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1 This article was downloaded by: [University of Oxford] On: 27 June 2009 Access details: Access Details: [subscription number ] Publisher Informa Healthcare Informa Ltd Registered in England and Wales Registered Number: Registered office: Mortimer House, Mortimer Street, London W1T 3JH, UK British Journal of Neurosurgery Publication details, including instructions for authors and subscription information: Deep brain stimulation of the pedunculopontine nucleus in Parkinson's disease. Preliminary experience at Oxford E. A. Pereira ab ; K. A. Muthusamy ab ; N. De Pennington ab ; C. A. Joint ab ; T. Z. Aziz ab a Oxford Functional Neurosurgery, Department of Neurological Surgery, John Radcliffe Hospital, b Nuffield Department of Surgery, University of Oxford, Oxford, UK Online Publication Date: 01 January 2008 To cite this Article Pereira, E. A., Muthusamy, K. A., De Pennington, N., Joint, C. A. and Aziz, T. Z.(2008)'Deep brain stimulation of the pedunculopontine nucleus in Parkinson's disease. Preliminary experience at Oxford',British Journal of Neurosurgery,22:1,S41 S44 To link to this Article: DOI: / URL: PLEASE SCROLL DOWN FOR ARTICLE Full terms and conditions of use: This article may be used for research, teaching and private study purposes. Any substantial or systematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material.

2 British Journal of Neurosurgery, December 2008; 22(Suppl. 1): S41 S44 TECHNICAL NOTE Deep brain stimulation of the pedunculopontine nucleus in Parkinson s disease. Preliminary experience at Oxford E. A. PEREIRA, K. A. MUTHUSAMY, N. DE PENNINGTON, C. A. JOINT & T. Z. AZIZ Oxford Functional Neurosurgery, Department of Neurological Surgery, John Radcliffe Hospital, and Nuffield Department of Surgery, University of Oxford, Oxford UK Abstract Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) is a novel neurosurgical therapy developed to address symptoms of gait freezing and postural instability in Parkinson s disease and related disorders. Here, we summarize our nonhuman primate and neuroimaging research of relevance to our surgical targeting of the PPN. We also describe our clinical experience of PPN DBS with greatest motor improvements achieved by stimulation at low frequencies. Key words: Deep brain stimulation, diffusion tensor imaging, Parkinson s disease, pedunculopontine nucleus. Introduction Drug resistant gait freezing and postural imbalance are the most crippling symptoms in approximately 10% of patients diagnosed with Parkinson s disease. 1 They are also prominent features of progressive supranuclear palsy, multi-system atrophy, and corticobasal syndromes. Conventional stereotactic surgery of the thalamus, pallidum and subthalamic nucleus have little effect on these symptoms. Several lines of evidence indicate that a brainstem nucleus, the pedunculopontine nucleus (PPN), may have a significant role to play in such axial symptoms. It degenerates in Parkinson s disease, PSP and MSA. 2 5 An unusual case report of bilateral infarcts of the PPN resulted in severe gait freezing and the severity of symptoms were found to correlate closely with loss of cholinergic neurones in the region. 6 After STN lesions in the Parkinsonian non-human primate, 2-deoxyglucose studies have demonstrated that diminished inhibition of the ipsilateral PPN accompanies symptom reversal. 7 In the normal, nonhuman, Parkinsonian primate, lesions and high frequency stimulation induce akinesia Microinjections of the GABA antagonist bicuculline into the PPN of a Parkinsonian monkey reversed akinesia and imbalance as did low frequency stimulation in the same animal model. 11,12 The results were considered significant enough for these observations to be taken up clinically with encouraging results Nevertheless, some controversy recently arose as to the actual target We believe that there is no longer such controversy, but that it may have occurred because a single study unfortunately had an inaccurate illustration of electrode placement. 15 At Oxford we have successfully started to implant the PPN with encouraging results and, in this paper, describe our targeting methodology. Given the variability in microelectrode recordings in the region in monkeys and man, we did not feel that there was anything to be gained by incorporating it into our surgical technique. The primate PPN lies in the upper brain stem from below the red nucleus inferiorly to the inferior colliculus superiorly, bounded medially by the superior cerebellar decussation and laterally by the medial lemniscus. The site as targeted in our primate studies is illustrated in a coronal section of a monkey brain injected with horseradish peroxidize (HRP) on one side and biotinylated dextran amine (BDA) on the other (Fig. 1). Imaging Clinically, the superior cerebellar decussation can be visualized on coronal and axial T2-weighted MRI scans, which are acquired in 0.9 mm contiguous slices. Patients also have diffusion tensor imaging (DTI) MRI scans acquired at the same time. Seeding the region just lateral to the cerebellar decussation Correspondence: Professor T. Z. Aziz, Oxford Functional Neurosurgery, Department of Neurological Surgery, West Wing, John Radcliffe Hospital, Oxford, OX3 9DU, UK. Tel: þ44 (0) Fax: þ44 (0) tipu.aziz@nds.ox.ac.uk Received for publication 27 May Accepted 1 June ISSN print/issn X online ª The Neurosurgical Foundation DOI: /

3 S42 E. A. Pereira et al. delineates the connectivity of the intended site, which in previous studies were shown to closely mimic what is known of the primate anatomy. 19,20 Patient selection At Oxford, to date, we have chosen to implant the PPN in patients with Parkinson s disease in whom symptoms of drug-resistant gait freezing and postural imbalance predominate. FIG. 1. Coronal section of a non-human primate brain injected with horseradish peroxidase (HRP) on one side highlighting the pedunculopontine nucleus and biotinylated dextran amine (BDA) on the other. Surgery Patients omit all dopaminergic medications the night before surgery. On the morning of surgery the base ring of the Cosman Roberts Wells (CRW) frame (Radionics Inc., Burlington, Massachusetts) is fitted to the skull and a stereotactic CT scan of the whole head at 1.0 mm contiguous slices is acquired. Using Radionics Image Fusion 1 and Stereoplan 1, the preoperatively acquired MRI scan is volumetrically fused to the stereotactic CT scan. The target chosen is that delineated by the seed point chosen on DTI tractography. A trajectory is chosen such that the electrode lies along the long axis of the brainstem from a level just below the red nucleus to the level of FIG. 2. Radionics Image Fusion 1 screen capture showing the pedunculopontine nucleus target chosen for electrode implantation.

4 Deep brain stimulation of the pedunculopontine nucleus S43 the inferior colliculus incorporating the seeded target site along the axis of implantation (Fig. 2). In our first patient experience, stimulation at 20 Hz during awake surgery induced loss of rigidity and marked reversal of bradykinesia. Bilateral PPN implants were performed. In our first two cases, the electrodes were externalized to confirm efficacy over a period of a week prior to full internalization. This and other aspects of our technique for deep brain stimulation are detailed elsewhere. 21,22 Postoperatively, we have found that bilateral stimulation confers little clinical benefit over unilateral stimulation and plan to proceed with unilateral implants in future. Postoperative assessments Assessment of such patients requires careful consideration presently. Gait freezing and postural imbalance comprise only four out of 42 questions in the Unified Parkinson Disease Rating Scale (UPDRS). Moreover, only two of these four questions occur within the 14 question UPDRS III in popular use for assessing motor function. A dramatic improvement of such signs, therefore, impacts little on the pre- and postoperative UPDRS changes. This may be addressed by giving patients daily diaries to complete including charting of falls, near falls and freezing episodes before and after surgery. In our first treated patient, such data show significant benefit with unilateral stimulation at frequencies of stimulation around 20 Hz (Fig. 3). We will continue to acquire such data preoperatively in future patients. FIG. 3. Graph of average number of gait freezes, near falls and falls per week over two week periods at different frequencies (Hz) of unilateral pedunculopontine nucleus deep brain stimulation. Conclusions As the first novel brain target for the surgical management of Parkinson s disease in nearly half a century, the PPN, its location and the best way to target it have provoked impassioned debate. Also under consideration are questions of which patients and when, and whether to implant the PPN in isolation or in combination with another deep brain stimulation target, such as the subthalamic nucleus for optimal efficacy. Patients that undergo PPN implants may also be best assessed in a different manner to using the UPDRS as is conventional. An exponential increase in clinical and translational research into the PPN is currently being fuelled by the many exciting unresolved issues surrounding it. Acknowledgements The authors are supported by grants from the UK Medical Research Council, Norman Collisson Foundation, Charles Wolfson Charitable Trust, Oxford Partnership Comprehensive Biomedical Research Centre, with funding from the Department of Health s NIHR Biomedical Research Centres funding scheme and by educational grants from Medtronic. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References 1 Giladi N, McDermott MP, Fahn S, Przedborski S, Jankovic J, Stern M, Tanner C. Freezing of gait in PD: prospective assessment in the DATATOP cohort. Neurology 2001;56: Schmeichel AM, Buchhalter LC, Low PA, et al. Mesopontine cholinergic neuron involvement in Lewy body dementia and multiple system atrophy. Neurology 2008;70(5): Frasca J, Blumbergs PC, Henschke P, Burns RJ. A clinical and pathological study of progressive supranuclear palsy. Clin Exp Neurol 1991;28: Hirsch EC, Graybiel AM, Duyckaerts C, Javoy-Agid F. Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. Proc Natl Acad Sci USA 1987;84: Rinne JO, Ma SY, Lee MS, Collan Y, Roytta M. Loss of cholinergic neurons in the pedunculopontine nucleus in Parkinson s disease is related to disability of the patients. Parkinsonism Relat Disord 2008;14(7): Kuo SH, Kenney C, Jankovic J. Bilateral pedunculopontine nuclei strokes presenting as freezing of gait. Mov Disord 2008;23: Aziz TZ, Peggs D, Sambrook MA, Crossman AR. 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 1991;6(4): Aziz TZ, Davies L, Stein J, France S. The role of descending basal ganglia connections to the brain stem in parkinsonian akinesia. Br J Neurosurg 1998;12: Munro-Davies L, Winter J, Aziz TZ, Stein J. Kainate acid lesions of the pedunculopontine region in the normal behaving primate. Mov Disord 2001;16:150 1.

5 S44 E. A. Pereira et al. 10 Munro-Davies LE, Winter J, Aziz TZ, Stein JF. The role of the pedunculopontine region in basal-ganglia mechanisms of akinesia. Exp Brain Res 1999;129: Nandi D, Aziz TZ, Giladi N, Winter J, Stein JF. Reversal of akinesia in experimental parkinsonism by GABA antagonist microinjections in the pedunculopontine nucleus. Brain 2002;125: Jenkinson N, Nandi D, Miall RC, Stein JF, Aziz TZ. Pedunculopontine nucleus stimulation improves akinesia in a Parkinsonian monkey. Neuroreport 2004;15: Stefani A, Lozano AM, Peppe A, et al. Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson s disease. Brain 2007;130: Plaha P, Gill SS. Bilateral deep brain stimulation of the pedunculopontine nucleus for Parkinson s disease. Neuroreport 2005;16: Mazzone P, Lozano A, Stanzione P, et al. Implantation of human pedunculopontine nucleus: a safe and clinically relevant target in Parkinson s disease. Neuroreport 2005;16: Yelnik J. PPN or PPD, what is the target for deep brain stimulation in Parkinson s disease? Brain 2007;130(Pt 9):e79; author reply e Zrinzo L, Zrinzo L, Hariz M. The peripeduncular nucleus: a novel target for deep brain stimulation? Neuroreport 2007;18: ; author reply Zrinzo L, Zrinzo LV, Hariz M. The pedunculopontine and peripeduncular nuclei: a tale of two structures. Brain 2007; 130(Pt 6):e73; author reply e Muthusamy KA, Aravamuthan BR, Kringelbach ML, et al. Connectivity of the human pedunculopontine nucleus region and diffusion tensor imaging in surgical targeting. J Neurosurg 2007;107: Aravamuthan BR, Muthusamy KA, Stein JF, Aziz TZ, Johansen-Berg H. Topography of cortical and subcortical connections of the human pedunculopontine and subthalamic nuclei. Neuroimage 2007;37: Liu X, Rowe J, Nandi D, et al. Localisation of the subthalamic nucleus using Radionics Image Fusion and Stereoplan combined with field potential recording. A technical note. Stereotact Funct Neurosurg 2001;76(2): Bittar RG, Burn SC, Bain PG, et al. Deep brain stimulation for movement disorders and pain. J Clin Neurosci 2005;12: