamic nucleus (STN; one animal) and the pars compacta of the lateral substantia nigra (SN; two animals) were targeted by a Novalis Shaped Beam Surgery System that included a 3-mm collimator and delivered a maximum dose of 150 Gy. Magnetic resonance images obtained 4, 5, and 9 months posttreatment were reviewed, and the animals were killed so that immunohistological characterizations could be made.

Conclusions. The generation of precise radiosurgical lesions by a 3-mm collimator was validated in studies that targeted the basal ganglia of the vervet monkey. The extent of the lesions created in all animals remained restricted in diameter (< 3 mm) throughout the duration of the studies, as assessed by reviewing MR images. Histological studies showed that the lesions were contained within the STN and SN target areas and that there were persistent increases in glial fibrillary acidic protein immunoreactivity. Increases in immunoreactivity for tyrosine hydroxylase, the serotonin transporter, and the GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate glutamate receptor in penumbral regions of the lesion were suggestive of compensatory neuronal adaptations. This radiosurgical approach may be of particular interest for the induction of lesions of the STN and SN in studies of experimental parkinsonism, as well as for the development of potential radiosurgical treatments for Parkinson disease.

Article Information

Address reprint requests to: Antonio A. F. De Salles, M.D., Ph.D., Division of Neurosurgery, 300 UCLA Medical Plaza Suite B205, Los Angeles, California 90095–6975. email: adesalles@mednet.ucla.edu.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Localization of targets in the vervet monkey basal ganglia as seen in our Internet-based atlas (http://www.nuc.ucla.edu/mellab/vervet_atlas/). A: Subthalamic nucleus target. B: Substantia nigra target.

  • View in gallery

    Gadodiamide-enhanced T1-weighted MR images demonstrating an SN lesion. A: Coronal section revealing lesion formation (arrow) 3 months postradiosurgery. B: Axial section demonstrating the lesion with a necrotic center (arrow) 9 months postradiosurgery.

  • View in gallery

    Magnetic resonance images demonstrating SN lesions (arrow) at postirradiation time points. A: A T2-weighted image obtained at 5 months. B and C: Two T1-weighted gadodiamideenhanced images revealing lesions in an axial section at 4 months (B) and a sagittal section at 5 months (C).

  • View in gallery

    Coronal sections (30 µm) of TH (rows 1 and 2), GFAP (row 3), GluR1 (row 4), and SERT (row 5) immunoreactivity at different postirradiation time points. A: Substantia nigra at 4 months. B: Substantia nigra at 5 months. C: Subthalamic nucleus at 9 months. Original magnification × 20 for rows 2–5.

  • View in gallery

    Axial and coronal isodose distributions in the SN target of the vervet monkey. The 50% isodose line traces the 3-mm-diameter circle with the 100% isodose at its center. The 20% isodose line traces the 5-mm-diameter circle.

References

  • 1.

    Alexander E IIIKooy HMvan Herk Met al: Magnetic resonance image—directed stereotactic neurosurgery: use of image fusion with computerized tomography to enhance spatial accuracy. J Neurosurg 83:2712761995Alexander E III Kooy HM van Herk M et al: Magnetic resonance image—directed stereotactic neurosurgery: use of image fusion with computerized tomography to enhance spatial accuracy. J Neurosurg 83:271–276 1995

    • Search Google Scholar
    • Export Citation
  • 2.

    Altschuler ELunsford LDKondziolka Det al: Radiobiologic models for radiosurgery. Neurosurg Clin N Am 3:61771992Altschuler E Lunsford LD Kondziolka D et al: Radiobiologic models for radiosurgery. Neurosurg Clin N Am 3:61–77 1992

    • Search Google Scholar
    • Export Citation
  • 3.

    Aziz TZPeggs DAgarwal Eet al: Subthalamic nucleotomy alleviates parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-exposed primate. Br J Neurosurg 6:5755821992Aziz TZ Peggs D Agarwal E et al: Subthalamic nucleotomy alleviates parkinsonism in the 1-methyl-4-phenyl-1236-tetrahydropyridine (MPTP)-exposed primate. Br J Neurosurg 6:575–582 1992

    • Search Google Scholar
    • Export Citation
  • 4.

    Aziz TZPeggs DSambrook MAet al: Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Mov Disord 6:2882921991Aziz TZ Peggs D Sambrook MA et al: Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-123 6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Mov Disord 6:288–292 1991

    • Search Google Scholar
    • Export Citation
  • 5.

    Benabid ALPollak PGervason Cet al: Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 337:4034061991Benabid AL Pollak P Gervason C et al: Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 337:403–406 1991

    • Search Google Scholar
    • Export Citation
  • 6.

    Betarbet RPorter RHPGreenamyre JT: GluR1 Glutamate receptor subunit is regulated differentially in the primate basal ganglia following nigrostriatal dopamine denervation. J Neurochem 74:116611742000Betarbet R Porter RHP Greenamyre JT: GluR1 Glutamate receptor subunit is regulated differentially in the primate basal ganglia following nigrostriatal dopamine denervation. J Neurochem 74:1166–1174 2000

    • Search Google Scholar
    • Export Citation
  • 7.

    Beurrier CBezard EBioulac Bet al: Subthalamic stimulation elicits hemiballismus in normal monkey. Neuroreport 8:162516291997Beurrier C Bezard E Bioulac B et al: Subthalamic stimulation elicits hemiballismus in normal monkey. Neuroreport 8:1625–1629 1997

    • Search Google Scholar
    • Export Citation
  • 8.

    Bezrukiy NVDeMarco JJChetty Iet al: Verification of output factors for small photon beams using Monte Carlo methods. Med Phys 27:12972000 (Abstract)Bezrukiy NV DeMarco JJ Chetty I et al: Verification of output factors for small photon beams using Monte Carlo methods. Med Phys 27:1297 2000 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 9.

    Blatt DRFriedman WABova FJet al: Temporal characteristics of radiosurgical lesions in an animal model. J Neurosurg 80:104610551994Blatt DR Friedman WA Bova FJ et al: Temporal characteristics of radiosurgical lesions in an animal model. J Neurosurg 80:1046–1055 1994

    • Search Google Scholar
    • Export Citation
  • 10.

    Boedeker KLSolberg TDFogg Ret al: Use of image fusion in radiosurgery treatment planning can reduce systematic MR image distortion. Med Phys 27:15122000 (Abstract)Boedeker KL Solberg TD Fogg R et al: Use of image fusion in radiosurgery treatment planning can reduce systematic MR image distortion. Med Phys 27:1512 2000 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 11.

    Cohen DSLustgarten JHMiller Eet al: Effects of coregistration of MR to CT images on MR stereotactic accuracy. J Neurosurg 82:7727791995Cohen DS Lustgarten JH Miller E et al: Effects of coregistration of MR to CT images on MR stereotactic accuracy. J Neurosurg 82:772–779 1995

    • Search Google Scholar
    • Export Citation
  • 12.

    Contreras CMMexicano GGuzman-Flores C: A stereotaxic brain atlas of the green monkey (Cercopithecus aethiops aethiops). Bol Est Med Biol 31:3834281981Contreras CM Mexicano G Guzman-Flores C: A stereotaxic brain atlas of the green monkey (Cercopithecus aethiops aethiops). Bol Est Med Biol 31:383–428 1981

    • Search Google Scholar
    • Export Citation
  • 13.

    Corn BWCurran WJ JrShrieve DCet al: Stereotactic radiosurgery and radiotherapy: new developments and new directions. Semin Oncol 24:7077141997Corn BW Curran WJ Jr Shrieve DC et al: Stereotactic radiosurgery and radiotherapy: new developments and new directions. Semin Oncol 24:707–714 1997

    • Search Google Scholar
    • Export Citation
  • 14.

    De Salles AAFHariz M: Functional radiosurgery in De Salles AAFGoetsch SJ (eds): Stereotactic Surgery and Radiosurgery. Madison, WI: Medical Physics Publishing1993 pp 389406De Salles AAF Hariz M: Functional radiosurgery in De Salles AAF Goetsch SJ (eds): Stereotactic Surgery and Radiosurgery. Madison WI: Medical Physics Publishing 1993 pp 389–406

    • Search Google Scholar
    • Export Citation
  • 15.

    De Salles AAFSolberg TDMischel Pet al: Arteriovenous malformation animal model for radiosurgery: the rete mirabile. AJNR 17:145114581996De Salles AAF Solberg TD Mischel P et al: Arteriovenous malformation animal model for radiosurgery: the rete mirabile. AJNR 17:1451–1458 1996

    • Search Google Scholar
    • Export Citation
  • 16.

    Duma CMJacques DBKopyov OVet al: Gamma knife radiosurgery for thalamotomy in parkinsonian tremor: a five-year experience. J Neurosurg 88:104410491998Duma CM Jacques DB Kopyov OV et al: Gamma knife radiosurgery for thalamotomy in parkinsonian tremor: a five-year experience. J Neurosurg 88:1044–1049 1998

    • Search Google Scholar
    • Export Citation
  • 17.

    Friedman WABova FJ: The University of Florida radiosurgery system. Surg Neurol 32:3343421989Friedman WA Bova FJ: The University of Florida radiosurgery system. Surg Neurol 32:334–342 1989

    • Search Google Scholar
    • Export Citation
  • 18.

    Harvey DCLacan GMelega WP: Regional heterogeneity of dopaminergic deficits in vervet monkey striatum and substantia nigra after methamphetamine exposure. Exp Brain Res 133:3493582000Harvey DC Lacan G Melega WP: Regional heterogeneity of dopaminergic deficits in vervet monkey striatum and substantia nigra after methamphetamine exposure. Exp Brain Res 133:349–358 2000

    • Search Google Scholar
    • Export Citation
  • 19.

    Hong JHChiang CSSun JRet al: Induction of c-fos and junB mRNA following in vivo brain irradiation. Brain Res Mol Brain Res 48:2232281997Hong JH Chiang CS Sun JR et al: Induction of c-fos and junB mRNA following in vivo brain irradiation. Brain Res Mol Brain Res 48:223–228 1997

    • Search Google Scholar
    • Export Citation
  • 20.

    Kondziolka DLacomis DNiranjan Aet al: Histological effects of trigeminal nerve radiosurgery in a primate model: implications for trigeminal neuralgia radiosurgery. Neurosurgery 46:9719772000Kondziolka D Lacomis D Niranjan A et al: Histological effects of trigeminal nerve radiosurgery in a primate model: implications for trigeminal neuralgia radiosurgery. Neurosurgery 46:971–977 2000

    • Search Google Scholar
    • Export Citation
  • 21.

    Kondziolka DLunsford LDMaitz Aet al: Radiobiologic considerations in gamma knife radiosurgery in Lunsford LDKondziolka DFlickinger JC (eds): Gamma Knife Brain Surgery. Basel: Karger1998 pp 2138Kondziolka D Lunsford LD Maitz A et al: Radiobiologic considerations in gamma knife radiosurgery in Lunsford LD Kondziolka D Flickinger JC (eds): Gamma Knife Brain Surgery. Basel: Karger 1998 pp 21–38

    • Search Google Scholar
    • Export Citation
  • 22.

    Krack PPollak PLimousin Pet al: Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson's disease. Brain 121:4514571998Krack P Pollak P Limousin P et al: Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson's disease. Brain 121:451–457 1998

    • Search Google Scholar
    • Export Citation
  • 23.

    Leksell L: The stereotaxic method and radiosurgery of the brain. Acta Chir Scand 102:3163191951Leksell L: The stereotaxic method and radiosurgery of the brain. Acta Chir Scand 102:316–319 1951

    • Search Google Scholar
    • Export Citation
  • 24.

    Limousin PPollak PBenazzouz Aet al: Effect on parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 345:91951995Limousin P Pollak P Benazzouz A et al: Effect on parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 345:91–95 1995

    • Search Google Scholar
    • Export Citation
  • 25.

    Lindquist CHindmarsh TKihlström Let al: MRI and CT studies of radionecrosis development in the normal human brain in Steiner LLindquist CForster Det al (eds): Radiosurgery Baseline and Trends. New York: Raven Press1992 pp 245253Lindquist C Hindmarsh T Kihlström L et al: MRI and CT studies of radionecrosis development in the normal human brain in Steiner L Lindquist C Forster D et al (eds): Radiosurgery Baseline and Trends. New York: Raven Press 1992 pp 245–253

    • Search Google Scholar
    • Export Citation
  • 26.

    Lindquist CSteiner LHindmarsh T: Gamma Knife thalamotomy for tremor: report of two cases in Steiner LLindquist CForster Det al (eds): Radiosurgery Baseline and Trends. New York: Raven Press1992 pp 237243Lindquist C Steiner L Hindmarsh T: Gamma Knife thalamotomy for tremor: report of two cases in Steiner L Lindquist C Forster D et al (eds): Radiosurgery Baseline and Trends. New York: Raven Press 1992 pp 237–243

    • Search Google Scholar
    • Export Citation
  • 27.

    Lunsford LDAltschuler EMFlickinger JCet al: In vivo biological effects of stereotactic radiosurgery: a primate model. Neurosurgery 27:3733821990Lunsford LD Altschuler EM Flickinger JC et al: In vivo biological effects of stereotactic radiosurgery: a primate model. Neurosurgery 27:373–382 1990

    • Search Google Scholar
    • Export Citation
  • 28.

    Lunsford LDKondziolka DMaitz Aet al: Black holes, white dwarfs and supernovas: imaging after radiosurgery. Stereotact Funct Neurosurg 70 (Suppl 1):2101998Lunsford LD Kondziolka D Maitz A et al: Black holes white dwarfs and supernovas: imaging after radiosurgery. Stereotact Funct Neurosurg 70 (Suppl 1):2–10 1998

    • Search Google Scholar
    • Export Citation
  • 29.

    Maciunas RJGalloway RL JrLatimer Jet al: An independent application accuracy evaluation of stereotactic frame systems. Stereotact Funct Neurosurg 58:1031071992Maciunas RJ Galloway RL Jr Latimer J et al: An independent application accuracy evaluation of stereotactic frame systems. Stereotact Funct Neurosurg 58:103–107 1992

    • Search Google Scholar
    • Export Citation
  • 30.

    Melega WPLacan GDesalles AAFet al: Long-term methamphetamine-induced decreases of [11C]WIN 35,428 binding in striatum are reduced by GDNF: PET studies in the vervet monkey. Synapse 35:2432492000Melega WP Lacan G Desalles AAF et al: Long-term methamphetamine-induced decreases of [11C]WIN 35428 binding in striatum are reduced by GDNF: PET studies in the vervet monkey. Synapse 35:243–249 2000

    • Search Google Scholar
    • Export Citation
  • 31.

    Ráliš HMBeesley RARáliš ZA: Techniques in Neurohistology. London: Butterworths1973 pp 5759Ráliš HM Beesley RA Ráliš ZA: Techniques in Neurohistology. London: Butterworths 1973 pp 57–59

    • Search Google Scholar
    • Export Citation
  • 32.

    Rubins DJAmbach KToga AWet al: Development of a digital brain atlas of the vervet monkey. J Cereb Blood Flow Metab 19 (Suppl 1):S7811999 (Abstract)Rubins DJ Ambach K Toga AW et al: Development of a digital brain atlas of the vervet monkey. J Cereb Blood Flow Metab 19 (Suppl 1):S781 1999 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 33.

    Solberg TDDe Salles AAFMedin PMet al: Technical aspects of LINAC radiosurgery for the treatment of small functional targets. J Radiosurg 1:1151271998Solberg TD De Salles AAF Medin PM et al: Technical aspects of LINAC radiosurgery for the treatment of small functional targets. J Radiosurg 1:115–127 1998

    • Search Google Scholar
    • Export Citation
  • 34.

    Solberg TDFogg RSelch MTet al: Conformal radiosurgery using a dedicated linac and micro multileaf collimator in Kondziolka D (ed): Radiosurgery 1999. Basel: Karger2000 Vol 3 pp 5363Solberg TD Fogg R Selch MT et al: Conformal radiosurgery using a dedicated linac and micro multileaf collimator in Kondziolka D (ed): Radiosurgery 1999. Basel: Karger 2000 Vol 3 pp 53–63

    • Search Google Scholar
    • Export Citation
  • 35.

    Spiegelmann RFriedman WABova FJet al: LINAC radiosurgery: an animal model. J Neurosurg 78:6386441993Spiegelmann R Friedman WA Bova FJ et al: LINAC radiosurgery: an animal model. J Neurosurg 78:638–644 1993

    • Search Google Scholar
    • Export Citation
  • 36.

    Starr PASubramanian TBakay RAEet al: Electrophysiological localization of the substantia nigra in the parkinsonian nonhuman primate. J Neurosurg 93:7047102000Starr PA Subramanian T Bakay RAE et al: Electrophysiological localization of the substantia nigra in the parkinsonian nonhuman primate. J Neurosurg 93:704–710 2000

    • Search Google Scholar
    • Export Citation
  • 37.

    Starr PAVitek JLBakay RAE: Ablative surgery and deep brain stimulation for Parkinson's disease. Neurosurgery 43:98910151998Starr PA Vitek JL Bakay RAE: Ablative surgery and deep brain stimulation for Parkinson's disease. Neurosurgery 43:989–1015 1998

    • Search Google Scholar
    • Export Citation
  • 38.

    Steiner LForster DLeksell Let al: Gammathalamotomy in intractable pain. Acta Neurochir 52:1731841980Steiner L Forster D Leksell L et al: Gammathalamotomy in intractable pain. Acta Neurochir 52:173–184 1980

    • Search Google Scholar
    • Export Citation
  • 39.

    Sumanaweera TSAdler JR JrNapel Set al: Characterization of spatial distortion in magnetic resonance imaging and its implications for stereotactic surgery. Neurosurgery 35:6967041994Sumanaweera TS Adler JR Jr Napel S et al: Characterization of spatial distortion in magnetic resonance imaging and its implications for stereotactic surgery. Neurosurgery 35:696–704 1994

    • Search Google Scholar
    • Export Citation
  • 40.

    Sun BDeSalles AAAFMedin PMet al: Reduction of hippocampal-kindled seizure activity in rats by stereotactic radiosurgery. Exp Neurol 154:6916951998Sun B DeSalles AAAF Medin PM et al: Reduction of hippocampal-kindled seizure activity in rats by stereotactic radiosurgery. Exp Neurol 154:691–695 1998

    • Search Google Scholar
    • Export Citation
  • 41.

    Tasker RR: Deep brain stimulation is preferable to thalamotomy for tremor suppression. Surg Neurol 49:1451541998Tasker RR: Deep brain stimulation is preferable to thalamotomy for tremor suppression. Surg Neurol 49:145–154 1998

    • Search Google Scholar
    • Export Citation
  • 42.

    Urgosik DLiscak RVymazal Jet al: The treatment of Parkinson's disease with Leksell Gamma Knife. Mov Disord 15 (Suppl 3):502000 (Abstract)Urgosik D Liscak R Vymazal J et al: The treatment of Parkinson's disease with Leksell Gamma Knife. Mov Disord 15 (Suppl 3):50 2000 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 43.

    Winston KRLutz W: Linear accelerator as a neurosurgical tool for stereotactic radiosurgery. Neurosurgery 22:4544641988Winston KR Lutz W: Linear accelerator as a neurosurgical tool for stereotactic radiosurgery. Neurosurgery 22:454–464 1988

    • Search Google Scholar
    • Export Citation
  • 44.

    Young RFJacques SMark Ret al: Gamma knife thalamotomy for treatment of tremor: long-term results. J Neurosurg (Suppl 3) 93:1281352000Young RF Jacques S Mark R et al: Gamma knife thalamotomy for treatment of tremor: long-term results. J Neurosurg (Suppl 3) 93:128–135 2000

    • Search Google Scholar
    • Export Citation
  • 45.

    Young RFShumway-Cook AVermeulen SSet al: Gamma knife radiosurgery as a lesioning technique in movement disorder surgery. J Neurosurg 89:1831931998Young RF Shumway-Cook A Vermeulen SS et al: Gamma knife radiosurgery as a lesioning technique in movement disorder surgery. J Neurosurg 89:183–193 1998

    • Search Google Scholar
    • Export Citation

Cited By

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 64 64 5
Full Text Views 109 109 0
PDF Downloads 63 63 0
EPUB Downloads 0 0 0

PubMed

Google Scholar