INTRODUCTION

Deep brain stimulation (DBS) [1] is a validated functional neurosurgical procedure for the treatment of Parkinson’s disease (PD). There is controversy about the effects of DBS on neuropsychological functions. Studies report either a lack of evidence of postsurgery cognitive impairments [2] or the presence of several impairments [3-5]. The inconsistency could be due to the use of a single cognitive test, which may fail to capture the complexity of a patient’s behavior, or to the assessment timing, which usually occurs only before or after DBS surgery, rather than at both times [6].

We believe that it would be useful to address an unexplored aspect, namely, cognitive processing, during the process of DBS implantation. Even though there is not a full consensus, intrasurgery monitoring is still believed to be very relevant, as it is known that the postoperative outcome depends on proper lead placement, which is based on preoperative neuroimaging techniques, intraoperative microrecordings of neuronal activity and microstimulation [7-9] and neurophysiological monitoring of motor functions. Cognitive monitoring could also be performed to add information about the patients’ status. As no study on neuropsychological intrasurgery evaluations has been performed, we did not formulate specific hypotheses about which tasks might show (if any) a different intrasurgery pattern from that at the baseline. During surgery, the time is constrained, and the potential for evaluation is limited compared with that at baseline and during follow-up. Nonetheless, intraoperative neuropsychological testing during surgery for awake glioma patients provides patients with substantial benefits, facilitating the monitoring and localization of their cognitive functions. Similarly, patients undergoing DBS implantation could benefit from cognitive feedback when the neurophysiologist delivers stimulation from electrodes placed in the target section of the subthalamic nucleus (STN). We present hereby a report of our preliminary experience.

MATERIALS & METHODS

Participants

We retrospectively analyzed data from a consecutive series of 14 patients (Table 1) with advanced PD (Supplementary Table 1 in the online-only Data Supplement) who underwent DBS surgery on the STN from January 2018 to September 2023. A total of 28 implanted nuclei were reviewed and analyzed. Supplementary Table 2 (in the online-only Data Supplement) shows the patient’s right and left STN width as defined during microelectrode recording (MER) and the individual site of STN microstimulation during real-time neuropsychological testing (RTNT). Two days before DBS surgery, with patients in the “ON” (levodopa) state, we recorded a neuropsychological baseline (Supplementary Table 3 in the online-only Data Supplement), which was later compared with the intrasurgery data. All patients underwent DBS surgery under local anesthesia as previously described (Supplementary Material in the online-only Data Supplement) [10,11].

The study was approved by the local Institutional Ethics Committee (Institutional Review Board) of the Department of Medicine, University of Udine (Prot. n 237/2023). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national re­search committee and with the 1975 Helsinki Declaration and its later amend­ments or comparable ethical standards. Informed consent was obtained from all the patients included in the study.

Procedure

All patients underwent intraoperative neurophysiological monitoring, comprehensive MER of neuronal electrical activity and microstimulation to verify possible side effects due to the current spreading to unwanted sites (for example, the medial lemniscus or internal capsule). A detailed description is reported elsewhere [10,11] and in the Supplementary Material (in the online-only Data Supplement). The procedure includes, as a new feature, the administration of the DBS-RTNT protocol (Supplementary Figure 1 in the online-only Data Supplement).

The first side of the surgery was balanced across the patients. Once the neurologist’s tests and the cognitive tests were completed and the appropriateness of the position was verified in one hemisphere, the electrode was inserted, and the surgery was finished for that side. Afterward, the same procedure was performed on the other hemisphere.

DBS-RTNT protocol

We used an approach we previously published for surgery on awake glioma patients, i.e., RTNT [12], which was adapted for DBS surgery, i.e., DBS-RTNT. The protocol included a list of tasks (Supplementary Table 3 in the online-only Data Supplement), each involving a limited number of items, in line with the length of the intervention. The surgical procedure took 1.5 hours. Within this time, the patient cooperated with the neuropsychologist twice, once for each hemisphere, with each test taking between 5 and 10 minutes. A total of 10 tasks were presented (Supplementary Table 3 in the online-only Data Supplement). Some tasks were performed during the procedures on both hemispheres (n = 3), while some tasks were specific to each hemisphere (n = 3 for the right STN and n = 4 for the left STN).

The tests were presented through a tablet hooked to a gooseneck stand. Before surgery, the patient familiarized themselves with the size of the stimuli. If necessary, the patient’s glasses were brought into the surgery room and used.

The patient underwent DBS-RTNT assessment during stimulation at the point identified as the target electrode (i.e., the STN motor site).

Statistical analysis

Descriptive statistical analyses were conducted for all study variables. The DBS-RTNT data were not normally distributed, so nonparametric statistics were performed on the DBS-RTNT data. For each single test, we compared patients’ DBS-RTNT score (number of correct responses) to their baseline score by means of a two related sample test (i.e., Wilcoxon or chi square test).

RESULTS

Compared with the data at the baseline, the scores during DBS-RTNT were significantly lower for some tasks belonging to the memory domain: 1) verbal (Z = -3.077, p = 0.002) and spatial (Z = -2.814, p = 0.005) learning/retrieval, 2) verbal short-term memory (Z = -2.309, p = 0.021), and 3) spatial working memory (Z = -2.325, p = 0.020). There were also significant changes in scores for tasks belonging to the executive functions domain: a decrease in 4) the sequencing score during DBS in the right hemisphere (RH) (Z = -2.805, p = 0.005) and in the left hemisphere (LH) (Z = -2.823, p = 0.005) and in 5) the verbal fluency score (Z = -2.383, p = 0.017) (Figure 1).

In contrast, no significant difference between the baseline score and the score during DBS-RTNT was found for other tasks belonging to the memory domain: 1) spatial short-term memory (Z = -0.722 , p = 0.470, not significant [n.s.]) and 2) verbal working memory (Z = -1.730, p = 0.084, n.s.); for tasks in the executive functions domain: 1) the Stroop test during DBS in the RH (Z = -1.404, p = 0.16, n.s.) and in the LH (Z = -0.105, p = 0.91, n.s.); or for tasks belonging to the emotion domain: 2) emotional processing during DBS in the RH (Z = 2.000, p = 0.388, n.s.) and in the LH (Z = 2.000, p = 0.388, n.s.).

Compared with the scores during DBS-RTNT in the LH, during DBS-RTNT in the RH, the scores for 1) short-term memory (Z = -2.565, p = 0.010) and 2) sequencing were significantly lower (Z = -2.326, p = 0.020). In contrast, no significant differences were found in the scores for 1) learning/retrieval (Z = -1.188, p = 0.236, n.s.), 2) working memory (Z = -1.155, p = 0.248, n.s.), 3) emotion processing (Z = -1.342, p = 0.180, n.s.) or the 4) Stroop test (Z = 0.000, p = 0.100, n.s.) when patients were undergoing DBS-RTNT in the LH and RH.

DISCUSSION

The STN is anatomically and functionally segregated into sensory‒motor, associative and limbic areas [13,14]; thus, we argue that selective fluctuations in test performance during STN-DBS surgery might be possible.

In recent years, anatomical targeting has achieved submillimeter precision. In our study, we corroborated the hypothesis of “functional targeting,” including an approach to already well-known sensory‒motor monitoring. We still do not know where the current spreads in the neuronal network of the nucleus. Therefore, cognitive monitoring aimed at disentangling cognitive- and limbic-related processing is crucial for the optimization of the clinical postoperative status. Our study demonstrated that placing the electrodes in the target position can worsen real-time cognitive performance, and this is ideally an outcome to be avoided. The future goal of DBS-RTNT can be to guide the surgeon in moving the microelectrode stimulation to identify the best site that produces positive motor effects without causing negative cognitive and/or emotional changes in individual patients. Such alterations, if not revealed in real time during surgery, would likely be observed as postsurgical outcomes.

In principle, medications (i.e., patients who underwent surgery in a levodopa-off state) could have influenced our results [15,16]. We acknowledge this as a limitation of our pilot study. Indeed, we cannot disentangle whether the results were due to medication effects or to stimulation. Medication can selectively affect some functions, whereas stimulation can affect others. In one study [15], the authors showed that stopping dopaminergic therapy impairs memory with regard to probabilistic information, whereas DBS to the region of the STN disrupts decision-making when multiple pieces of acquired information must be combined. In another study [17], the authors showed that working memory and verbal learning increase acutely after levodopa administration. In future investigations with larger sample sizes, we should match levodopa use during cognitive assessments before and after surgery or compare the cognitive effects before and after stimulation during surgery to assess the pure impact of electronic stimulation.

Furthermore, as this pilot study was performed with the aim of evaluating the feasibility of performing intraoperative neuropsychological assessments in patients with DBS, we could not address predictive research questions. It is reasonable to imagine that any adverse effect on cognitive functions during intraoperative stimulation could be predictive of analogous persistent adverse effects during chronic stimulation; however, only longitudinal studies on larger case series will be able to confirm this hypothesis.

Supplementary Materials

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This work was supported by the Ricerca Corrente 2024 (Italian Ministry of Health) to B.T.

Author Contributions

Conceptualization: Barbara Tomasino, Christian Lettieri, Massimo Mondani. Data curation: all authors. Formal analysis: Barbara Tomasino, Christian Lettieri. Funding acquisition: Barbara Tomasino. Investigation: all authors. Methodology: Ilaria Guarracino, Barbara Tomasino. Writing—original draft: Ilaria Guarracino, Barbara Tomasino. Writing—review & editing: all authors.

Acknowledgments

None

Figure 1.

Patient performance during DBS-RTNT. Tasks belonging to memory domain (A), executive functions (B), emotion processing (C), and between hemisphere comparisons (D). *p < 0.05; ^†p < 0.01. DBS-LH, DBS in the left hemisphere; DBS-RH, DBS in the right hemisphere; DBS-RTNT, DBS-real-time neuropsychological testing; DBS, deep brain stimulation.

REFERENCES

• 1. Lozano AM, Lipsman N, Bergman H, Brown P, Chabardes S, Chang JW, et al. Deep brain stimulation: current challenges and future directions. Nat Rev Neurol 2019;15:148–160.ArticlePubMedPMCPDF
• 2. Mehanna R, Bajwa JA, Fernandez H, Wagle Shukla AA. Cognitive impact of deep brain stimulation on Parkinson’s disease patients. Parkinsons Dis 2017;2017:3085140.ArticlePubMedPMCPDF
• 3. Rački V, Hero M, Rožmarić G, Papić E, Raguž M, Chudy D, et al. Cognitive impact of deep brain stimulation in Parkinson’s disease patients: a systematic review. Front Hum Neurosci 2022;16:867055.PubMedPMC
• 4. Tomasino B, Marin D, Eleopra R, Rinaldo S, Cristian L, Marco M, et al. To move or not to move: subthalamic deep brain stimulation effects on implicit motor simulation. Brain Res 2014;1574:14–25.ArticlePubMed
• 5. Aiello M, Eleopra R, Lettieri C, Mondani M, D’Auria S, Belgrado E, et al. Emotion recognition in Parkinson’s disease after subthalamic deep brain stimulation: differential effects of microlesion and STN stimulation. Cortex 2014;51:35–45.ArticlePubMed
• 6. Acera M, Molano A, Tijero B, Bilbao G, Lambarri I, Villoria R, et al. Long-term impact of subthalamic stimulation on cognitive function in patients with advanced Parkinson’s disease. Neurologia (Engl Ed) 2019;34:573–581.ArticlePubMed
• 7. Hutchison WD, Allan RJ, Opitz H, Levy R, Dostrovsky JO, Lang AE, et al. Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson’s disease. Ann Neurol 1998;44:622–628.ArticlePubMed
• 8. Rodriguez-Oroz MC, Rodriguez M, Guridi J, Mewes K, Chockkman V, Vitek J, et al. The subthalamic nucleus in Parkinson’s disease: somatotopic organization and physiological characteristics. Brain 2001;124(Pt 9):1777–1790.ArticlePubMed
• 9. Vinke RS, Geerlings M, Selvaraj AK, Georgiev D, Bloem BR, Esselink RAJ, et al. The role of microelectrode recording in deep brain stimulation surgery for Parkinson’s disease: a systematic review and meta-analysis. J Parkinsons Dis 2022;12:2059–2069.ArticlePubMedPMC
• 10. Lettieri C, Rinaldo S, Devigili G, Pauletto G, Verriello L, Budai R, et al. Deep brain stimulation: subthalamic nucleus electrophysiological activity in awake and anesthetized patients. Clin Neurophysiol 2012;123:2406–2413.ArticlePubMed
• 11. Eleopra R, Rinaldo S, Devigili G, Mondani M, D’Auria S, Lettieri C, et al. Frameless deep brain stimulation surgery: a single-center experience and retrospective analysis of placement accuracy of 220 electrodes in a series of 110 patients. Stereotact Funct Neurosurg 2019;97:337–346.ArticlePubMedPDF
• 12. Skrap M, Marin D, Ius T, Fabbro F, Tomasino B. Brain mapping: a novel intraoperative neuropsychological approach. J Neurosurg 2016;125:877–887.ArticlePubMed
• 13. Hamani C, Saint-Cyr JA, Fraser J, Kaplitt M, Lozano AM. The subthalamic nucleus in the context of movement disorders. Brain 2004;127(Pt 1):4–20.ArticlePubMed
• 14. Lambert C, Zrinzo L, Nagy Z, Lutti A, Hariz M, Foltynie T, et al. Confirmation of functional zones within the human subthalamic nucleus: patterns of connectivity and sub-parcellation using diffusion weighted imaging. Neuroimage 2012;60:83–94.ArticlePubMedPMC
• 15. Coulthard EJ, Bogacz R, Javed S, Mooney LK, Murphy G, Keeley S, et al. Distinct roles of dopamine and subthalamic nucleus in learning and probabilistic decision making. Brain 2012;135(Pt 12):3721–3734.ArticlePubMedPMC
• 16. Wang J, Pan R, Cui Y, Wang Z, Li Q. Effects of deep brain stimulation in the subthalamic nucleus on neurocognitive function in patients with Parkinson’s disease compared with medical therapy: a meta-analysis. Front Neurol 2021;12:610840.ArticlePubMedPMC
• 17. Poletti M, Bonuccelli U. Acute and chronic cognitive effects of levodopa and dopamine agonists on patients with Parkinson’s disease: a review. Ther Adv Psychopharmacol 2013;3:101–113.ArticlePubMedPMCPDF

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