Targeting mechanisms in cognitive training for neurodegenerative diseases

“Cognitive training” (CT) is a label used to describe paper-and-pen or computerized exercises designed engage desired set of mental skills for the purpose enhancing neurocognitive functioning. Although literature on topic considerably rich (on PubMed, sole 2018, use “cognitive as title keyword returns 123 results), very few studies pose fundamental question: “How does CT work?”, or, more precisely, “Based which computational mechanisms would engaging in result into meaningful changes outcome measures?”. The overwhelming majority focus treatment efficacy by modelling measure(s) function (e.g., an active condition versus control condition), but do not detail exact mechanistic reason why should have effect first place (De Marco et al., 2014). Biological frameworks been proposed [i.e., hypothetical role played neurotrophic factors, synaptic connections and neuroplasticity (Castells-Sánchez 2019)] these introduced posteriori interpretation, driving principle design exercises. From merely clinical viewpoint, biological explanations are necessarily central importance. In fact, it normal clinicians researchers prioritize benefits patients over description instruments (once proven feasible, ethical safe). After all, same logic, we still able clarify with rigorous biophysical certain popular neuromodulation techniques operate, such transcranial direct-current stimulation (Pelletier Cicchetti, Identifying might rely particular importance neurodegenerative diseases. This no means trivial issue. A like Alzheimer’s disease, instance, characterized multiple pathophysiological against that be conceptualized. prevalent hallmark diseases accumulation abnormal protein forms aggregates (Bayer, 2015). It simple align processes, there theoretical distance between peptidic behavioral variables preventing us from drawing direct causative links. Reflecting this apparent incompatibility, however, can productive exercise. enables define common ground both cellular well transposed investigated. level neural systems deputed information processing, already identified Imaging Genetics framework “a proximate link genes” “an obligatory intermediate cognition, behavior emergent phenomenon” (Mattay 2008). at devised instrument target specific mechanism. possibility relying cognitive operations overall also conveniently aligned neuroimaging methodology measure systems. Techniques magnetic resonance imaging positron emission tomography enable investigate properties brain throughout its entire topography. On note, functional particularly helpful because allows calculation large-scale haemodynamic networks. relevant study neurodegeneration, affect networks large degree selectivity (Seeley 2009). As result, focusing whole-brain patterns connectivity provides disease mechanisms, training principles test-retest measurements (Figure 1).Figure 1: Theoretical diseases.Although pathological processes frontotemporal lobar degeneration normally defined aberrant deposition misfolded proteins, inflammation, impaired metabolism), important establish alignment mechanisms. achieved systems, show neuropsychological functions basis CT. Moreover, measures MRI (the latter allowing systemic connectivity). CT: Cognitive training.Based alignment, hypothesis aimed inducing synchronized activity selected regions. Referring diagnosis interest, underlying defining our was repeated task-related co-activation areas increased resting-state among those (Martínez 2013). pathology selectively affects brain’s default-mode network 2009; Pasquini 2017), hubs network. These centrally reliant retrieval semantic memory, required recruit significant amount executive resources order solve tasks. combined processing content, memory (each supported theory-informed pattern areas) task-induced regions including hippocampus, lateral temporal cortex, posterior cingulate medio-prefrontal cortex. validating cohort healthy older adults 2016), found approach up-regulates mild impairment working prodromal 2018), favor hypothesis. further support construct validity conceptualization, presence high load white-matter hyperintensities (small lesions impair inter-neuronal connectivity) associated significantly fewer modifications after (Bentham 2019). To corroborate network-based completely different diagnostic scenario which, has linked disruption (Hou ran pilot group 23 diagnosed Parkinson’s (PD) impairment, up-regulation translate improvements group. Twelve PD underwent described previous adult participants 2016, 2018; Bentham remaining acted controls they followed pathway care usual. two groups were compared only, assessments baseline, four weeks longer-term follow-up, 6 months baseline. hypothesis, 4 CT, improvement baseline observed across most tests (Additional Figure 1). Significant survived correction comparisons, only detected Semantic Fluency test (P = 0.001), Scales Outcomes PD–Cognition 0.002) Trail Making - part 0.003). contrast, showed any tests. just termination (at weeks) maintained months, their scores remained higher than recorded suggesting time limited benefit absence sustained Interestingly, reaction times accuracy course sessions, receiving dependent improved motor performance. Aside small sample size prevents definite generalizable conclusions effectiveness major limitations identified: first, data limits margin interpretation sample; second, general, concurrent neurovascular factors may impact response. inclusion sequences future investigations robust findings. conclusion, findings evidence effective supporting performance gains neurodegeneration. Central identification Our proposition suitable aligning pathology, functioning outcomes We argue definition strong rationale confers considerable advantage comparison pragmatic solely interested often conceive “symptomatic” form (i.e., “memory difficulties, then exercises”). Non-pharmacological interventions powerful diseases, yet tacitly regarded subsidiary, auxiliary tools alongside main recognized usually consists one medications. Pharmacological treatments seen “natural” avenue counteract decline way, i.e., drug brain. see approaches become primary therapeutic option necessary follow address either directly indirectly. For reason, transition symptom-driven mechanism-driven will underdeveloped field research progress development options due