**5. Functional neuroimaging in motor neuron diseases**

#### **5.1 Functional neuroimaging of motor network**

In fMRI studies, ALS patients present higher volumes of activated brain areas in motor tasks compared with healthy controls, thus providing evidence for functional reorganisation and cortical plasticity in MND (Brooks et al., 2000; Lulé et al., 2009). Konrad et al. observed this in eleven ALS patients (Konrad et al., 2002) who performed a simple finger flexion task with 10% of each individual´s maximum grip force. Increased activity was found in motor areas such as the premotor area, supplementary motor area, and the cerebellum. A similarly

the BOLD signal, however, derives from the interaction of multiple parameters (e.g. perfusion, metabolic turnover of neurons, density of venous vasculature of tissue, medication etc.) and may vary between brain areas and individuals as well as experimental and clinical settings, quantitative analysis in absolute terms is precluded (Kim et al., 1997a;

MRI sequences that are best suited for functional neuroimaging should be both fast and sensitive to changes in the deoxyhaemoglobin concentration (Frahms et al., 1999). The MRI sequence that is generally considered to be the first choice for measuring BOLD in fMRI is a T2\*-weighted echo-planar imaging (EPI) sequence, with its high speed yielding imaging times which translate into a maximum temporal resolution (Edelman et al., 1994; Kwong et al., 1995; Schmitt et al., 1998; Roberts et al., 2007). Temporal and spatial parameters of MRI scanning such as repetition time (TR) or slice thickness are limited by the T2\* signal decay of the MRI sequence and determined according to study-specific factors, e.g. region of interest and field strength (Schmitt et al., 1998; Turner et al., 1998; Triantafyllou et al., 2005; Norris et al., 2006; Figure 2). Other MRI sequences such as fast low angle shot (FLASH) techniques facilitate access to higher spatial resolution at the expense of temporal resolution and volume coverage of larger volumes leading to higher scanning times (Frahms et al., 1999),

Fig. 2. Example of orientation of EPI-sequence (white lines) along the anterior-posterior commissure overlaid onto a t1 weighted image (mprage) of a head (sagittal view)

In fMRI studies, ALS patients present higher volumes of activated brain areas in motor tasks compared with healthy controls, thus providing evidence for functional reorganisation and cortical plasticity in MND (Brooks et al., 2000; Lulé et al., 2009). Konrad et al. observed this in eleven ALS patients (Konrad et al., 2002) who performed a simple finger flexion task with 10% of each individual´s maximum grip force. Increased activity was found in motor areas such as the premotor area, supplementary motor area, and the cerebellum. A similarly

**5. Functional neuroimaging in motor neuron diseases** 

**5.1 Functional neuroimaging of motor network** 

Di Salle et al., 1999; Logothesis et al., 2001).

which is not always favourable in clinical settings.

increased activity in motor areas was observed in fifteen ALS patients compared to fifteen healthy controls during a sequential finger tapping movement task (Han et al., 2006) and in ALS patients compared both to patients with upper limb weakness due to peripheral nerve lesions and to controls during freely selected random joystick movements of the right hand (Stanton et al., 2007a). It has been proposed that these changes may represent cortical plasticity, as new synapses and pathways are developed to compensate for the selective loss of pyramidal cells in the motor cortex (Schoenfeld et al., 2005). A shift of activity to more anterior regions of the premotor cortex, i.e. Brodmann area (BA) 6, during upper limb movement has been observed in ALS patients (Konrad et al., 2002; Han et al., 2006), such findings being supported by previous functional imaging studies with PET (Kew et al., 1993a; 1994). Furthermore, there is longitudinal fMRI evidence of progressive involvement of the premotor area in upper limb motor tasks in the course of the disease (Lulé et al., 2007a). Thirteen patients with sporadic ALS and 14 healthy controls were asked to perform tasks involving a grip movement of the left, right, and both hands and to imagine the same without any overt movement of the hand. Motor imagery is known to involve similar areas as motor execution without being affected by confounding factors of effort and strain. In two consecutive fMRI measurements at a six-month interval, evidence for progressive recruitment of premotor areas in motor imagery was found in the course of the disease (Lulé et al., 2007a).

Furthermore, a changed pattern and an anterior shift of activity in ALS were also observed in further cortical areas besides the premotor cortex for various motor tasks. For instance, increased involvement of supplementary motor areas (SMA) (Konrad et al., 2002; 2006; Han et al., 2006) and sensorimotor cortices has been seen (Brooks et al., 2000; Han et al., 2006; Stanton et al., 2007a; Mohammadi et al., 2011). Activity in contralateral sensorimotor cortex activity was increased the stronger the physical impairments were in patients (Mohammadi et al., 2011). Furthermore, activity in adjacent areas such as the bilateral inferior parietal lobe (BA 40) and bilateral superior temporal gyrus (BA 22) was increased in ALS patients compared to healthy controls during upper limb motor task performance in different fMRI studies (Stanton et al., 2007a). Altered somatotopy in the sensorimotor cortices was not observed in patients with exclusive lower motor neuron involvement (Kew et al., 1994), but only in ALS patients with clinical and functional involvement of both upper and lower motor neurons (Han et al., 2006; Kew et al., 1993a; 1994) or upper motor neuron only (Stanton et al., 2007a). This suggests that this changed pattern of activity might represent the loss of the pyramidal tract (Kew et al., 1994). A similar shift of activity in motor tasks into more anterior regions of sensorimotor and premotor areas and the SMA has been demonstrated for different neuropathologies with distinct aetiology such as stroke (Weiller et al., 2006). Thus, it may be assumed that this anterior shift represents a general pattern of plasticity as a response to neuronal loss in primary motor areas as a more or less efficient way to compensate motor function rather than an ALS-specific pattern of altered motor activation (Weiller et al., 2006).

Increasing activity in ipsilateral cortical areas such as the sensorimotor cortex (Han et al., 2006; Stanton et al., 2007a) and primary motor areas (Schoenfeld et al., 2005) has been observed in ALS patients. In a motor task of upper limb movement with varying task difficulty, six ALS patients presented an increased activity in ipsilateral primary motor areas compared to six healthy controls, corresponding to the degree of difficulty (Schoenfeld et al., 2005). The fact that healthy controls recruit ipsilateral areas with increasing complexity of a

Degeneration of the Human Nervous System and Magnetic Resonance Neuroimaging 25

of the disease retain the potential for compensatory activity and how training of e.g. movement imagery might slow down the "compensatory" process. Functional MRI seems to

The multisystemic character of ALS has been supported by various findings of functional imaging studies, although there are few fMRI studies. Involvement of sensory pathways in ALS has been reported by histopathological (Isaacs et al., 2007) and electrophysiological studies (Mai et al., 1998; Pugdahl et al., 2007). Evidence from fMRI studies for changed cortical patterns for sensory processing suggests the involvement of sensory processing areas in ALS (Lulé et al., 2010). In a visual, auditory and somatosensory stimulus paradigm, ALS patients presented reduced activity in primary and secondary sensory areas and an increased activity in higher associative areas. This increase in activity was correlated with loss of movement ability: The higher the physical restrictions were, the higher was the

BA 37

thalamus

activity in those areas of third order sensory processing in ALS patients (Figure 3).

Visual Auditory Somatosensory

BA 40

Fig. 3. Changes in brain activity associated with loss of physical function in amyotrophic lateral sclerosis (ALS). Statistical maps presenting significantly increased and decreased blood oxygen level dependent activity associated with loss of physical function (measured with ALS functional rating scale, ALS-FRS) in ALS patients for visual, auditory and somatosensory stimulation. Areas with increasing (upper row, red) and decreasing (lower row, green) activity are shown. Significant activations are overlaid onto an axial (top row) and sagittal (bottom row) mean anatomical image of all subjects. Displayed are clusters >5

putamen

Structural analysis of white matter integrity in this study measured with DTI provided evidence for a disruption of sensory nerve fibres in those ALS patients (Lulé et al., 2010).

voxels with uncorrected threshold p<0.001. P, posterior; R, right.

be an appropriate way to gain more knowledge on this issue.

**5.2 Functional imaging of extramotor paradigms in MND** 

BA 40

P

P

BA 7

R

TEO

task suggests that ipsilateral involvement may reflect difficulty-dependent compensation and not a pathological pattern of activation *per se*. Accordingly, ALS patients may recruit existing neuronal pathways to compensate for functional loss in primary motor cortex (Schoenfeld et al., 2005).

Furthermore, a more pronounced involvement of other motor functional areas at cortical and subcortical levels has been demonstrated in fMRI studies of motor tasks. For motor execution, a stronger involvement of areas involved in motor learning, such as the basal ganglia, cerebellum (Han et al., 2006; Konrad et al., 2006) and/or brainstem (Konrad et al., 2006) is evident. It may be assumed that alterations in functioning of basal ganglia are likely to be related to upper motor neuron pathology since they were observed in patients with exclusive upper motor neuron involvement (Tessitore et al., 2006). For motor imagery, a stronger recruitment of higher cognitive areas of motor control (frontal areas BA 9, 44, 45) and motor representation (inferior parietal activity, BA 40) in the course of the disease has been demonstrated in ALS patients compared to healthy controls (Lulé et al., 2007a). Overall, functional connectivity in the motor system network is altered in ALS (Mohammadi et al., 2009).

Moreover, an increased involvement of extra motor areas, e.g. in the anterior cingulate cortex for movements of the right hand, is evident for patients with exclusive upper motor neuron involvement by fMRI (Tessitore et al., 2006). Similarly, an increased activity in anterior insular cortex and anterior cingulate cortex has been shown in other functional studies of motor execution (Brooks et al., 2000; Kew et al., 1993a; 1994).

Whether the changed pattern of activity in other motor functional areas and higher cognitive areas during motor tasks represents the recruitment of redundant parallel motor system pathways or whether they map functional compensation or reorganisation can only be speculated upon. There is evidence that the change in cortical functioning of other motor and extramotor systems is primarily related to upper motor neuron pathology (Tessitore et al., 2006).

For motor imagery, which is known to involve similar areas as motor execution, a different pattern of cortical activity is seen in ALS compared to motor tasks. In a movement imagery task of the right hand in 16 ALS patients, there was reduced BOLD activity in the left anterior parietal lobe, the anterior cingulate, and medial pre-frontal cortex compared to 17 healthy controls (Stanton et al., 2007b). Reduced BOLD activity in the anterior cingulate cortex was also evident in a movement imagery task of both hands in the study by Lulé et al. (2007a). This reduction in cortical activation during motor imagery is at odds with the pattern observed during motor execution. This may represent the disruption of normal motor imagery networks by ALS pathology outside the primary motor cortex (Lulé et al., 2007a; Stanton et al., 2007b).

In summary, these data suggest an additional recruitment in brains of patients with ALS comprising bilateral areas in the premotor cortex in early stages along with involvement of higher order motor processing areas, determined by motor impairments (especially associated with upper motor neuron pathology) in the long run. This additional recruitment might be a (futile) way to compensate ALS-associated progressive functional loss.

The cardinal feature of ALS is the loss of giant pyramidal Betz cells in the primary motor cortex (Brownell et al., 1970). It is nowadays assumed, however, that degeneration extends beyond the motor cortex. Neurodegeneration in motor areas might lead to progressive compensation of secondary motor areas for movement representation. Compensation terminates in a non-functional distributed cortical and subcortical ALS-specific motor network. More research needs to be done on how well the ALS patients in advanced stages of the disease retain the potential for compensatory activity and how training of e.g. movement imagery might slow down the "compensatory" process. Functional MRI seems to be an appropriate way to gain more knowledge on this issue.
