Abstracts

Rationale: We sought to elucidate the mechanism of evoked laughter, positive affect, and anxiolysis during applied direct electrical stimulation to the anterior cingulum bundle. In the index patient, stimulation was later applied during an awake neurosurgery to assist with anxiolysis and facilitate language functional screening during resection. Methods: Patients with treatment-refractory epilepsy underwent stereotactic depth electrode (AdTech SEEG) implantation for seizure focus localization. Stimulation testing occurred during the intracranial monitoring phase, where electrical stimulation was delivered via a current-controlled cerebral stimulator. Stimulation did not cause after-discharges or epileptiform activity. Subjective effects of stimulation were recorded via video, and objective effects were quantified in terms of network-evoked potentials, autonomic responses, and shifts in affective bias, a cognitive proxy for emotional state.  Results: In the index patient, a 25-year-old woman with moderate comorbid anxiety, focal stimulation to the dorsal anterior cingulum bundle was observed to produce involuntary laughter and smiling which emanated from the side of the face contralateral to stimulation. The patient reported happiness and relaxation that persisted over the course of twenty minutes of stimulation. Stimulation was accompanied by a significant positive shift in emotional bias (p=.023), as well as dose-dependent transient increases in skin conductance and heart rate. Neuroimaging revealed stimulation engagement of the cingulum bundle and fibers innervating the supplementary motor area and dorsal prefrontal cortex (Figure 1). We examined the impact of active and sham stimulation upon local field potentials at the stimulated location (cingulum) as well as globally across all 127 implanted contacts, revealing significant reductions in endogenous 6-11hz power in the cingulum, as well as reduced coherence between other network locations and the cingulum following active stimulation (ps < .0001, Figure 2).The patient’s clinical team (neurosurgeon, neurologist, psychologist, and anesthesiologist) determined that cingulum stimulation was likely to provide substantive relief to the patient’s anxiety during surgery, and it was successfully applied in the operating room to produce anxiolysis without sedation which facilitated ongoing language testing during awake resection in the dominant temporal lobe. Systematic examination of fourteen subsequent patients help to clarify the role of anterior/posterior location of stimulation in the cingulum bundle, as well as orientation of bipolar stimulation (parallel vs. orthogonal to the bundle) for evoking effects similar to those observed in the index case. Findings from the systematic study provide replication for initial findings of evoked mirth and laughter, positive affect, anxiolysis, as well as providing clear evidence of analgesic effects. Conclusions: The current findings significantly expand the literature on the role of the anterior cingulate in negative-valenced emotional system function. The novel application of this stimulation in the index patient to evoke sense of well-being and anxiolysis without sedation during the patient’s awake resection suggests it may be a novel target for anxiety management, especially in the context of awake neurosurgical procedures. Funding: The current research was supported in part by an NIH KL2 Mentored Translational and Clinical Scholar Award (PI: Bijanki, KL2-TL000455).