Brain Advance Access published November 2, 2014 doi:10.1093/brain/awu317
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BRAIN A JOURNAL OF NEUROLOGY
LETTER TO THE EDITOR Reply: Does dominant pedunculopontine nucleus exist? Probably not 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, Department of Neurology School of Medicine, Oregon Health and Science University 3181 SW Sam Jackson Park Rd., Portland, OR 97239-3098, USA E-mail: [email protected]
Sir, We are pleased to continue the discussion with regards to our recent manuscript detailing altered structural connectivity of the locomotor network within the right hemisphere of individuals with Parkinson’s disease who experience freezing of gait (Fling et al., 2013). Our previous work has asserted the possibility of right hemisphere pathology as a principal neural component underlying freezing of gait, with an emphasis placed on disrupted communication between locomotor centres in the brainstem and cerebellum with medial areas of the frontal and prefrontal cortices (Fling et al., 2013, 2014a). In their letter to the editor, Hall and colleagues (2014) provide data demonstrating that freezing of gait is evident in Parkinson’s disease regardless of which side of the body is more affected. The authors report no difference in the proportion of subjects (n = 70) with self-reported freezing of gait and left-side motor symptom dominance in 40/70 participants compared to right-side dominance in 30/70. It is suggested that because there are substantial numbers of individuals with greater right-side motor involvement (and by proxy, lefthemispheric striatal pathology), freezing of gait is not caused by pathology of the right-hemisphere alone. Idiopathic Parkinson’s disease is characterized by asymmetry of symptoms at disease onset, which is generally maintained, although symptoms tend to become more bilateral with disease progression (Hornykiewicz, 1966).
The characteristic asymmetric manifestation of motor symptoms is related to greater impairment of dopaminergic function in the contralateral striatum as indicated by reduced dopamine storage and dopamine transporter uptake (Leenders et al., 1986; Brooks et al., 1990a, b). The ‘choice’ of side predominance in patients with Parkinson’s disease could be pure chance (Djaldetti et al., 2006). These authors suggest that ‘similar to other complex diseases such as cancer, the ignition of detrimental cellular pathways might be randomly determined by a combination of factors too numerous to fully characterize’ (Djaldetti et al., 2006). The dominant side of hemispheric neurodegeneration can differentially affect particular functions for people with Parkinson’s disease. For example, recent work demonstrates that individuals with greater right-hemisphere pathology have larger kinaesthetic deficits than those with principally left-hemisphere involvement (Wright et al., 2010). This is in agreement with literature reporting similar results for visual and visuospatial tasks (Starkstein et al., 1987; Ebersbach et al., 1996; Harris et al., 2003; Davidsdottir et al., 2005). The fact that both visual and kinaesthetic asymmetries seem to predominantly affect left-side dominant Parkinson’s disease may mean that both originate from early asymmetrical nigrostriatal neuron loss (Wright et al., 2010). Whereas these functions seem to be defined by asymmetric striatal dysfunction,
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]
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freezing of gait is not associated with the cardinal motor features of Parkinson’s disease (tremor, bradykinesia or rigidity) (Giladi, 2001; Bartels et al., 2003). However, freezing of gait is correlated with postural instability (Giladi et al., 2001), spatial contrast sensitivity deficits (Davidsdottir et al., 2005), and an inability to appropriately engage and release inhibition (Cohen et al., 2014), rather than with general motor and/or executive deficits. These functions (body schema, spatial orientation, proprioceptive processing and cognitive inhibitory control) are all principally lateralized to the brain’s right hemisphere (Wolpert et al., 1998; Aron, 2007; Goble et al., 2012). We suggest that while the results of Hall and colleagues are interesting, they are not necessarily inconsistent with the results of Lam et al. (2014) and Fling et al. (2013, 2014b), nor do they negate the interpretations reached in those studies. In our original paper (Fling et al., 2013), as well as the majority of manuscripts examining the clinical phenomenon of freezing, there is a relatively equal number of patients with motor symptomology on the right or left side of the body. We therefore suggest that freezing of gait is not necessarily reflective of asymmetric striatal involvement, which defines motor-symptom dominant side in Parkinson’s disease, but is more likely the result of impaired neural circuitry within the locomotor and cognitive/higher-order motor networks of the brain’s right hemisphere, regardless of motor-symptom dominant side.
References Aron AR. The neural basis of inhibition in cognitive control. Neuroscientist 2007; 13: 214–28. Bartels AL, Balash Y, Gurevich T, Schaafsma JD, Hausdorff JM, Giladi N. Relationship between freezing of gait (FOG) and other features of Parkinson’s: FOG is not correlated with bradykinesia. J Clin Neurosci 2003; 10: 584–8. Brooks DJ, Ibanez V, Sawle GV, Quinn N, Lees AJ, Mathias CJ, et al. Differing patterns of striatal 18F-dopa uptake in Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Ann Neurol 1990a; 28: 547–55. Brooks DJ, Salmon EP, Mathias CJ, Quinn N, Leenders KL, Bannister R, et al. The relationship between locomotor disability, autonomic dysfunction, and the integrity of the striatal dopaminergic system in patients with multiple system atrophy, pure autonomic failure, and Parkinson’s disease, studied with PET. Brain 1990b; 113 (Pt 5): 1539–52.
Letter to the Editor 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. Davidsdottir S, Cronin-Golomb A, Lee A. Visual and spatial symptoms in Parkinson’s disease. Vision Res 2005; 45: 1285–96. Djaldetti R, Ziv I, Melamed E. The mystery of motor asymmetry in Parkinson’s disease. Lancet Neurol 2006; 5: 796–802. Ebersbach G, Trottenberg T, Ha¨ttig H, Schelosky L, Schrag A, Poewe W. Directional bias of initial visual exploration. A symptom of neglect in Parkinson’s disease. Brain 1996; 119 (Pt 1): 79–87. 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 (Pt 8): 2405–18. 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 2014a; 9: e100291. Fling BW, Nutt JG, Horak FB. Reply: does dominant pedunculopontine nucleus exist? Brain 2014b. doi: 10.1093/brain/awu226. Giladi N. Gait disturbances in advanced stages of Parkinson’s disease. Adv Neurol 2001; 86: 273–8. Giladi N, McDermott MP, Fahn S, Przedborski S, Jankovic J, Stern M, et al. Freezing of gait in PD: prospective assessment in the DATATOP cohort. Neurology 2001; 56: 1712–21. Goble DJ, Coxon JP, Van Impe A, Geurts M, Van Hecke W, Sunaert S, et al. The neural basis of central proprioceptive processing in older versus younger adults: an important sensory role for right putamen. Hum Brain Mapp 2012; 33: 895–908. Hall JM, Gilat M, Lewis SJG, Shine JM. Does dominant pedunculopontine nucleus exist? Probably not. Brain 2014. doi: 10.1093/brain/ awu315. Harris JP, Atkinson EA, Lee AC, Nithi K, Fowler MS. Hemispace differences in the visual perception of size in left hemiParkinson’s disease. Neuropsychologia 2003; 41: 795–807. Hornykiewicz O. Dopamine (3-hydroxytyramine) and brain function. Pharmacol Rev 1966; 18: 925–64. Lam S, Moro E, Poon YY, Lozano AM, Fasano A. Does dominant pedunculopontine nucleus exist? Brain 2014. doi: 10.1093/brain/ awu225. Leenders KL, Palmer AJ, Quinn N, Clark JC, Firnau G, Garnett ES, et al. Brain dopamine metabolism in patients with Parkinson’s disease measured with positron emission tomography. J Neurol Neurosurg Psychiatry 1986; 49: 853–60. Starkstein S, Leiguarda R, Gershanik O, Berthier M. Neuropsychological disturbances in hemiparkinson’s disease. Neurology 1987; 37: 1762–4. Wolpert DM, Goodbody SJ, Husain M. Maintaining internal representations: the role of the human superior parietal lobe. Nat Neurosci 1998; 1: 529–33. Wright WG, Gurfinkel VS, King LA, Nutt JG, Cordo PJ, Horak FB. Axial kinesthesia is impaired in Parkinson’s disease: effects of levodopa. Exp Neurol 2010; 225: 202–9.
BRAIN 2014: Page 1 of 2
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BRAIN A JOURNAL OF NEUROLOGY
LETTER TO THE EDITOR Reply: Does dominant pedunculopontine nucleus exist? Probably not 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, Department of Neurology School of Medicine, Oregon Health and Science University 3181 SW Sam Jackson Park Rd., Portland, OR 97239-3098, USA E-mail: [email protected]
Sir, We are pleased to continue the discussion with regards to our recent manuscript detailing altered structural connectivity of the locomotor network within the right hemisphere of individuals with Parkinson’s disease who experience freezing of gait (Fling et al., 2013). Our previous work has asserted the possibility of right hemisphere pathology as a principal neural component underlying freezing of gait, with an emphasis placed on disrupted communication between locomotor centres in the brainstem and cerebellum with medial areas of the frontal and prefrontal cortices (Fling et al., 2013, 2014a). In their letter to the editor, Hall and colleagues (2014) provide data demonstrating that freezing of gait is evident in Parkinson’s disease regardless of which side of the body is more affected. The authors report no difference in the proportion of subjects (n = 70) with self-reported freezing of gait and left-side motor symptom dominance in 40/70 participants compared to right-side dominance in 30/70. It is suggested that because there are substantial numbers of individuals with greater right-side motor involvement (and by proxy, lefthemispheric striatal pathology), freezing of gait is not caused by pathology of the right-hemisphere alone. Idiopathic Parkinson’s disease is characterized by asymmetry of symptoms at disease onset, which is generally maintained, although symptoms tend to become more bilateral with disease progression (Hornykiewicz, 1966).
The characteristic asymmetric manifestation of motor symptoms is related to greater impairment of dopaminergic function in the contralateral striatum as indicated by reduced dopamine storage and dopamine transporter uptake (Leenders et al., 1986; Brooks et al., 1990a, b). The ‘choice’ of side predominance in patients with Parkinson’s disease could be pure chance (Djaldetti et al., 2006). These authors suggest that ‘similar to other complex diseases such as cancer, the ignition of detrimental cellular pathways might be randomly determined by a combination of factors too numerous to fully characterize’ (Djaldetti et al., 2006). The dominant side of hemispheric neurodegeneration can differentially affect particular functions for people with Parkinson’s disease. For example, recent work demonstrates that individuals with greater right-hemisphere pathology have larger kinaesthetic deficits than those with principally left-hemisphere involvement (Wright et al., 2010). This is in agreement with literature reporting similar results for visual and visuospatial tasks (Starkstein et al., 1987; Ebersbach et al., 1996; Harris et al., 2003; Davidsdottir et al., 2005). The fact that both visual and kinaesthetic asymmetries seem to predominantly affect left-side dominant Parkinson’s disease may mean that both originate from early asymmetrical nigrostriatal neuron loss (Wright et al., 2010). Whereas these functions seem to be defined by asymmetric striatal dysfunction,
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]
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| BRAIN 2014: Page 2 of 2
freezing of gait is not associated with the cardinal motor features of Parkinson’s disease (tremor, bradykinesia or rigidity) (Giladi, 2001; Bartels et al., 2003). However, freezing of gait is correlated with postural instability (Giladi et al., 2001), spatial contrast sensitivity deficits (Davidsdottir et al., 2005), and an inability to appropriately engage and release inhibition (Cohen et al., 2014), rather than with general motor and/or executive deficits. These functions (body schema, spatial orientation, proprioceptive processing and cognitive inhibitory control) are all principally lateralized to the brain’s right hemisphere (Wolpert et al., 1998; Aron, 2007; Goble et al., 2012). We suggest that while the results of Hall and colleagues are interesting, they are not necessarily inconsistent with the results of Lam et al. (2014) and Fling et al. (2013, 2014b), nor do they negate the interpretations reached in those studies. In our original paper (Fling et al., 2013), as well as the majority of manuscripts examining the clinical phenomenon of freezing, there is a relatively equal number of patients with motor symptomology on the right or left side of the body. We therefore suggest that freezing of gait is not necessarily reflective of asymmetric striatal involvement, which defines motor-symptom dominant side in Parkinson’s disease, but is more likely the result of impaired neural circuitry within the locomotor and cognitive/higher-order motor networks of the brain’s right hemisphere, regardless of motor-symptom dominant side.
References Aron AR. The neural basis of inhibition in cognitive control. Neuroscientist 2007; 13: 214–28. Bartels AL, Balash Y, Gurevich T, Schaafsma JD, Hausdorff JM, Giladi N. Relationship between freezing of gait (FOG) and other features of Parkinson’s: FOG is not correlated with bradykinesia. J Clin Neurosci 2003; 10: 584–8. Brooks DJ, Ibanez V, Sawle GV, Quinn N, Lees AJ, Mathias CJ, et al. Differing patterns of striatal 18F-dopa uptake in Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Ann Neurol 1990a; 28: 547–55. Brooks DJ, Salmon EP, Mathias CJ, Quinn N, Leenders KL, Bannister R, et al. The relationship between locomotor disability, autonomic dysfunction, and the integrity of the striatal dopaminergic system in patients with multiple system atrophy, pure autonomic failure, and Parkinson’s disease, studied with PET. Brain 1990b; 113 (Pt 5): 1539–52.
Letter to the Editor 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. Davidsdottir S, Cronin-Golomb A, Lee A. Visual and spatial symptoms in Parkinson’s disease. Vision Res 2005; 45: 1285–96. Djaldetti R, Ziv I, Melamed E. The mystery of motor asymmetry in Parkinson’s disease. Lancet Neurol 2006; 5: 796–802. Ebersbach G, Trottenberg T, Ha¨ttig H, Schelosky L, Schrag A, Poewe W. Directional bias of initial visual exploration. A symptom of neglect in Parkinson’s disease. Brain 1996; 119 (Pt 1): 79–87. 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 (Pt 8): 2405–18. 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 2014a; 9: e100291. Fling BW, Nutt JG, Horak FB. Reply: does dominant pedunculopontine nucleus exist? Brain 2014b. doi: 10.1093/brain/awu226. Giladi N. Gait disturbances in advanced stages of Parkinson’s disease. Adv Neurol 2001; 86: 273–8. Giladi N, McDermott MP, Fahn S, Przedborski S, Jankovic J, Stern M, et al. Freezing of gait in PD: prospective assessment in the DATATOP cohort. Neurology 2001; 56: 1712–21. Goble DJ, Coxon JP, Van Impe A, Geurts M, Van Hecke W, Sunaert S, et al. The neural basis of central proprioceptive processing in older versus younger adults: an important sensory role for right putamen. Hum Brain Mapp 2012; 33: 895–908. Hall JM, Gilat M, Lewis SJG, Shine JM. Does dominant pedunculopontine nucleus exist? Probably not. Brain 2014. doi: 10.1093/brain/ awu315. Harris JP, Atkinson EA, Lee AC, Nithi K, Fowler MS. Hemispace differences in the visual perception of size in left hemiParkinson’s disease. Neuropsychologia 2003; 41: 795–807. Hornykiewicz O. Dopamine (3-hydroxytyramine) and brain function. Pharmacol Rev 1966; 18: 925–64. Lam S, Moro E, Poon YY, Lozano AM, Fasano A. Does dominant pedunculopontine nucleus exist? Brain 2014. doi: 10.1093/brain/ awu225. Leenders KL, Palmer AJ, Quinn N, Clark JC, Firnau G, Garnett ES, et al. Brain dopamine metabolism in patients with Parkinson’s disease measured with positron emission tomography. J Neurol Neurosurg Psychiatry 1986; 49: 853–60. Starkstein S, Leiguarda R, Gershanik O, Berthier M. Neuropsychological disturbances in hemiparkinson’s disease. Neurology 1987; 37: 1762–4. Wolpert DM, Goodbody SJ, Husain M. Maintaining internal representations: the role of the human superior parietal lobe. Nat Neurosci 1998; 1: 529–33. Wright WG, Gurfinkel VS, King LA, Nutt JG, Cordo PJ, Horak FB. Axial kinesthesia is impaired in Parkinson’s disease: effects of levodopa. Exp Neurol 2010; 225: 202–9.
