Functional reorganization is a maladaptive response to injury – YES

Multiple sclerosis (MS) patients with cognitive deficits have an abnormal recruitment of cognitive network regions during the performance of different cognitive tasks compared to healthy individuals and cognitively preserved patients. ¹ Fatigue in MS is associated with an altered activity of fronto-thalamic regions during motor and cognitive task execution. An altered recruitment of motor network regions has been shown in MS patients with more severe disability (as measured by the Expanded Disability Status Scale) and motor impairment. These are just a few examples, taken from the abundant literature on this topic, supporting the idea of maladaptive functional reorganization in MS patients.

Even when we control for task performance by introducing an analysis of resting-state (RS) functional magnetic resonance imaging (fMRI), measures of synchronization and functional connectivity (FC) within and between the main brain functionally relevant networks are more abnormal in patients who are more clinically and cognitively impaired. ² In the attempt to clarify what drives functional plasticity in MS, the majority of studies have integrated measures derived from fMRI with structural imaging measures of tissue damage. Independently from the imaging technique and the complexity of the analysis method applied, abundant correlations between functional and structural abnormalities have been consistently demonstrated, even when relatively simple measures of structural damage, such as T2 lesion volume, have been considered. ³ All of this indicates that ‘functional reorganization is a maladaptive response to injury’ in these patients. This is clearly only a partial view of the complex role of functional reorganization in MS, which opens several questions.

The first is, ‘What is the definition of maladaptive functional reorganization’? Certainly, such a definition cannot be based simply on the direction (i.e. increased vs decreased) of activity and (RS) FC modifications in groups of patients in comparisons to healthy subjects or other diseased subjects. Conversely, it should take into consideration, on the one hand, the connections (i.e. excitatory vs inhibitory) that areas within a given network have, and on the other, the modulation played by other synergic or competing networks. As previously anticipated, structural damage is yet an additional key player in this complex scenario. Based on these considerations, we believe that preservation of functional competence (which can be judged based on the clinical and cognitive performance of the subjects) remains at present the only valid criterion to define the adaptive or maladaptive role of functional plasticity.

The second question is, ‘What are, in addition to disease-related structural damage, the factors that can influence maladaptive functional reorganization?’ Regretfully, this aspect has been investigated only marginally. So far, gender, age of disease onset, cognitive reserve and substance abuse are among the factors that have been identified. Specifically, compared to female patients matched for disability, disease duration and white matter damage, male patients had more RS FC abnormalities, which were correlated with cognitive impairment. ⁴ Patterns of brain reorganization within cognitive and motor networks differed between adult and paediatric patients with MS. During a cognitive fMRI task, MS patients with greater intellectual enrichment (a measure of cognitive reserve) had less deactivation of brain default/resting state and less recruitment of prefrontal cortices which was associated with better cognitive status. ⁵ Compared to nonusers with similar disease-related structural magnetic resonance imaging (MRI) damage, MS patients who smoke cannabis had more extensive working memory problems that were associated with a different pattern of cognitive network recruitment. ⁶

The third question is, ‘When does maladaptive reorganization occur and how does this evolve?’ While it is intuitive that maladaptive reorganization may occur and may play an important contribution to disease clinical manifestations in patients with progressive MS and/or long-lasting disease, as a consequence of continuous accumulation of damage and exhaustion of compensatory capacities, results in patients at the earliest stages of the disease and in clinically unimpaired patients are controversial and limited by the cross-sectional design of the majority of the studies. The best strategy to try to answer this question is to perform longitudinal, correlative, multiparametric studies. Regretfully, such longitudinal studies are currently scarce and, the few available, have provided inconclusive results. While one study correlated increasing parietal activation over time with worse cognitive performance (suggesting maladaptation), ⁷ another described an association between changes of recruitment of frontal lobe regions and improvement at cognitive performance (supporting adaptation). ⁸ The study of functional recovery following an acute central nervous system (CNS) insult may further help clarifying this issue. After an acute relapse affecting a given functional system (e.g. the motor system), resolution of inflammation and recovery of functional competence of the affected cerebral regions (e.g. the primary motor cortex) have been associated with a better clinical recovery. ⁹ This highlights an important mechanism of functional reorganization that is restoration of functional specialization and consequently of clinical functional competence. Combined with the results of some recent graph-analysis studies, these data support the importance of maintenance of functional segregation (i.e. the ability of specialized processes to occur within highly interconnected groups of brain regions) as an important mechanism related to better clinical outcome in MS patients. On the other hand, the loss of diversity and flexibility in functional interactions among large-scale functional networks might result in functional inefficiency with consequently clinical and cognitive deficits.

This introduces the final question that is, ‘Can we modify maladaptive reorganization and how’? Promising results derive from studies of cognitive rehabilitation in relapsing–remitting (RR) MS patients which have consistently demonstrated that improved cognitive performance following treatment parallels modifications of activations (and FC) within cognitive networks with a critical role for the trained function. ¹⁰ Interestingly, measures derived from fMRI accounted for the beneficial effect of cognitive rehabilitation (not only on cognitive performance, but also on fatigue, depression and quality of life) several months after its termination. ¹¹ Combined with the results of the studies from patients with acute relapses previously discussed, these findings further support the importance of preservation (or restoration) of functional specialization within specific networks as an important mechanism ensuring favourable clinical outcomes. Whether this behaviour applies to all functional systems and to the different stages of the disease (so far it has been shown in relapsing–remitting multiple sclerosis (RRMS) patients only) and whether there is a threshold of intervention should be matter of future investigations.