The current study examined functional and structural differences using fMRI and VBM in drug-naïve TD and NTD patients with PD. Follow-up analysis using an ROI approach was performed to confirm between patient group differences and to examine how these between-patient group differences related to a healthy control group. Robust findings across both analysis methods showed significant differences both cortically (prefrontal cortex) and subcortically (globus pallidus) between patients with NTD PD and TD PD, with NTD patients showing reduced activation. Compared to controls, NTD patients always showed reduced activation, whereas TD patients were either not significantly different than controls or in the case of contralateral DLPFC, showed higher activation. These results could not be explained by differences in grey or white matter volume. Therefore, BOLD changes in the prefrontal cortex and basal ganglia differ in early stage PD patients clustered into NTD and TD groups.
In the cortex, NTD patients showed reduced bilateral prefrontal cortical activation in bilateral DLPFC compared to TD patients. NTD patients also had lower PSC compared to controls in ipsilateral DLPFC. One possibility is that the presence of resting tremor in the TD group could not explain these findings since higher resting activity in the TD group could reduce task related BOLD signal change in the TD group thus minimizing any between group differences. Another possibility is that DLPFC activity was higher in the TD group to suppress tremor since DLPFC has been related to inhibiting force output.14
We compared the BOLD activity with and without covariates that included action tremor and bradykinesia minus resting tremor, and the findings were similar for DLPFC and all other areas with and without the covariates. Thus, while the presence of rest tremor in the TD group and absence of rest tremor in the NTD group led to between group differences in the BOLD signal, these group findings are robust to the UPDRS values as covariates.
Prior post-mortem analysis of brain structure in PD has shown significantly higher mean overall Lewy body score for NTD PD patients than for TD PD patients, particularly in the prefrontal regions of the cortex.7
NTD PD patients show more bradykinesia than TD patients and minimal tremor at disease onset.7
It is not clear whether this is due to pathological differences in brain structure between phenotypes at the outset of the disease, or whether this is due to adaptive changes from symptom differences between phenotypes. To resolve this question, it would be necessary to perform correlational analyses between Lewy body deposition and measures of bradykinesia. Nevertheless, brain changes observed post-mortem seem to support clinical subtyping of patients into either NTD or TD PD phenotypes. Since the current study examined TD and NTD patients relatively early in the disease process prior to starting dopaminergic medication, our findings suggest that grouping patients into TD and NTD based on motoric features reveals changes in the BOLD signal in areas such as DLPFC. Whether these changes in the BOLD signal in the DLPFC have any relation to cortical Lewy body deposition is beyond the current study and caution should be taken in attempting to relate these findings without further inquiry.
The task used in the current study was chosen because it requires robust activation of frontal cortical regions and parietal cortical regions, including M1, dorsal and ventral premotor cortex, SMA, DLPFC, IPL, superior parietal lobule, and anterior cingulate cortex.16, 17
However, in the current study only DLPFC in the prefrontal cortex was different between patient groups in both voxel wise and ROI analysis suggesting that this prefrontal area is robustly sensitive to differences in patients clustered into TD and NTD groups. DLPFC has been suggested to play an important role in working memory and executive function. Indeed, the DLPFC activation has previously been shown to be sensitive to changes in learning in early-stage PD, with activation being normal at baseline but declining to sub-normal levels after 2 years.18
Kikuchi et al.19
used single-photon emission computed tomography to show hypoperfusion in DLPFC, SMA and insular cortex in PD. However, only hypoperfusion in DLPFC and insular cortex was correlated with disease severity leading the authors to suggest that DLPFC and insular cortex may play key roles in specific symptoms of impairment at advanced stages, such as impaired working memory, postural instability and autonomic dysfunction. The results of the current study suggest that disease severity alone may not be the driving feature of this difference, and that symptom specific differences could be another factor that should be considered. That is, patients with a NTD subtype, even in the earliest stages of the disease may show greater deficits in frontal cortical areas compared to patients with a TD subtype.
Subcortically, the current study showed reduced BOLD activation in GPi, GPe and thalamus in NTD versus TD ( and ). Since the basal ganglia have established connections with the DLPFC, it could be that the cortical findings are due to changes in the basal ganglia or it could be that these cortical and subcortical findings are not directly related. The reduced activation in GPi in the NTD group was in the ventral part of the GPi, and this is location and pattern of findings for the BOLD signal are consistent with previous post-mortem findings of reduced dopamine in the ventral part of the GPi in NTD PD compared to TD PD 9
. It is also consistent with the previous finding in a group of drug-naïve PD patients with mixed phenotype that found higher tremor scores on the UPDRS are associated with higher PSC in GPi.11
In the previous study by Prodoehl et al.11
, there was a negative correlation between disease severity and PSC in all other BG nuclei and thalamus, and bradykinesia was the symptom that most consistently predicted BOLD activation in these regions. In a different study moderate PD patients were tested following a 12-hr withdrawal from medication, and it was found that pallidal dopamine depletion correlated with clinical tremor severity, and that GPi, GPe, and putamen were transiently active during the onset of tremor episodes.20
Our findings extend this work by showing that early stage, drug-naïve patients clustered into a NTD group had reduced BOLD signal compared to those patients clustered into a TD group in specific nuclei of the basal ganglia (GPi, GPe) as well as the thalamus. Further, our findings suggest that group differences in basal ganglia activation between patients with PD and healthy controls may be driven in part by patients with motoric features consistent with the NTD group rather than the TD group.
Comparing PD patients to healthy controls, only one area in the ROI analysis showed significantly increased activation in PD. Contralateral DLPFC had a significantly higher PSC in TD patients compared to controls. Although rest tremor in PD has been associated with increased metabolism in the thalamus, subthalamus, pons, and premotor-cortical network, suggesting an increased functional activity of thalamo-motor projections21
, what underlies increased DLPFC activation in TD patients deserves further study. Additionally, future study of symptom-specific differences with patients in a more advanced stage of the disease process should examine cognitive changes that might accompany the functional activation deficits found in the current study. Since the patients included in this study were drug-naive, it could be argued that patients with atypical parkinsonism were included, particularly in the NTD group. To minimize this possibility, reconfirmation of the diagnosis was made two years after MRI testing was performed. Also, after two years, all but three patients had started dopamine therapy and each patients was responding positively to medication giving us confidence in the findings.
In conclusion, the present study confirmed that fMRI differences in the basal ganglia and cortex between patients with PD and control subjects are primarily due to patients with the NTD subtype rather than the TD subtype. These findings suggest that objective measures of brain function may be useful in future genotype-phenotype analyses and targeted therapeutic trials focused on PD subtypes.