Monitoring Cognitive Functions During Deep Brain Stimulation Interventions by Real Time Neuropsychological Testing
Article information
Abstract
Objective
We monitored cognition in 14 Parkinson’s disease (PD) patients during deep brain stimulation (DBS) surgery when the electrode was positioned at the target subthalamic nucleus (STN) (i.e., the STN motor area).
Methods
We present the DBS-real-time neuropsychological testing (DBS-RTNT) protocol and our preliminary experience with it; we also compared the intraoperative patient performance with the baseline data.
Results
Compared with the baseline data, patients undergoing DBS-RTNT in the target area demonstrated a significantly decreased performance on some tasks belonging to the memory and executive function domains. Patients undergoing right hemisphere DBS-RTNT had significantly lower short-term memory and sequencing scores than did patients undergoing left hemisphere DBS-RTNT.
Conclusion
PD patient cognitive performance should be monitored during DBS surgery, as STN-DBS may induce changes. These preliminary data contribute to improving our understanding of the anatomo-functional topography of the STN during DBS surgery, which will enable the identification of the best site for producing positive motor effects without causing negative cognitive and/or emotional changes in individual patients in the future. In principle, medications (i.e., patients who underwent surgery in a levodopa-off state) could have influenced our results; therefore, future studies are needed to address the possible confounding effects of levodopa use.
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).

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.
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
The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.24102.
Inclusion/exclusion criteria
Individual patients’ clinical and demographic details
Details of the DBS-RTNT protocol and of the pre-surgery neuropsychological evaluation
The figure represents the DBS-RTNT procedure. DBS-RTNT, deep brain stimulation-real-time neuropsychological testing.
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.
Acknowledgements
None