# Connectivity Alterations in Vascular Parkinsonism: A Structural Covariance Study
## 4 Discussion  
To the best of our knowledge, this is the first study investigating structural covariance in VP patients compared to PD and controls. We found that VP patients had a significant reduction in structural connectivity between the corpus striatum (bilateral caudate and putamen nuclei) and a variety of brain regions, including cortical (insula, hippocampi, anterior cingulate cortex, gyrus rectus, fronto-orbital cortex) and subcortical (thalami) structures, compared to both PD patients and controls. Furthermore, the structural connectivity reduction between Right Caudate-Right Insula, Right Caudate--Left Thalamus and Right Putamen-Left Thalamus was significantly modulated by cognitive performances, in particular, executive functions, memory, anxiety and depression. Our findings demonstrate that altered connectivity in the basal ganglia circuits may contribute to the pathophysiology of cognitive impairment in VP. The results of the present study add significant insight to supporting the hypothesis that the structural vulnerability of basal ganglia is reflected in the breakdown of the structural association with large-scale circuits. Indeed, in our study cohort, VP patients showed a decrease in structural association between the bilateral striatum and several regions, including the thalamus, insula, parahippocampus, hippocampus, orbitofrontal and anterior cingulate cortices. The reduction in structural covariance was a finding consistently repeated among all the different seeds we explored, independently of the region (caudate and putamen) and the hemisphere (right and left). Furthermore, in all comparisons, the \begin{table}
\begin{tabular}{c c} \hline \hline
**A. Seed region: Right Caudate; Target Region: Right Insula** \\ \hline _Cognitive variable_ & _Significance of the interaction term_ \\ \hline COWAT & T = \(-\)2.26; \(p\) = 0.029 \\ RAVLT- DR & T = \(-\)2.33; \(p\) = 0.045 \\ MCST & T = \(-\)2.59; \(p\) = 0.029 \\ BDI & T = \(-\)3.09; \(p\) = 0.013 \\ HAMA & T = \(-\)2.64; \(p\) = 0.027 \\ \hline \hline
**B. Seed region: Right Caudate; Target Region: Left Thalamus** \\ \hline BDI & T = \(-\)2.64; \(p\) = 0.027 \\ \hline
**C. Seed region: Right Putamen; Target Region: Left Thalamus** \\ \hline MCST & T = \(-\)2.28; \(p\) = 0.048 \\ \hline \hline \end{tabular}
\end{table} 
Table 6: Modulation Analysis of Structural Covariance. reduced covariance in the VP group has clearly emerged in comparison with both PD and control subjects. More in detail, it is interesting to note that VP patients showed a decreased structural covariance between the caudate and the thalamus, insula, orbitofrontal and anterior cingulate cortices. A similar situation was also evident when we evaluated the Right Putamen as a seed. VP showed reduced structural covariance with almost the same regions (thalamus, insula, and orbitofrontal cortex). Interestingly, considered as a whole, many of the structures involved in our results are fundamental nodes that are part of the salience network. The salience network is a key pathway in the human brain [28; 29] and is considered the core brain system involved in identifying biologically and cognitively relevant events to guide flexible behavior and emotional information processing. Moreover, it acts as an internal switch supporting the brain to decrease default mode network activity (associated with heed to internal stimuli) and increase central executive network activity (associated with external processing stimuli) [30]. In addition, our VP patients displayed reduced structural covariance between striatum, mainly the Left Putamen and hippocampus. In the mesolimbic pathway, neurons in the ventral striatum obtain converging excitatory afferents from the hippocampus and thalamus. The combined elaboration of these afferent signals is crucial for the correct configuration of goal-directed behaviors.