Alterations of mean diffusivity of pedunculopontine nucleus pathway in Parkinson's disease patients with freezing of gait Jinyoung Youn a , Jong-Min Lee b , Hunki Kwon b , Ji Sun Kim c , Tae Ok Son a , Jin Whan Cho a, * a Department of Neurology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea b Department of Biomedical Engineering, Hanyang University, Seoul, Republic of Korea c Department of Neurology, Soonchunhyang University College of Medicine, Seoul, Republic of Korea article info Article history: Received 14 April 2014 Received in revised form 29 September 2014 Accepted 1 October 2014 Keywords: Parkinson's Freezing Pedunculopontine Diffusion tensor Gait abstract Background: Although freezing of gait (FOG) is a common and disabling symptom in Parkinson's disease (PD), the underlying mechanism of FOG has not been clearly elucidated. Using analysis of diffusion tensor imaging (DTI), we investigated anatomic structures associated with FOG in PD patients. Methods: We enrolled 33 controls and 42 PD patients (19 patients with FOG and 23 without FOG). DTI data were compared between PD patients and controls, and also between PD patients with and without FOG. Whole brain voxel-based analysis and regions of interest analysis in the pedunculopontine nucleus were used for DTI analysis. Results: Compared with normal controls, PD patients showed microstructural changes in various subcortical structures (substantia nigra, globus pallidum and thalamus), frontal and insula cortex. PD patients with FOG demonstrated altered mean diffusivities in subcortical structures connected with pedunculopontine nucleus, such as basal ganglia, thalamus and cerebellum in voxel-based analysis. Using region of interest analysis of pedunculopontine nucleus, fractional anisotropy values were reduced and mean diffusivity values were increased bilaterally in PD patients with FOG. In correlation analysis, the fractional anisotropy value of the right pedunculopontine nucleus was moderately correlated with the severity of FOG. Conclusions: Based on our results, microstructural changes of pedunculopontine nucleus and connected subcortical structures are closely related with FOG in PD patients. © 2014 Elsevier Ltd. All rights reserved. 1. Introduction Freezing of gait (FOG) is a gait disorder described as a brief, episodic absence or marked reduction of forward progression of the feet despite the intention to walk [1,2]. FOG is a common but disabling symptom in Parkinson's disease (PD) patients, because of its relationship to falling, fracture and impact on quality of life [2]. Furthermore, unlike other parkinsonian symptoms, FOG is hard to manage with medication or surgical treatment [3]. Despite its clinical impact, the pathogenesis of FOG is not yet clearly understood. Two neural networks have recently been sug- gested for the control of gait based on animal electrophysiology and human brain mapping data [4]. One is a direct pathway from the motor cortex to the spinal cord, and the other is an indirect pathway from the frontal cortex, via the basal ganglia, to brainstem locomotor centers. In PD patients, the direct pathway cannot compensate for all the deficiencies in the indirect pathways, and FOG may develop. The pedunculopontine nucleus (PPN) is one of the main brain- stem locomotor centers and is associated with the regulation of gait and posture [5,6]. Previous studies, using kinetic analysis of gait, reported abnormal gait coordination in PD patients with FOG [7,8] and using imaging analysis, demonstrated that FOG is related with abnormalities in PPN area [9,10]. Furthermore, electrophysiologic abnormalities in PPN area were also reported in PD patients with FOG [6,11]. Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique sensitive to the orientation of mobility in intra- voxel water molecules [12]. Fractional anisotropy (FA) and mean * Corresponding author. Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-Dong, Gangnam-Gu, Seoul 135-710, Republic of Korea. Tel.: þ82 2 3410 1279; fax: þ82 2 3410 0052. E-mail address: jinwhan.cho@samsung.com (J.W. Cho). Contents lists available at ScienceDirect Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis http://dx.doi.org/10.1016/j.parkreldis.2014.10.003 1353-8020/© 2014 Elsevier Ltd. All rights reserved. Parkinsonism and Related Disorders 21 (2015) 12e17