In this study, aside from a modest lateralized correlation between left nigrosome score and contralateral motor outcome, no significant associations were found between preoperative nigrosome integrity -- as visualized using advanced 3 T MRI techniques -- and baseline clinical features or postoperative motor outcomes. Our study was sufficiently powered to detect moderate-to-large effects. Any small associations would likely be of limited clinical utility relevant to DBS patient selection. These findings imply that, although nigrosome imaging has diagnostic utility, this marker alone may have limited prognostic value as a selection criterion for DBS surgery.
Notably, we identified 9 PD patients (out of 68) who exhibited non-fully abnormal nigrosomes yet were deemed suitable candidate for DBS surgery. This subgroup even included a patient with bilaterally normal nigrosomes who demonstrated a favorable response to DBS. Importantly, effect size analyses consistently yielded small estimates with wide confidence intervals frequently crossing zero, which argues against the presence of a large or clinically meaningful effect. Nevertheless, smaller associations cannot be definitively excluded, underscoring the need for larger cohorts to fully evaluate the predictive value of nigrosome grading.
Although Ultra-high-field 7 T MRI enhances visualization of fine-grained, iron-rich subcortical nuclei and achieves over 90% diagnostic accuracy for nigrosome-1 loss, our 3 T findings align with emerging evidence that nigral degeneration correlates poorly with functional reserve in advanced PD. From an imaging standpoint, while SWI can detect nigral hyperintensity, it lacks quantification capabilities, limiting its usefulness for monitoring Parkinsonism progression. In contrast, DaT imaging, such as I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (I-FP-CIT) SPECT, provides quantifiable striatal uptake, enabling both diagnosis and longitudinal monitoring of disease progression. Recent advancements in deep learning have further enhanced the integration of SPECT and MRI to predict nigrostriatal dopaminergic degeneration. If nigral hyperintensity loss on MRI proves to correlate with declining DaT uptake, combining SWI and SPECT may allow MRI to function as a predictive biomarker for Parkinsonism.
Another critical factor is the role of compensatory mechanisms, spanning from local synaptic plasticity to reorganization of the basal ganglia-thalamocortical circuit. In some cases, preserved striatal dopamine terminals may sustain motor function through mechanisms like DaT downregulation or increased dopamine synthesis. These adaptations may help explain the frequent mismatch between tracer uptake and motor symptom severity. Beyond subcortical processes, Johansson et al. recently demonstrated that clinical variability in PD is more closely linked to compensatory activity in the parieto-premotor cortex than to basal ganglia dysfunction. While striatal dopamine preservation may support basal ganglia plasticity, cortical compensation plays a central role in shaping clinical outcomes. Taken together, this growing body of evidence supports the notion that nigral pathology alone is unlikely to be sufficient to reliably predict disease severity or therapeutic responsiveness in PD.
Similarly, the relationship between nigrosome asymmetry and clinical laterality remains uncertain. Several studies have established a strong association between nigrosome-1 abnormalities and clinical motor asymmetry in PD. Stezin et al. reported that poorly visualized nigrosome-1 correlated with greater contralateral motor asymmetry in 64.8% of cases, while Noh et al. found high concordance between clinical asymmetry and contralateral nigrosome loss. In contrast, our findings do not support a lateralizing effect of nigrosome-1 abnormalities, aligning more closely with the results of Kathuria et al., who demonstrated that nigrosome imaging with 3 T MRI and 18F-DOPA PET failed to consistently predict the predominant clinical side. The lack of correlation may stem from heterogeneous compensatory responses across different disease stages, reinforcing the need for multimodal imaging approaches to improve prognostic accuracy in PD.
Among the non-fully abnormal nigrosome cohort, one particularly noteworthy case is that of a 69-year-old patient with an 11-year history of PD. Despite exhibiting completely normal nigrosome imaging, her diagnosis was confirmed through a comprehensive neurological assessment and clinical evaluation. At baseline, her OFF-medication UPDRS III score was 71, yet she demonstrated a 77% improvement in the levodopa challenge test. Consequently, she underwent bilateral GPi DBS implantation in consideration of her prominent axial symptoms, particularly impairments in balance and phonation. Postoperatively, her UPDRS III score improved to 20, reflecting a remarkable 72% improvement. Importantly, this case underscores the value of a multimodal biomarker approach, such as DaT imaging, to refine diagnostic accuracy and optimize patient stratification. The absence of DaT-SPECT imaging in this patient is a key limitation, as it could have provided critical insight into the relationship between nigrosome integrity and presynaptic dopaminergic function. The observed discordance may reflect compensatory mechanisms or extranigral pathology, reinforcing the need for integrative imaging strategies in assessing DBS candidates.
Beyond DaT imaging, advanced modalities such as perfusion SPECT, dopaminergic PET, and diffusion-based microstructural MRI techniques offer complementary perspectives on disease biology. When integrated with connectomic analyses, these techniques enhance the precision of DBS targeting. While each modality contributes unique strengths, converging evidence supports a multimodal strategy that synthesizes structural, functional, and network-level data as the most promising pathway toward personalized outcome prediction in PD neuromodulation.
Reviewing the application of the STS on SWI MRI, most studies report fair-to-high diagnostic accuracy in distinguishing PD from healthy controls, largely due to improved visualization of the nigrosome and reduced confounds from vascular and anatomical variants. However, diagnostic performance remains inconsistent due to factors such as low field strength (e.g., 1.5 T), protocol heterogeneity, disease duration, and the need for experienced raters. Given these limitations, few studies have advanced to rigorously evaluate whether detailed STS grading correlates with disease severity or predicts DBS outcomes. Our findings address this gap, albeit with negative results, emphasizing the need for a more comprehensive imaging framework.
Several limitations warrant consideration. The absence of DaT imaging in this cohort limited opportunities for direct comparison with dopaminergic imaging, which could have provided complementary validation. At the same time, reliance on visual nigrosome grading may still entail a degree of reader bias, highlighting the value of future quantitative or automated approaches. Our cohort encompassed both STN and GPi targets and included a spectrum of clinical presentations, reflecting a typical phenotypic diversity inherent to Parkinson's disease when selecting DBS patients. This reflects real-world clinical diversity and thus enhances the external validity of our observations. However, detailed characterization of tremor predominance, motor fluctuations, and dyskinesias was not systematically available. As such, potential influences of these features on DBS target selection and postoperative outcomes could not be assessed, which should be addressed in future studies. More fundamentally, the retrospective design and relatively small number of patients without fully abnormal nigrosomes increase the risk of Type II errors, particularly in subgroup analyses (e.g., lateralized outcomes). Although small effects cannot be excluded, such effects are typically difficult to translate into meaningful clinical uses. The 2:1 controls/cases matching approach is consistent with common methodological practice, but instead of using the entire available control group, this may have reduced statistical power, potentially obscuring subtle effects. Independent replication in larger, prospectively acquired datasets will be critical to corroborate and generalize these preliminary findings. Additionally, the ≤2-year follow-up period limits the evaluation of long-term DBS outcomes, where disease progression and neuroadaptive plasticity may further influence the relationship between baseline nigrosome integrity and treatment response.
While nigrosome-1 integrity assessed via 3 T SMWI MRI remains diagnostically informative for PD, no moderate-to-large associations were observed with baseline clinical features or postoperative DBS outcomes in this small and heterogeneous cohort. Although small effects cannot be excluded, such effects are generally difficult to translate into meaningful clinical benefits. These findings suggest that nigral imaging may have limited predictive value as a standalone biomarker and should instead be interpreted within the context of broader clinical and imaging measures. Future efforts should focus on validating these observations in larger, prospective cohorts and integrating nigrosome assessment into multimodal biomarker frameworks to support individualized DBS planning.