Structural and functional evaluation of cortical motor areas in Amyotrophic Lateral Sclerosis

Abstract

The structural and functional data gathered with Magnetic Resonance Imaging (MRI) techniques about the brain cortical motor damage in Amyotrophic Lateral Sclerosis (ALS) are controversial. In fact some structural MRI studies showed foci of gray matter (GM) atrophy in the precentral gyrus, even in the early stage, while others did not. Most functional MRI (fMRI) studies in ALS reported hyperactivation of extra-primary motor cortices, while contradictory results were obtained on the activation of the primary motor cortex. We aimed to investigate the cortical motor circuitries in ALS patients by a combined structural and functional approach.

Twenty patients with definite ALS and 16 healthy subjects underwent a structural examination with acquisition of a 3D T1-weighted sequence and fMRI examination during a maximal force handgrip task executed with the right-hand, the left-hand and with both hands simultaneously. The T1-weighted images were analyzed with Voxel-Based Morphometry (VBM) that showed several clusters of reduced cortical GM in ALS patients compared to controls including the pre and postcentral gyri, the superior, middle and inferior frontal gyri, the supplementary motor area, the superior and inferior parietal cortices and the temporal lobe, bilaterally but more extensive on the right side. In ALS patients a significant hypoactivation of the primary sensory motor cortex and frontal dorsal premotor areas as compared to controls was observed. The hypoactivated areas matched with foci of cortical atrophy demonstrated by VBM. The fMRI analysis also showed an enhanced activation in the ventral premotor frontal areas and in the parietal cortex pertaining to the fronto-parietal motor circuit which paralleled with disease progression rate and matched with cortical regions of atrophy. The hyperactivation of the fronto-parietal circuit was asymmetric and prevalent in the left hemisphere.

VBM and fMRI identified structural and functional markers of an extended cortical damage within the motor circuit of ALS patients. The functional changes in non-primary motor cortices pertaining to fronto-parietal circuit suggest an over-recruitment of a pre-existing physiological sensory–motor network. However, the concomitant fronto-parietal cortical atrophy arises the possibility that such a hyper-activation reflects cortical hyper-excitability due to loss of inhibitory inter-neurons.

Introduction

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder selectively affecting upper (UMN) and lower (LMN) motor-neurons (Wijesekera and Leigh, 2009). ALS diagnosis is mainly based on clinical and electrophysiological findings, according to revised “El-Escorial” criteria (Brooks et al., 2000). Neuroimaging examination has a secondary role in the diagnostic work-up and is essentially utilized to exclude “ALS-mimics” disorders.

A major problem in diagnosis and follow-up of ALS patients is represented by the inadequate assessment of the UMNs that is masked by the contemporary impairment of LMNs. Many efforts have been made to find alternative methods to explore UMNs including neuroimaging techniques. A large number of studies with conventional Magnetic Resonance Imaging (MRI) (Abe et al., 1997, Charil et al., 2009, Cheung et al., 1995, Goodin et al., 1988, Thorpe et al., 1996), magnetization transfer techniques (Da Rocha et al., 2004, Kato et al., 1997) and diffusion tensor imaging (Charil et al., 2009, Cosottini et al., 2005, Ellis et al., 1999, Hong et al., 2004, Iwata et al., 2008) focused their attention respectively to signal or microstructural changes mainly along the corticospinal tracts of patients with ALS. Neuroimaging investigation of UMN at cortical level has been less extensively pursued. In particular conventional MRI revealed an abnormal hypointense signal of the motor cortex in the posterior bank of precentral gyrus (Cheung et al., 1995, Hecht et al., 2002, Ishikawa et al., 1993, Oba et al., 1993, Thorpe et al., 1996, Waragai, 1997). However these changes are age related and were observed also in patients without ALS (Ngai et al., 2007). Moreover conventional MRI revealed a focal enlargement of the central sulcus as an indirect sign of motor cortical atrophy (Pringle et al., 1992) and a reduction of cortical thickness in the motor cortex of precentral gyrus as a possible biomarker of UMN disease (Butman and Floeter, 2007). Voxel-Based Morphometry (VBM) is a quantitative automated method which performs a voxel-wise comparison of the local concentration of gray matter (GM) between two groups of subjects without any a priori knowledge bias (Ashburner and Friston, 2000). Previous VBM studies demonstrated a significant reduction of the GM within the precentral gyrus of ALS patients, reflecting the neuronal loss (Agosta et al., 2007). However such a finding was not replicated in other VBM studies (Mezzapesa et al., 2007).

More recently functional MRI (fMRI) has been applied to the evaluation of the motor cortex dysfunction in patients with ALS and has demonstrated altered patterns of cortical activation during motor tasks in patients with ALS compared to controls. Most studies showed an enhanced activation of several cortical regions, including the premotor frontal areas and the parietal cortex, and in subcortical regions (Konrad et al., 2002, Konrad et al., 2006, Stanton et al., 2007). Intriguingly, although the classic neuropathological studies indicated that the degenerative changes in ALS are mainly confined to the giant Betz cells of the precentral gyrus (Lawyer and Netsky, 1953), the results currently available on the functional changes within the primary motor cortex are controversial. In fact hyperactivation (Schoenfeld et al., 2005, Stanton et al., 2007), hypoactivation (Tessitore et al., 2006) or lack of significant differences with the controls (Konrad et al., 2002) were reported in the sensory–motor cortex contralateral to hand movement. Inhomogeneity of the motor paradigms adopted in different studies and differences in data analysis may account for these discrepancies.

The aim of our work was to explore with MRI the structural and functional alterations of the cortical motor areas in ALS patients, with particular regard to the damage of the UMN at level of precentral gyrus, using a combined VBM and fMRI approach.