Discussion
behavioral performance gain, stroke
STROKE, CORTEX
Three-week brain stimulation-assisted cognitive training in healthy older adults resulted in modifications of microstructure in white matter pathways and gray matter cortical target area as well as functional connectivity changes in a broader frontoparietal network. FA in prefrontal tracts originating from the stimulation target was increased in the group that had received anodal vs. sham tDCS, indicating higher integrity (i.e., directional preference of diffusion/directional coherence) of frontoparietal white matter tracts which was associated with higher (transfer task) performance gains following the intervention. Further, gray matter microstructure changes differed between the stimulation groups, mainly in individuals with higher microstructural integrity (i.e., molecular diffusion rate/magnitude of water molecule diffusion) at baseline that showed decreased MD values after anodal vs. sham tDCS. Increased resting-state FC between prefrontal areas indicated additional synchronization within frontoparietal networks induced by tDCS. Overall, we provide evidence for microstructural and network modifications through brain stimulation in the human brain, which may characterize the underlying mechanisms of functional benefits due to the intervention.We reconstructed individual tracts originating from the stimulation target in the left prefrontal cortex. Canonical images across our group of participants suggested that white matter fibers project from the stimulation target towards ipsilateral parietal and contralateral prefrontal areasThe DTI-derived index FA reflects the directional preference of diffusion and can be used to quantify the integrity of fiber organization in the human brain with higher values describing higher integrityIn a seminal study investigating structural changes induced by a combined tDCS-and-physical therapy intervention in stroke patients, Zheng and Schlaug observed increased FA in descending motor tracts in the treatment but not in the control groupCandidate cellular mechanisms reflected in FA variations include alterations in cell membrane and fiber density, fiber coherence, axon diameter, myelination, collateral sprouting. While intracellular directional coherence contributes to the FA metric, extracellular properties have been shown to affect the diffusion of water molecules as wellNo correlation was observed for microstructural alterations with behavioral performance gain in the training (LU) task. Differences in the task related to the procedure of administration (e.g., repeated vs. single sessions), content (e.g. letters vs. numbers) and involved executive processes (continuous updating in conjunction with memorizing temporal order vs. active comparison operations) may not only affect brain activation patterns and, thus, magnitudes of behavioral modulation, but also the relationships to neural plasticityIn order to examine microstructural changes within the gray matter of the stimulation target, MD values were extracted. A between-group comparison revealed an interaction between baseline MD values and the stimulation group effect, indicating a decrease after the intervention in the anodal compared to the sham group for individuals with initially lower values in the stimulation target.The DTI-derived index MD reflects the molecular diffusion rate and is used to quantify tissue microstructure. Higher MD values indicate reduced restriction of water molecule diffusion by cellular structuresOur finding of decreased MD in the anodal compared to sham group may indicate increases in tissue density (due to reshaping of neuronal or glial processes) or enhanced tissue organization (due to strengthened dendrites or axons) due to tDCSIt is important to note that DTI metrics are only indirect measures of microstructureIn our data, regional MD modulation was not related to performance gain, suggesting a more complex relationship with potentially other influencing factors, such as general training abilityIn order to examine potential functional connectivity modulations, we conducted seed-based FC analyses using resting-state fMRI. We found increases in FC in the prefrontal task-independent frontoparietal network in the anodal compared to the sham group. Similar FC modulations have been observed in task fMRI during single tDCS applications and after repeated tDCS sessions combined with working memory training in older adultsA limitation of our study is the relatively small sample size. In particular, in the context of brain-behavior associations, large sample sizes may be required for the observed relationships to be reliable/reproducibleIn sum, the present study advances the understanding of neurobiological after-effects of non-invasive brain stimulation combined with repeated training interventions and shows that tDCS exerts its effects on multiple levels, including microstructural properties of white matter tracts and gray matter regions and coordinated activitivity between distant brain regions. This rapid remodeling of neuro-glial networks and long-range signaling as the result of neuromodulation may underlie the functional effects, as indicated by their (partial) association with the observed performance gains