Cingulum stimulation enhances positive affect and anxiolysis to facilitate awake craniotomy

Abstract

Background: Awake neurosurgery requires patients to converse and respond to visual or verbal prompts to identify and protect brain tissue supporting essential functions such as language, primary sensory modalities, and motor function. These procedures can be poorly tolerated because of patient anxiety, yet acute anxiolytic medications typically cause sedation and impair cortical function.

Methods: In this study, direct electrical stimulation of the left dorsal anterior cingulum bundle was discovered to reliably evoke positive affect and anxiolysis without sedation in a patient with epilepsy undergoing research testing during standard inpatient intracranial electrode monitoring. These effects were quantified using subjective and objective behavioral measures, and stimulation was found to evoke robust changes in local and distant neural activity.

Results: The index patient ultimately required an awake craniotomy procedure to confirm safe resection margins in the treatment of her epilepsy. During the procedure, cingulum bundle stimulation enhanced positive affect and reduced the patient's anxiety to the point that intravenous anesthetic/anxiolytic medications were discontinued and cognitive testing was completed. Behavioral responses were subsequently replicated in 2 patients with anatomically similar electrode placements localized to an approximately 1-cm span along the anterior dorsal cingulum bundle above genu of the corpus callosum.

Conclusions: The current study demonstrates a robust anxiolytic response to cingulum bundle stimulation in 3 patients with epilepsy.

Trial registration: The current study was not affiliated with any formal clinical trial.

Funding: This project was supported by the American Foundation for Suicide Prevention and the NIH.

Keywords: Neuroimaging; Neurological disorders; Neuroscience; Psychiatric diseases; Therapeutics.

Figure 1. Location of stimulated electrodes in the index patient.

(A) Postimplantation lateral skull radiograph showing relative positions of the intracranial electrodes; red and blue volumes indicated by a black arrow highlight the contact pair yielding anxiolytic benefit. (B–D) Postimplantation MRI demonstrating positions of stimulated cingulate contacts; coronal slices in B and C correspond to the anode (red) and cathode (blue) of stimulation-eliciting anxiolysis and mirth. Cingulate gray matter stimulation utilized contacts 1–2 (yellow, green), cingulum bundle stimulation eliciting anxiolysis and mirth utilized contacts 3–4 (red, blue), cingulum bundle stimulation eliciting mirth and motor activation utilized contacts 5–6 (purple, magenta). The recording site for single-channel and coherence electrophysiological analyses was contact 5 (purple). (E–G) Sagittal views of deterministic tractography seeded at all tested contact pairs using modeled bipolar volumes of tissue activated via artificial neural nets based on 1.5 mA, 130 Hz, 300-μs pulse width stimulation. (E) Contacts 1 (anode; yellow) and 2 (cathode; green). (F) Contacts 3 (anode; red) and 4 (cathode; blue). (G) Contacts 5 (anode; purple) and 6 (cathode; pink). SFG, superior frontal gyrus; PCS, paracingulate sulcus, CG, cingulate gyrus; CC, corpus callosum; LV, lateral ventricle; Cd, caudate; Put, putamen; M1, primary motor cortex; S1, primary sensory cortex.

Figure 2. Localization of stimulated electrodes for the 3 patients.

(A and B) Sagittal and coronal views of stimulated locations across the full patient set (n = 3). Numbers inside circular indicators on the sagittal view reflect the number of 1-mm incremental sections from the displayed section in which the contact was located, where “–” corresponds to sections more medial and “+” corresponds to sections more lateral. Red circles indicate behaviorally active contacts, whereas black circles indicate behaviorally inactive contacts. (C) Overlap of the volumes of tissue activated (red) by all behaviorally active contacts across the full patient set (n = 3), relative to the index patient’s diffusion tensor imaging data set, collapsed by side of stimulation. The VTA for all patients robustly engage the cingulum bundle to the exclusion of other fiber systems. cb, cingulum bundle; CG, cingulate gyrus; PrG, precentral gyrus; PCun, precuneus; SFG, superior frontal gyrus; Cun, cuneus; OcG, occipital gyrus; cc, corpus callosum; OFG, orbitofrontal gyrus; SG, straight gyrus; HCd, head of caudate nucleus; FStr, fundus striati; LTh, lateral thalamic nucleus; MD, mediodorsal thalamic nucleus; CM, centromedial thalamic nucleus; LD, lateral dorsal thalamic nucleus; MTG, middle temporal gyrus. The underlying anatomical drawings in A and B were adapted with permission from Elsevier (52).

Figure 3. Mirth induced by acute cingulum stimulation in the index patient.

Continuous intracranial EEG record and associated sequential still images of patient’s face showing temporal progression of facial expression (smiling, laughter) during a 6-second period of acute cingulum bundle stimulation (3.0 mA, 130 Hz, 300-μs pulse width marked by stimulation artifact). No epileptiform after-discharges from cingulum stimulation were detected in any channel. The patient described the experience as follows: “I just feel my face smile and I feel happy. [The happiness] lingers for a while and then it kind of slows down a little and I just feel happy and relaxed.”

Figure 4. Distinct neural activity patterns associated with stimulation-induced mirth in the index patient.

(A) Top: LFP shows reduced power in decibels (dB) of an endogenous cingulum oscillation of 6 to 11 Hz following stimulation (blue) compared with prestimulus baseline (gray), but not following nonstimulated sham (green). Bottom: Ten natural (unstimulated) social smiles were analyzed during intracranial recording. The endogenous oscillation of 6 to 11 Hz was again observed in the naturalistic data set at the pre-smile baseline (gray) and following sham LFP epochs in which smiling was not present (green) and showed no evidence of reduced power associated with natural smiling (blue). Lighter-colored areas indicate 95% CIs generated by a random reshuffling procedure. (B) LFP shows distinct reduction in power across the recorded lateral-opercular frontal-parietal lobe network (including ipsilateral motor and sensory cortices of the head and face) following stimulation, but not following sham stimulation or unstimulated natural smiles. Ventral ACC, amygdala, parahippocampus, and medial precuneus showed increased in 6- to 11-Hz power (increased synchrony) following cingulum stimulation. (C) After stimulation, LFP likewise showed reduced network coherence between the cingulum and multiple contacts corresponding to the ipsilateral motor/sensory cortices of the head/face, but not following sham stimulation or unstimulated natural smiles. For B and C, the colored dots indicate electrode locations and the corresponding power, using the heatmap as indicated in the legend. Only contacts with statistically significant changes in power or coherence are presented with colored dots; gray dots indicate contact locations with nonsignificant changes in power or coherence. Statistical significance reflects the percentile of the null (random) distribution at which the actual value was observed. For more precise colocalization of significant contacts within the anatomic MRI, see Supplemental Figures 2 and 3.

Figure 5. Intraoperative timeline, photographs, and impact of stimulation on tolerance of awake brain surgery in the index patient.

(A) Chart shows the timing of the intraoperative interventions, and observations are indicated in the color bars at the top; periodic measurements of heart rate and blood pressure are reported in the lower grid. Initially, continued dexmedetomidine (a sedative-anxiolytic agent) infusion alone was associated with periods of both sedation and anxiety, which confounded the initial language assessment. As cingulum stimulation was titrated up to maintain anxiolysis, dexmedetomidine was ultimately discontinued completely, and language assessments were performed successfully. For a period during awake surgery, cingulum stimulation was discontinued as well, resulting in recurrent anxiety, but this was again immediately alleviated by resuming stimulation. After the completion of the language assessment, a bolus of propofol (sedative anesthetic) was administered (green star), dexmedetomidine was reinitiated, and cingulum stimulation was discontinued. All intraoperative stimulation was voltage-controlled at 130-Hz frequency, 300-μs pulse width and was delivered in a bipolar, biphasic, and charge-balanced manner. Blood oxygenation remained at 100%, and other vital signs were stable throughout the procedure. (B–F) Intraoperative images show the spatial extent of the grid coverage with 1-cm-spaced electrode contacts over the left lateral surface of the brain (B), the appearance of the brain after lifting off a grid array with depth electrodes, with an inset (dotted white rectangle) focused on the location of the resection (C), and a magnified view of the location of the resection in the posterior inferior and middle temporal gyri (D). For size reference in B, electrocorticography grid contacts are spaced at 1-cm intervals, and for size reference in D, the white surgical cotton strip pointing into the surgical field is 0.5 in. wide. The patient is positioned laterally, with the head parallel to the floor and left side up, creating a space to examine her beneath the surgical drape. Intraoperative images of her face without stimulation (E) and with anxiolytic stimulation (F), showing a characteristic smile.