Functional MRI of the cortical sensorimotor system in patients with hereditary spastic paraplegia

Spinal Cord (2012) 50, 885–890 & 2012 International Spinal Cord Society All rights reserved 1362-4393/12 www.nature.com/sc ORIGINAL ARTICLE Functional MRI of the cortical sensorimotor system in patients with hereditary spastic paraplegia T Tomberg1,2,6, M Braschinsky3,6, K Rannikmäe3, J Kepler4, K Kepler5, J Kõrv3, Ü Linnamägi3 and T Asser3 Objectives: The study aimed to use functional magnetic resonance imaging (fMRI) to ascertain changes in sensorimotor system function in patients with hereditary spastic paraplegia (HSP) and to correlate it with severity of spasticity and paresis. Setting: Tartu University Hospital, Tartu, Estonia. Methods: Nine patients with autosomal-dominant pure HSP and 14 age- and sex-matched healthy controls were investigated with a 1.5T fMRI scanner during flexion/extension of the right-hand fingers and right ankle. Images were analysed with a general linear model and Statistical Parametrical Mapping software. Highest Z-scores were identified from probability maps, and weighted laterality indices were calculated using combined bootstrap/histogram analysis; these were correlated with clinical severity of spasticity and paresis. Results: During hand movements, clusters located in contralateral primary sensorimotor and premotor areas activated in both controls and patients. Bilateral activation occurred in the supplementary motor area, parietal operculum (predominantly contralateral) and cerebellum (predominantly ipsilateral). During the ankle task, bilateral activation was noted in the primary sensorimotor area, supplementary motor area and cerebellum. Activation clusters in HSP patients were smaller than those in controls in the sensorimotor area, especially during the ankle task, and more pronounced ipsilaterally in cerebellum both during hand and ankle motor tasks. Spasticity was significantly associated with contralateral activation in the sensory area and correlated negatively with the highest Z-scores in Brodmann areas 1-2-3 and 4. Conclusion: Our results suggest changes in cortical sensorimotor network function in patients with HSP compared with healthy subjects. Lower activation in patients might reflect damage to the corticospinal tract, be influenced by compensatory mechanisms, and/or be a reflection of neurorehabilitation. Spinal Cord (2012) 50, 885–890; doi:10.1038/sc.2012.70; published online 3 July 2012 Keywords: cortical reorganisation; functional magnetic resonance imaging; hereditary spastic paraplegia; Strümpell–Lorrain disease INTRODUCTION Hereditary spastic paraplegia (HSP) or the Strümpell-Lorrain disease is a group of rare chronic neurodegenerative disorders marked by clinical and genetic heterogeneity. It has been classified into two forms, ‘pure’ (pHSP) and ‘complex’ (cHSP). pHSP presents with spasticity and motor deficit in the legs, brisk reflexes and Babinski’s signs; deep sensory impairment and sphincter disturbances are also common. For cases of cHSP, other neurological or extra-neurological features can be present.1 The disease affects substantially health related quality of life of persons with HSP.2 The primary pathology in HSP is axonal degeneration that is maximal at the distal ends of the corticospinal tracts and at the distal ends of dorsal column fibres.3 Previous studies in HSP patients have revealed cerebral involvement as well, including cognitive decline, white matter abnormalities, involvement of motor cortex and alterations of regional cerebral blood flow and brain activity.4–8 However, the pattern of possible cortical functional reorganisation and its correlates with motor impairments are yet poorly understood. The objectives of this study were to ascertain changes in sensorimotor system function in patients with HSP by using functional magnetic resonance imaging (fMRI) and to correlate fMRI changes with the severity of spasticity and paresis in legs. MATERIALS AND METHODS Subjects Patient data were acquired from an epidemiological study database consisting of 59 persons with HSP.9 Patients with autosomal-dominant pHSP (ADpHSP) and mutations in the SPAST gene (also known as the SPG4 gene—the most frequent genetic pathology found in HSP worldwide in general and in Estonia in particular) were invited to participate in the study as were their affected family members with the same phenotype. Other Estonian patients with HSP were not included in this study in order to ensure the genetic and clinical homogeneity of the study group. Nine right-handed patients (5 women, 4 men, mean age 47 years, age range 22–69 years) and 14 age- and sex-matched right-handed healthy controls (8 women, 6 men, mean age 47 years, age range 22–70 years) consented for participation. All nine patients studied had a positive family history for HSP and belonged to three different pedigrees (Table 1). Five patients had pathogenic mutations in the SPAST gene, and two patients had non-pathogenic mutations in the SPAST gene. One patient had no changes in the SPAST gene but belonged to a pedigree with other affected members with non-pathogenic mutation. One patient refused to participate in genetic testing but belonged to a larger family 1Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia; 2Department of Radiology, Tartu University Hospital, Tartu, Estonia; 3Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia; 4Diagnostics Service, Pärnu Hospital, Pärnu, Estonia and 5Institute of Physics, University of Tartu, Tartu, Estonia 6These authors contributed equally to this work. Correspondence: Dr M Braschinsky, Department of Neurology, University of Tartu, Puusepa 8H, Tartu 51014, Estonia. E-mail: Received 20 February 2012; revised 20 April 2012; accepted 11 May 2012; published online 3 July 2012 fMRI in hereditary spastic paraplegia T Tomberg et al 886 with pathogenic mutation in the SPAST gene, where all affected members had the same phenotype of the disease.10 Eight included patients had lower spastic paraparesis with different degree of spasticity and paresis (Table 1). One man was asymptomatic but had pyramidal signs present—his data were analysed also separately. Four patients used antispasticity medications (tizanidine or baclofen) before the study, but were taken off the medication for 3 days before the time of the study. Spasticity was evaluated using the Modified Ashworth Scale (MAS) to assess the antagonist muscles: hamstrings, thigh adductor, gastrocnemius and soleus.11 A 0–5 grading system was applied (0, no increase in muscle tone; 5, affected part rigid).11 Severity of paresis of the lower limbs was assessed using on the Medical Research Council (MRC) Scale for Muscle Strength grading it from 0–5 (5, normal strength; 0, no movement).12 Image acquisition Images were obtained on a 1.5-T MR scanner (Magnetom Symphony; Siemens Medical Systems, Erlangen, Germany). Before obtaining functional scans, a high-resolution T1-weighted anatomical image was obtained with the (...truncated)