Brain Advance Access published August 13, 2014 Brain 2014: Page 1 of 2
doi:10.1093/brain/awu226
| e1
BRAIN A JOURNAL OF NEUROLOGY
LETTER TO THE EDITOR Reply: Does dominant pedunculopontine nucleus exist? Brett W. Fling,1,2 John G. Nutt1 and Fay B. Horak1,2 1 Department of Neurology School of Medicine, Oregon Health and Science University 3181 SW Sam Jackson Park Rd., Portland, OR 97239-3098, USA 2 Portland VA Medical Centre, 3710 SW US Veterans Hospital Rd, Portland, OR 97239-9264, USA Correspondence to: Brett W. Fling, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239-3098, USA E-mail: [email protected]
et al., 2014). Similar to our recent interpretation, other researchers have pointed to poorer performance on tasks requiring cognitive inhibition and conflict resolution within this population (Shine et al., 2013; Cohen, et al., 2014). While this sub-domain of cognitive control is clearly differentially affected in those who experience FOG, there is also an historical body of literature that supports a dominant role of the right hemisphere in gait itself. Dating back to the seminal work of Geschwind (1965), left hemispheric lesions are often associated with bilateral limb apraxia, whereas whole body movements are largely unaffected. Following stroke, right hemiparetics (in whom the right hemisphere was uninjured) progressed more rapidly and achieved higher levels of functional mobility following gait training (Cassvan et al., 1976). Further, Rapcsak et al. (1993) suggested that the right hemisphere is preferentially involved in programming and executing familiar, automated movements (e.g. locomotion). These findings may be explained by a right hemisphere dominance in body schema, spatial orientation (Wolpert et al., 1998), and proprioceptive control (Goble and Brown, 2008). Taken together, these studies indicate that the right hemisphere may play a preferential role in controlling axial, whole body movements like gait, and that dysfunction within this hemisphere leads to greater mobility impairments. The differential loss of fibre tracts within the right locomotor network of Parkinson’s disease individuals who are FOG + in combination with the promising results in Lam and colleagues’ Letter to the Editor further underscores the importance of the right hemisphere’s role in gait. It is possible that the lack of improvement in right PPN stimulation that Lam et al. observed is due to reduced structural connectivity within the right hemisphere’s locomotor network. As a result of reduced white matter connectivity, the nervous system is
ß The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]
Downloaded from by guest on November 2, 2014
Sir, We appreciate the thoughtful comments and additional contributions from Lam and colleagues with regards to our recent manuscript in Brain, which demonstrated substantial asymmetry of structural connectivity strength within the locomotor network of individuals with Parkinson’s disease who experience freezing of gait (FOG + ) (Fling et al., 2013). Specifically, we reported reduced white matter tract volume between the right pedunculopontine nucleus (PPN) and the midline of the right frontal cortex, assessed by diffusion tensor imaging. This was in contrast to those patients with Parkinson’s disease who did not have freezing issues and age-matched controls. In addition, this asymmetric reduction of the right hemisphere’s locomotor network was strongly related to inhibitory cognitive control, a process that is uniquely lateralized to the right hemisphere (Aron, 2007). In their letter, Lam and colleagues report how the PPN asymmetry results from our study are supported by post hoc analysis of PPN DBS data previously collected by Moro et al. (2010). The authors present data demonstrating that left PPN stimulation presented an improvement in axial symptoms 12 months post-surgery in comparison with right PPN stimulation. Due to strong bilateral projections, the authors suggest that the less involved, left PPN has the potential to serve a compensatory role in the pathophysiology of FOG + and other axial symptoms. The advent of neuroimaging has significantly furthered our knowledge of the neural mechanisms underlying behaviour. One of the more striking findings has been the extensive hemispheric lateralization of both cognitive and motoric function. A growing body of literature suggests that right-hemisphere circuitry seems to be more affected than the left in patients with FOG (Snijders et al., 2011; Tessitore et al., 2012; Fling et al., 2013; Peterson
e2
| Brain 2014: Page 2 of 2
likely at a disadvantage to transmit stimulation and may provide strong rationale for left PPN stimulation. This interpretation must be taken with caution as recent work from our group demonstrates bilateral alterations in functional communication within the locomotor network of FOG + patients (Fling et al., 2014). Our findings of unilateral structural loss, but bilateral changes in functional communication underscore the complex pathophysiology of FOG. Future studies will benefit from studying additional clinical populations with similar behavioural phenomena such as vascular parkinsonism and frontal gait disorders (Nutt et al., 2011).
References
Geschwind N. Disconnexion syndromes in animals and man. II. Brain 1965; 88: 585–644. Goble DJ, Brown SH. The biological and behavioral basis of upper limb asymmetries in sensorimotor performance. Neurosci Biobehav Rev 2008; 32: 598–610. Moro E, Hamani C, Poon YY, Al-Khairallah T, Dostrovsky JO, Hutchison WD, et al. Unilateral pedunculopontine stimulation improves falls in Parkinson’s disease. Brain 2010; 133: 215–24. Nutt JG, Bloem BR, Giladi N, Hallett M, Horak FB, Nieuwboer A. Freezing of gait: moving forward on a mysterious clinical phenomenon. Lancet Neurol 2011; 10: 734–44. Peterson DS, Pickett KA, Duncan R, Perlmutter J, Earhart GM. Gait-related brain activity in people with Parkinson disease with freezing of gait. PLoS One 2014; 9: e90634. Rapcsak SZ, Ochipa C, Beeson PM, Rubens AB. Praxis and the right hemisphere. Brain Cogn 1993; 23: 181–202. Shine JM, Moustafa AA, Matar E, Frank MJ, Lewis SJ. The role of frontostriatal impairment in freezing of gait in Parkinson’s disease. Front Syst Neurosci 2013; 7: 61. Snijders AH, Leunissen I, Bakker M, Overeem S, Helmich RC, Bloem BR, et al. Gait-related cerebral alterations in patients with Parkinson’s disease with freezing of gait. Brain 2011; 134: 59–72. Tessitore A, Amboni M, Esposito F, Russo A, Picillo M, Marcuccio L, et al. Resting-state brain connectivity in patients with Parkinson’s disease and freezing of gait. Parkinsonism Relat Disord 2012; 18: 781–7. Wolpert DM, Goodbody SJ, Husain M. Maintaining internal representations: the role of the human superior parietal lobe. Nat Neurosci 1998; 1: 529–33.
Downloaded from by guest on November 2, 2014
Aron AR. The neural basis of inhibition in cognitive control. Neuroscientist 2007; 13: 214–28. Cassvan A, Ross PL, Dyer PR, Zane L. Lateralization in stroke syndromes as a factor in ambulation. Arch Phys Med Rehabil 1976; 57: 583–7. Cohen RG, Klein KA, Nomura M, Fleming M, Mancini M, Giladi N, et al. Inhibition, executive function, and freezing of gait. J Parkinsons Dis 2014; 4: 111–22. Fling BW, Cohen RG, Mancini M, Carpenter SD, Fair DA, Nutt JG, et al. Functional reorganization of the locomotor network in Parkinson patients with freezing of gait. PLoS One 2014; 9: e100291. Fling BW, Cohen RG, Mancini M, Nutt JG, Fair DA, Horak FB. Asymmetric pedunculopontine network connectivity in parkinsonian patients with freezing of gait. Brain 2013; 136: 2405–18.
Letter to the Editor
doi:10.1093/brain/awu226
| e1
BRAIN A JOURNAL OF NEUROLOGY
LETTER TO THE EDITOR Reply: Does dominant pedunculopontine nucleus exist? Brett W. Fling,1,2 John G. Nutt1 and Fay B. Horak1,2 1 Department of Neurology School of Medicine, Oregon Health and Science University 3181 SW Sam Jackson Park Rd., Portland, OR 97239-3098, USA 2 Portland VA Medical Centre, 3710 SW US Veterans Hospital Rd, Portland, OR 97239-9264, USA Correspondence to: Brett W. Fling, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239-3098, USA E-mail: [email protected]
et al., 2014). Similar to our recent interpretation, other researchers have pointed to poorer performance on tasks requiring cognitive inhibition and conflict resolution within this population (Shine et al., 2013; Cohen, et al., 2014). While this sub-domain of cognitive control is clearly differentially affected in those who experience FOG, there is also an historical body of literature that supports a dominant role of the right hemisphere in gait itself. Dating back to the seminal work of Geschwind (1965), left hemispheric lesions are often associated with bilateral limb apraxia, whereas whole body movements are largely unaffected. Following stroke, right hemiparetics (in whom the right hemisphere was uninjured) progressed more rapidly and achieved higher levels of functional mobility following gait training (Cassvan et al., 1976). Further, Rapcsak et al. (1993) suggested that the right hemisphere is preferentially involved in programming and executing familiar, automated movements (e.g. locomotion). These findings may be explained by a right hemisphere dominance in body schema, spatial orientation (Wolpert et al., 1998), and proprioceptive control (Goble and Brown, 2008). Taken together, these studies indicate that the right hemisphere may play a preferential role in controlling axial, whole body movements like gait, and that dysfunction within this hemisphere leads to greater mobility impairments. The differential loss of fibre tracts within the right locomotor network of Parkinson’s disease individuals who are FOG + in combination with the promising results in Lam and colleagues’ Letter to the Editor further underscores the importance of the right hemisphere’s role in gait. It is possible that the lack of improvement in right PPN stimulation that Lam et al. observed is due to reduced structural connectivity within the right hemisphere’s locomotor network. As a result of reduced white matter connectivity, the nervous system is
ß The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected]
Downloaded from by guest on November 2, 2014
Sir, We appreciate the thoughtful comments and additional contributions from Lam and colleagues with regards to our recent manuscript in Brain, which demonstrated substantial asymmetry of structural connectivity strength within the locomotor network of individuals with Parkinson’s disease who experience freezing of gait (FOG + ) (Fling et al., 2013). Specifically, we reported reduced white matter tract volume between the right pedunculopontine nucleus (PPN) and the midline of the right frontal cortex, assessed by diffusion tensor imaging. This was in contrast to those patients with Parkinson’s disease who did not have freezing issues and age-matched controls. In addition, this asymmetric reduction of the right hemisphere’s locomotor network was strongly related to inhibitory cognitive control, a process that is uniquely lateralized to the right hemisphere (Aron, 2007). In their letter, Lam and colleagues report how the PPN asymmetry results from our study are supported by post hoc analysis of PPN DBS data previously collected by Moro et al. (2010). The authors present data demonstrating that left PPN stimulation presented an improvement in axial symptoms 12 months post-surgery in comparison with right PPN stimulation. Due to strong bilateral projections, the authors suggest that the less involved, left PPN has the potential to serve a compensatory role in the pathophysiology of FOG + and other axial symptoms. The advent of neuroimaging has significantly furthered our knowledge of the neural mechanisms underlying behaviour. One of the more striking findings has been the extensive hemispheric lateralization of both cognitive and motoric function. A growing body of literature suggests that right-hemisphere circuitry seems to be more affected than the left in patients with FOG (Snijders et al., 2011; Tessitore et al., 2012; Fling et al., 2013; Peterson
e2
| Brain 2014: Page 2 of 2
likely at a disadvantage to transmit stimulation and may provide strong rationale for left PPN stimulation. This interpretation must be taken with caution as recent work from our group demonstrates bilateral alterations in functional communication within the locomotor network of FOG + patients (Fling et al., 2014). Our findings of unilateral structural loss, but bilateral changes in functional communication underscore the complex pathophysiology of FOG. Future studies will benefit from studying additional clinical populations with similar behavioural phenomena such as vascular parkinsonism and frontal gait disorders (Nutt et al., 2011).
References
Geschwind N. Disconnexion syndromes in animals and man. II. Brain 1965; 88: 585–644. Goble DJ, Brown SH. The biological and behavioral basis of upper limb asymmetries in sensorimotor performance. Neurosci Biobehav Rev 2008; 32: 598–610. Moro E, Hamani C, Poon YY, Al-Khairallah T, Dostrovsky JO, Hutchison WD, et al. Unilateral pedunculopontine stimulation improves falls in Parkinson’s disease. Brain 2010; 133: 215–24. Nutt JG, Bloem BR, Giladi N, Hallett M, Horak FB, Nieuwboer A. Freezing of gait: moving forward on a mysterious clinical phenomenon. Lancet Neurol 2011; 10: 734–44. Peterson DS, Pickett KA, Duncan R, Perlmutter J, Earhart GM. Gait-related brain activity in people with Parkinson disease with freezing of gait. PLoS One 2014; 9: e90634. Rapcsak SZ, Ochipa C, Beeson PM, Rubens AB. Praxis and the right hemisphere. Brain Cogn 1993; 23: 181–202. Shine JM, Moustafa AA, Matar E, Frank MJ, Lewis SJ. The role of frontostriatal impairment in freezing of gait in Parkinson’s disease. Front Syst Neurosci 2013; 7: 61. Snijders AH, Leunissen I, Bakker M, Overeem S, Helmich RC, Bloem BR, et al. Gait-related cerebral alterations in patients with Parkinson’s disease with freezing of gait. Brain 2011; 134: 59–72. Tessitore A, Amboni M, Esposito F, Russo A, Picillo M, Marcuccio L, et al. Resting-state brain connectivity in patients with Parkinson’s disease and freezing of gait. Parkinsonism Relat Disord 2012; 18: 781–7. Wolpert DM, Goodbody SJ, Husain M. Maintaining internal representations: the role of the human superior parietal lobe. Nat Neurosci 1998; 1: 529–33.
Downloaded from by guest on November 2, 2014
Aron AR. The neural basis of inhibition in cognitive control. Neuroscientist 2007; 13: 214–28. Cassvan A, Ross PL, Dyer PR, Zane L. Lateralization in stroke syndromes as a factor in ambulation. Arch Phys Med Rehabil 1976; 57: 583–7. Cohen RG, Klein KA, Nomura M, Fleming M, Mancini M, Giladi N, et al. Inhibition, executive function, and freezing of gait. J Parkinsons Dis 2014; 4: 111–22. Fling BW, Cohen RG, Mancini M, Carpenter SD, Fair DA, Nutt JG, et al. Functional reorganization of the locomotor network in Parkinson patients with freezing of gait. PLoS One 2014; 9: e100291. Fling BW, Cohen RG, Mancini M, Nutt JG, Fair DA, Horak FB. Asymmetric pedunculopontine network connectivity in parkinsonian patients with freezing of gait. Brain 2013; 136: 2405–18.
Letter to the Editor
