The standard model of PD pathophysiology attempts to explain the disease as well as the effects of antiparkinsonian treatment in terms of interactions within circumscribed cortico-basal ganglia-thalamocortical circuits () (2
). DA agonist therapy and STN DBS are present prototypical treatments, each acting at different sites within the network described by this model, resulting in improvement of parkinsonian symptoms.
As with all centrally acting drug and surgical treatments, both of these treatments produced a wide range of responses as revealed by neuroimaging; some of these represent therapeutic effects while others represent side effects that are otherwise nonspecific.
The common effects identified by the conjunctions of the two treatments should, at least in part, reveal the common pathway by which they work. That is, these overlaps should constitute the essential features of effective antiparkinsonian therapy but, of course, may also reflect motor complications that happen to be common to these treatments. The latter possibility appears unlikely, however. The most common motor side effects of antiparkinsonian treatment are dyskinesia, such as choreiform, dystonic, or other involuntary movements commonly seen with DA agonist medications but infrequently seen with DBS. Moreover, while antiparkinsonian effects were clearly demonstrated in our patients, no dyskinesia or dystonia were present during the scans included in the analysis. Therefore, rCBF responses related to abnormal involuntary movements are less likely to appear in a conjunction of treatment effects.
Responses that are unique to each treatment, i.e., those that do not overlap should, on the other hand, reflect differences in efficacy or production of motor complications, or idiosyncratic effects unrelated to primary antiparkinsonian activity, perhaps related to unique side effects of these treatments. In this context, it is important to note that the two groups of PD patients did not significantly differ in age, disease duration, or disease severity.
Common effects of treatments
Most of the significant conjunctions we report involve regions included in the standard pathophysiological model of PD. Apomorphine injection and DBS each produced decreases of rCBF in the putamen, SMA, PrG, and PoG and increases in the SPL and midbrain in the region of the SN/STN. These changes in rCBF have been reported in other functional neuroimaging studies of PD patients at rest undergoing STN DBS (8
) or receiving DA agonist medication (7
). Studies have shown that regions of the SMA/primary sensorimotor cortex and SPL are hyperactive and hypoactive respectively at rest in untreated PD patients relative to healthy controls (11
); therefore, treatment may normalize activity in these regions of interest. These findings are consistent with our observed deactivation of the SMA, PrG, and PoG and activation of the SPL due to treatment. It is possible that decreased activity in the putamen could be due to a reduction in afferent input from the deactivated SMA and primary sensorimotor cortex (25
While the mechanism by which stimulation brings about therapeutic benefit is controversial, one view focuses on a decrease in afferent input to the target region (26
) while another view focuses on increased activity in target outputs of the structure in which the stimulating leads are implanted (27
). We believe our findings support the latter view. Since the SN receives excitatory input from the STN, this might provide a mechanism whereby STN stimulation activates the midbrain in the region of the SN/STN, consistent with the standard model (8
In contrast, the significant change in activity in the cerebellum that is common to both treatments is not readily explained by synaptic connections within the standard model. The modulation of cerebellar activity we observed could represent antiparkinsonian treatment effects, but might also reflect adventitious motor side effects common to both treatments although, as noted above, the latter appears less likely. Instead the significant deactivation of the cerebellum may represent essential features of antiparkinsonian therapy that are not accounted for by the standard model. It is well established that the cerebellum, like the BG, plays a central role in motor control, facilitating tasks such as self-paced movement preparation and motor adaptation and learning: functions shown to be impaired in PD (15
). Evidence for its involvement in the pathophysiology and treatment of PD has been demonstrated by functional neuroimaging and anatomical studies. In the functional neuroimaging literature, hyperactivity of the cerebellum in untreated PD has been reported (11
) as has normalization of this hyperactivity due to antiparkinsonian treatments (7
). One explanation for these findings is that the cerebellum could play a compensatory role in the organization of movement in the face of BG dysfunction (24
It is also possible that the cerebellum plays a more integral role in the pathophysiology and treatment of PD. The neocerebellum has a pattern of connections that are roughly parallel to those outlined in the standard model: like the BG, the cerebellum receives massive projections from the cerebral cortex and projects back to the cortex via the ventral thalamic nuclei. Previously, it had been assumed that the BG and cerebellum communicated principally via convergent projections to the motor cortex (35
). However, a relatively recent study has demonstrated more direct synaptic connections between cerebellar and BG circuitry (36
). Neurons of the deep cerebellar output nuclei project to the ventrolateral and intralaminar thalamic nuclei, both of which project in turn to the putamen. In the putamen, the target of these cerebello-thalamic projections appears to be the population of medium spiny stellate neurons that project to the GPe. The cerebellum is thus in a position to regulate activity within the “indirect” BG-thalamocortical pathway, which mediates the effects of DBS and, in part, DA agonist therapy. The establishment of direct pathways connecting cerebellar output to the input stage of BG processing raises the intriguing possibility that the significant impact of each of the two successful therapeutic interventions on cerebellar activity might represent an essential antiparkinsonian feature of these treatments.
Unique effects of treatments
In addition to conjunctions, each treatment had unique effects on rCBF in frontal, parietal, temporal, occipital, striatal, thalamic, limbic, and cerebellar regions. and and summarize these findings. However, for clarity of presentation, we focus here on the regions we believe to be most pertinent to our investigation.
These unique effects on rCBF may, in part, reflect differences in efficacies for treatment of rigidity, tremor, bradykinesia, and disturbed gait. Varma et al. (37
) demonstrated that STN DBS may be more effective in remediating these symptoms than apomorphine therapy alone, thus, the fact that DBS deactivated the SMA, PrG, and PoG in a more widespread fashion than apomorphine might reflect its greater efficacy in reducing cardinal parkinsonian symptoms. In fact apomorphine additionally increased activity in anterior portions of the SMA and anterolateral portions of the PrG and PoG. Several studies that investigated the neural correlates of symptoms found that activity in SMA and PrG negatively covaried with improvement in rigidity (14
). Since rigidity is more improved with DBS than with DA agonist therapy alone (37
), these unique effects of apomorphine in central motor regions might reflect the limited improvement in rigidity by DA agonists. While both treatments caused decreased activity in some regions of the cerebellum, DBS uniquely activated the left posterolateral cerebellar in Crus II. Interestingly this cerebellar region has been associated with gait imagery (38
), which could represent a mechanism by which DBS improves gait disturbances in PD patients (39
Probably the most intriguing treatment difference that may relate to possible motor consequences is that STN DBS increases but DA agonist medication decreases activity in the ventrolateral thalamus, a finding that has been reported previously (12
). It is possible that this differential effect of treatment on thalamic activity is related to unique effects of treatment on tremor and on bradykinesia. Sturman et al. (40
) and Blahak et al. (41
) reported that STN DBS improved tremor more than DA agonist therapy, possibly suggesting an improved therapeutic benefit associated with the unique way in which tremor-related cells in the thalamus (42
) are altered by DBS. Karimi et al. (14
) found that increased thalamic activity due to STN DBS was correlated with improvement in bradykinesia. This putative connection between thalamic activity and bradykinesia and our report of reciprocal activation could further explain the observation of Timmermann et al. (43
) that DA agonist therapy and STN DBS exhibit complementary effects on bradykinesia.
Despite the uncertainty of their motor consequences, several additional treatment differences deserve attention. First, we found that DBS exclusively activated the GP. This finding is supported by Hilker et al. (8
) and Hershey et al. (12
) (but see Asanuma et al. (44
)). Again assuming that DBS activates target regions, it follows that STN stimulation may directly increase synaptic input to GP. Second, apomorphine deactivated relatively wider areas of the putamen and cerebellum. Synaptic connections linking the putamen and cerebellum (36
) might account for the fact that these effects are coupled, however the significance remains unclear.
Other unique treatment effects we observed may reflect non-motor consequences of antiparkinsonian therapy. In the limbic system, the treatments differentially activated the hippocampus and amygdala, which play a central role in emotional and mnemonic processing. Both treatments strongly activated the hippocampus, but apomorphine activated a more ventral section. DBS exclusively activated the amygdala. Other unique changes possibly related to differences in emotional processing were observed in the middle frontal and orbital gyri and the anterior and posterior cingulate cortices.
While there are a variety of reports that have examined neuropsychological changes due to these therapies, the most consistent finding is that verbal fluency is negatively affected by STN DBS (45
). We found that in the inferior frontal gyrus was differentially affected by the treatments, DBS causing increased, and apomorphine causing decreased activity. Broca’s area plays a central role in verbal fluency (46
), and Schroeder et al. (47
) found that activity in this canonical anterior perisylvian language area correlated with declines in verbal fluency, consistent with our observation. We also observed differing responses to treatment in posterior perisylvian language areas – middle and superior temporal gyri – that might also reflect treatment-unique effects on verbal fluency (48
We have identified both common and unique effects of two antiparkinsonian therapies, each of which acts at a different node within a network connecting the BG, thalamus, and cortex. Each treatment produced common changes in SMA, PrG, PoG, SPL, BG, and cerebellum. A number of these effects are consistent with the standard model of the pathophysiology of idiopathic PD; others suggest that the model might be modified to integrate regions that are significantly affected by both treatments. Particularly with respect to changes in the cerebellum, it will be important to further examine its functional connectivity with elements of the cortico-basal ganglia-thalamocortical circuitry and evaluate these interactions using computational models to determine the consequences of incorporating this region into the standard pathophysiological model of PD. Differential effects of apomorphine and DBS observed in other portions of the SMA, PrG, BG, thalamus, limbic system, and inferior frontal gyrus may offer preliminary explanations for differing motor consequences or potential explanations of non-motor consequences of the two treatments. It should again be noted that in this study, we chose to image the effects of treatment in PD patients at rest in order to provide a baseline for future evaluations of the clinical impact of these antiparkinsonian treatments on the cognitive or motor functions that they ultimately affect.