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

24 Neuroimaging for Clinicians – Combining Research and Practice

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

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

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

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

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.,

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

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

might be a (futile) way to compensate ALS-associated progressive functional loss.

(Schoenfeld et al., 2005).

al., 2006).

2007a; Stanton et al., 2007b).

system network is altered in ALS (Mohammadi et al., 2009).

studies of motor execution (Brooks et al., 2000; Kew et al., 1993a; 1994).

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

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

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).

Degeneration of the Human Nervous System and Magnetic Resonance Neuroimaging 27

pathway might represent an altered sensitivity to social-emotional cues in ALS patients without cognitive deficits (Lulé et al., 2007b). Reduced activity in right sided frontal areas during processing of aversive emotional stimuli in ALS patients compared to controls support the assumption of an impaired processing pathway in ALS (Palmieri et al., 2010). More research is required to determine how successful and stable this compensatory

There is the described overlap of dementia and motor neuron diseases, however, contrary to the above described prominent role in MND, the role of imaging in dementia has traditionally been directed at ruling out treatable and reversible aetiologies (Tartaglia et al., 2011). Contrary to motor neuron diseases it was rarely used to better understand the

Structural CT and MRI scans are mainly used to assess volumetric changes in dementias with decreases in gyral and increases in sulcal size secondary to decrease in synaptic density, neuronal loss, and cell shrinkage (Tartaglia et al., 2010). The medial temporal lobes, especially the hippocampus and entorhinal cortex (ERC), are among the earliest sites of pathologic involvement in AD (Braak & Braak, 1991), and studies have repeatedly shown decreased hippocampal and ERC volumes in patients with AD compared with age-matched controls (Appel et al., 2009). Other severely affected areas include the lateral parietal and posterior superior temporal regions and medial posterior portion of the cingulate gyrus (Jones et al., 2006), but atrophy is also evident in the frontal, temporal, and occipital lobes (Rusinek et al., 1991). Recent neuropathological data provide evidence that disease pathology starts in locus coeruleus and propagates into transentorhinal region and other cerebral regions (Braak & Del Tredici, 2011a). MRI of hippocampal and cortical regions in the parietal and lateral temporal regions has been successfully used as prognostic marker in patients with mild cognitive impairment (MCI) to develop AD (Du et al., 2003; Schott et al., 2003). High field MRI provided evidence for a sensitivity of the thickness of CA1 to distinguish subjects with AD from normal controls (Kerchner et al., 2010). Like in ALS, white matter (WM) pathology was long not in focus of research. However, recent work provides evidence for WM changes in AD and MCI in association with cognitive changes (Zhang et al., 2007; Sexton et al., 2010). It might even be useful to distinguish different forms of dementia (Firbank et al., 2007; Zhang et al., 2009). NAA spectroscopy has been used as a possible diagnostic marker in dementia. NAA is consistently reported as being lower in the parietal gray matter and hippocampus of patients with AD than in cognitively normal

On the functional level of the brain, evidence for a reduced function of frontal areas in FTD compared to AD was seen using fMRI (Rombouts et al., 2003). Furthermore, alterations in the default mode network (areas active during rest and idling of the brain) in resting state have been found for AD and MCI patients (Tartaglia et al., 2011). In the future, the application of neuroimaging in dementia will increase, as there will be extended evidence

for prognostic and clinical marker for different forms of dementia.

**6. Functional neuroimaging in other neurodegenerative diseases like** 

**dementia, Parkinson's disease, and Huntington's disease** 

recruitment is and again fMRI may be an important step.

**6.1 Functional neuroimaging in dementia** 

pathophysiology of the different dementias.

elderly subjects (Schuff et al., 2002).

Auditory processing underlying stimulus detection measured by MEG and subsequent memory-based comparison processes were abnormal in ten ALS patients with bulbar signs (Pekkonen et al., 2004), and a reduced response to auditory and visual stimuli was observed in ALS patients compared to healthy controls using EEG (Münte et al., 1998; Vieregge et al., 1999). This finding may indicate a changed sensory processing capacity as well as reduced attention capacity (Pinkhardt et al., 2008), an ability assigned to the frontal cortex known to be involved in ALS (Ludolph et al., 1992; Kew et al., 1993b).

The association of functional cortical changes and cognitive deficits has been confirmed by an fMRI paradigm of letter fluency and confrontation naming in 28 non-demented ALS patients compared to 18 healthy controls (Abrahams et al., 2004) and had been demonstrated previously by other functional imaging techniques (Ludolph et al., 1992; Kew et al., 1993b; Abrahams et al., 2004). There is increasing evidence that not only do 2–5% of ALS patients present an ALS/dementia complex but also that patients with classical ALS without obvious clinical evidence of cognitive deficits may have subtle changes in frontal cortical function (Ludolph et al., 1992; Kew et al., 1993b; Lulé et al., 2005; Lomen-Hoerth et al., 2002). The cognitive impairment has been reported as more pronounced in ALS patients with a bulbar onset compared to patients with spinal onset (Abrahams et al., 1997; Strong et al., 1999; Lomen-Hoerth et al., 2002; Schreiber et al., 2005) and is also evident in patients with primary lateral sclerosis (PLS; Piquard et al., 2006). Longitudinal investigation of ALS patients (up to 18 months) revealed that cognitive dysfunction in ALS occurred early in the disease course and that the cognitive deficits may not progress in synchrony with motor decline, but distinctly more slowly (Schreiber et al., 2005). Functional imaging studies confirm hypoperfusion in the resting state in the frontal cortex in ALS with or without cognitive deficits (Ludolph et al., 1992; Anzai et al., 1990; Tanaka et al., 1993). Apart from the local hypometabolism, there is also evidence for decreased activity in different cortical areas during the performance of different tasks. Findings from fMRI studies support the association of reduced frontal executive function and reduced activity in fronto-parietal areas, and confirm findings from studies using other imaging techniques (Kew et al., 1993b; Abrahams et al., 1996). In non-demented ALS patients, a correlation between reduced verbal fluency and reduced activity in middle and inferior frontal gyrus, anterior cingulate cortex, and parietal and temporal lobe have been observed in an fMRI study by Abrahams et al. which included 22 non-demented ALS patients compared with 18 healthy controls (Abrahams et al., 2004). There is no evidence of additional recruitment in other areas to compensate the functional loss in the frontal cortex, as has been shown for the motor system. Cognitive functions of frontal areas do not exhibit redundancy of motor pathways, and compensation is therefore not possible. Further longitudinal fMRI studies of different cognitive functions in ALS might improve our understanding of subclinical cognitive deficits in ALS.

Further differences in cortical pattern activation were observed in ALS patients without significant cognitive impairments during processing of socio-emotional stimuli. Pictures of persons in emotional situations were presented to 13 ALS patients and 15 healthy controls at an initial measurement and to 10 of these ALS patients and 14 healthy controls at a second measurement after six months. ALS patients presented an increased activity in the rightsided supramarginal area (BA 40), which is part of the social-information processing network. This difference in social-information processing pattern increased over the course of six months (Lulé et al., 2007b). The increased activity in the social information-processing pathway might represent an altered sensitivity to social-emotional cues in ALS patients without cognitive deficits (Lulé et al., 2007b). Reduced activity in right sided frontal areas during processing of aversive emotional stimuli in ALS patients compared to controls support the assumption of an impaired processing pathway in ALS (Palmieri et al., 2010). More research is required to determine how successful and stable this compensatory recruitment is and again fMRI may be an important step.
