**4. Navigated TMS mapping in ALS**

*3.2.4. Neuroplasticity in ALS: evidence from fMRI studies*

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in ALS patients performing motor tasks are of special interest.

correlation with the rate of disease progression (*p* = 0.001) [110].

the views about the negative role of hyperexcitability in this disease.

Nowadays, fMRI is the key method for studying neuroplasticity in ALS patients. Numerous studies have revealed the changes in activation patterns of various brain regions in ALS both in rest and using various paradigms [2]. In this publication, the changes in activation patterns

In the study performed by Konrad et al. (2002), ALS patients and healthy volunteers underwent fMRI as they performed a motor paradigm (bending fingers) [107]. Significant changes in the patterns of cortex activation were observed: a forward displacement of the activation cluster, into the supplementary motor area, and an increase in its volume. Activation volume in the inferior frontal gyrus (Brodmann area 6) in the contralateral hemisphere and parietal lobes increased bilaterally. The authors have put forward a hypothesis that these changes represent the structural and functional rearrangement of the motor system induced by degeneration of the upper and lower motor neuron [107]. Lule et al. (2007) reported that an increase in activation of the primary motor and premotor cortex in ALS patients is revealed not only when performing the movement but also when imaging it [108]. Stanton et al. (2007) detected that activation in the sensorimotor cortex (Brodmann areas 1, 2, and 4), the inferior parietal lobule, and the superior temporal gyrus increased when the ALS patients performed a motor task, while activation in the dorsolateral prefrontal cortex decreased [109]. It is noteworthy that these changes were observed when comparing ALS patients not only to healthy volunteers but also to patients with peripheral nerve disorders [109]. This confirms that involvement of the upper motor neuron plays a crucial role in development of these changes and does not give grounds for considering them as just a response to the development of muscle fatigue.

Thus, an analysis of the results of fMRI with the motor paradigm in ALS patients demonstrates that the activation areas expand when a motor task is being performed. Interestingly, the changes in activation during fMRI can have a prognostic value. Poujois et al. (2013) reported that activation in the somatosensory and parietal cortex increases in ALS patients performing a simple motor task compared to the control group. The dynamic follow-up for 1 year has shown that activity of the contralateral parietal lobe has a statistically significant negative

These findings give grounds for suggesting that expansion of activation areas as an ALS patient performs a motor task has the compensatory mechanism and is probably aimed at maintaining the motor function in response to progressive degeneration of cortical motor neurons. Meanwhile, certain researchers believe that the activation areas can increase due to degener‐ ation of inhibitory interneurons [2]. The relationship between alterations in activation patterns in ALS patients according to fMRI data and changes in motor cortex excitability according to TMS data has not been studied yet. It should be mentioned that the positive prognostic significance of neuroplastic alterations demonstrated by Poujois et al. (2013) is in contrast with

Navigated TMS (nTMS) is today considered to be the most promising method to answer the question about the relationship between hyperexcitability and neuroplastic alterations in the motor cortex under kinetic conditions. On the one hand, nTMS is a neuroimaging technique and allows visualization of the location of cortical representation of certain muscles on individual MR images and provides an opportunity to assess the changes in their size and displacement with respect to anatomical landmarks. On the other hand, nTMS is a neurophy‐ siological method that allows one to assess various parameters showing the excitability and degeneration of the motor cortex. The nTMS method uses the brain of a person being examined as a landmark when applying stimuli for an individual MR model; the stimuli can be accurately applied to a certain area with allowance for the area of interest, the individual anatomy, and topography of the gyri [111].

In our recent study, we mapped the cortical representation of m. abductor pollicis brevis (APB) in 30 ALS patients and 24 healthy volunteers [29]. It was demonstrated that ALS patients exhibit a statistically significant increase in the resting motor threshold and a decrease in the MEPs amplitude, as well as a statistically significant reduction of the volume of cortical representation of APB (*p* < 0.001). The latter observation agrees with the results of the findings of Carvalho et al. (1999) who demonstrated a progressive decrease in size of the cortical representation in ALS patients [112]. This phenomenon is probably based on the neurodege‐ nerative process that reduces motor cortex excitability and decreases the number of cortical motor neurons. According to our data, the volume of cortical representation statistically significantly correlates with disease duration and negatively correlates with strength of the corresponding muscle and disease severity according to ALS Functional Rating Scale Revised (ALS FRS-R). These data give grounds for hypothesizing that the size of cortical representation can be regarded as a neurophysiological marker of disease severity, which opens new avenues for using it both in fundamental research and in clinical trials of new therapy methods. Further studies are needed to determine the sensitivity and specificity of this marker compared to other neurophysiological parameters and to determine its diagnostic significance.

The capabilities of navigated TMS made it possible not only to determine the size of cortical representation but also to accurately localize the maps within the anatomic landmarks. In most ALS patients, the maps were localized within the precentral gyrus (Brodmann area 4); some active sites, similar to those in healthy volunteers, were detected within the postcentral gyrus (Brodmann area 1) and the premotor cortex.

Meanwhile, we detected expanded boundaries of individual maps of the APB in some ALS patients, usually presenting as a displacement of the greatest portion of the map toward the postcentral gyrus. It was found by analyzing these cases that the aforementioned reorganiza‐ tion is mostly typical of patients at onset of the disease or when the disease course is relatively benign (**Figures 1** and **2**). It is important to mention that the motor threshold in these cases remained within the normal values or was decreased.

**Figure 1.** Map of cortical representation of the APB in a healthy volunteer (28 years old, motor threshold—43%). Here and in other figures, the points whose stimulation provides MEPs with amplitude over 50 μV from the contralateral APB are shown in white.

**Figure 2.** Maps of cortical representation of the APB in ALS patient with the relatively benign course of the disease (54 years old, right-side motor threshold—31%, left-side motor threshold—35%, duration of the disease—25 months, APB strength is bilaterally reduced to MRC score 4).

Although we have not performed mathematical analysis of the relationship between motor cortex excitability and reorganization of cortical representation, we suppose that hyperexcit‐ ability can be one of the mechanisms of the aforementioned neuroplastic alterations. Thus, a statistically significant relationship between the passive threshold as an excitability marker and the volume of cortical representation has been revealed. So the largest cortical represen‐ tation was revealed in patients with lower thresholds. This made it possible to rule out the possible role of higher-intensity stimuli in expansion of the map boundaries in ALS patients compared to the control group. Indeed, the motor threshold in some patients was 100% and we used this intensity in mapping. However, only single MEPs were detected in the afore‐ mentioned cases and the size of cortical representation was very small (**Figure 3**).

**Figure 1.** Map of cortical representation of the APB in a healthy volunteer (28 years old, motor threshold—43%). Here and in other figures, the points whose stimulation provides MEPs with amplitude over 50 μV from the contralateral

**Figure 2.** Maps of cortical representation of the APB in ALS patient with the relatively benign course of the disease (54 years old, right-side motor threshold—31%, left-side motor threshold—35%, duration of the disease—25 months, APB

APB are shown in white.

60 Update on Amyotrophic Lateral Sclerosis

strength is bilaterally reduced to MRC score 4).

**Figure 3.** Maps of cortical representation of the APB in a 62-year-old female patient with ALS. Upper-limb form of the disease; disease duration—8 months. ALS-FRS-R—38. APB strength is bilaterally reduced to MRC score 2. Motor threshold on the right and left sides—100%. The volume of cortical representation is significantly decreased.

Our findings agree with the fMRI data described above that attest to expansion of the activation areas in ALS patients performing a motor task. Like fMRI, visual assessment of nTMS mapping data allows one to detect displacement of cortical representation. Our preliminary data demonstrate that displacement of the boundaries of cortical representation as a result of neuroplastic alterations can be caused by decreased motor cortex excitability. Hence, the phenomenon of motor cortex hyperexcitability can have the compensatory function in ALS patients.
