DISCUSSION from the article above:

Discussion

Our findings clearly show that during the first session, when the patients are still under the effects of apomorphine and have their best performances, the activation patterns are similar to the patterns of normal subjects; however, the total volume of the activated regions is more than doubled if compared to the healthy subjects. Apparently, the drug can restore, at least partially, the subcortical circuitry, thus resulting in particular in SMA activity, but the cooperation of neuronal populations larger than in healthy subjects is required. On the other hand, when the apomorphine effects decrease, the total activated volume also tends to decrease, but the activity spreads in an increasing number of little clusters also present in the ipsilateral region.

These findings and, in particular, the fact that the declining of the drug effects induces a reduction of activated volume, but an increase of involved regions, strongly suggest that the pharmacological effect of apomorphine is at least partially related to its vasodilatory properties.

While the same data from literature agree on the positive effects of the dopaminergic treatment on patients performances [5], [6], [7], [13], [14], [15] and [16], they diverge as regards the interpretation of the pharmacological mechanism and, in particular, about the effects on regional brain activity.

An increase of activity in the SMA induced by dopaminergic treatment was often reported in patients affected by PD in advanced [13], [14] and [15] and early stages [5]. Our results confirm this finding, which can be related to a restoration of efficiency of subcortical loops induced by the drug. However, we observed also a partial recovery of SMA activity during the third session, while activation spots appear in other regions and, specifically, in the ipsilateral M1. On the basis of these results, a switch of circuitry can be hypothesized: as the pharmacological effects decline, a kind of neuronal recruitment seems to occur as the brain copes with the reduction of efficiency of the normal subcortical loops that the drug can typically sustain only at the price of a very large volume of activated brain. However, this hypothesis requires a stronger evidence to be proven.

In fact, the observed clusterization could be ascribed to the expected variation of physiological parameters due to the decreasing vasodilatory effect of the infused drug. This variation has a well-known clinical effect, which is headache related to a CO2 backlog, due to increased blood pressure. But this alternative interpretation does not explain the reappearing of SMA activity, coupled with the development of little activity spots, in particular, in the ipsilateral region. However, an interaction between the hand involved in the task and the extension of the activated regions cannot be ruled out.

A treatment-related increase of activity in the primary sensorimotor cortex of the contralateral side was reported in PET and single photon emission computed tomography studies [13], [14] and [15]. Also, in our results, the activity in contralateral M1 declines when subjects are out of the apomorphine effect, but the overall decrease of activity is comparatively less pronounced due to the corresponding increase of small activated clusters. Activity in the ipsilateral sensorimotor cortex in levodopa-treated PD patients was also reported [15] and ascribed to drug-related involuntary movements of the corresponding hand. In our study, we did not observe significant ipsilateral activity during the first session.

Buhmann et al. [6] tested the levodopa effects on early-stage idiopathic hemiparkinsonian syndrome patients using fMRI. In PD patients, the authors found that bilateral SMA and contralateral M1 showed less activation when the task was performed with the affected side and that levodopa administration lead to an increase of these activations. These areas overlapped with those in which healthy volunteers had stronger activation than PD patients, suggesting a normalization (increase) effect on underactivation of SMA and M1 by levodopa. These results on early stage, hemiparkinsonian subjects are hardly comparable to our findings; however, our data are in good agreement with their results during the first two sessions, confirming the reduced input to the motor cortex coming from the subcortical motor loop in untreated PD subjects, which is reversible by dopaminergic treatment.

Also, Peters et al. [7] studied the effects of apomorphine on activation patterns during a finger-tapping fMRI experiment in PD patients, all of whom were symptomatic on the right side only. An overall decrease of activation areas after apomorphine application was reported: activations were restricted in the contralateral gyrus of both sides (affected and unaffected), while prior to drug injection, a significant extent of ipsilateral and cerebellar activity was observed. The ipsilateral and cerebellar activations were interpreted as indication of coactivation aimed to compensate for the lack of subcortical motor loops. However, rather surprisingly, also when the unaffected side was stimulated, the activation patterns spread in the ipsilateral side, and the injection of apomorphine induced a reduction and focusing of activated patterns. The contradiction between these and other results can be partially explained by taking into account the heterogeneity of the sample, but probably, it is also related to the complex interaction between dispersion and extent of activation areas that we attempted to address with our quantitative approach.

The increase of total volume of regions with task-correlated signal variations during the last session and the corresponding general odd aspect of BOLD maps and quantitative parameters are probably related to different events not easily interpretable basing on these data. Actually, the performances of subjects that in these conditions were very poor (Table 1) and the collapse of BOLD intensity (Fig. 6) suggests a disorganized activity, probably related to the almost complete lacking of the required subcortical loops.

In this work, we reported results that suggest a dynamic change of used subcortical loops corresponding to the decrease of apomorphine plasma concentration in PD-affected patients at advanced state. Our data suggest that the normal circuitry (but with comparatively large activated areas) is maintained by apomorphine and that the brain attempts to deal with reduced apomorphine effects with alternative circuitry, evidenced by spot-like activations located in particular in the ipsilateral motor primary cortex. In advanced-state PD patients, this mechanism cannot indefinitely sustain the motor performances, and the activation patterns evolve to disorganized widespread shapes where BOLD signal changes without clear sign.

In conclusion, the main objective of our study was to point out, by a cluster-based approach, the usefulness of quantitative assessment in evaluating the degree of activation in those subjects when a spread activation is present, causing a possible ambiguity in the interpretation of the results.