Default mode network electrophysiological dynamics and causal role in creative thinking.

The default mode network (DMN) is a widely distributed, intrinsic brain network thought to play a crucial role in internally-directed cognition. The present study employs stereo-electroencephalography in 13 human patients, obtaining high resolution neural recordings across multiple canonical DMN regions during two processes that have been associated with creative thinking: spontaneous and divergent thought. We probe these two DMN-associated higher cognitive functions through mind wandering and alternate uses tasks, respectively. Our results reveal DMN recruitment during both tasks, as well as a task-specific dissociation in spatiotemporal response dynamics. When compared to the fronto-parietal network, DMN activity was characterized by a stronger increase in gamma band power (30-70 Hz) coupled with lower theta band power (4-8 Hz). The difference in activity between the two networks was especially strong during the mind wandering task. Within the DMN, we found that the tasks showed different dynamics, with the alternate uses task engaging the DMN more during the initial stage of the task, and mind wandering in the later stage. Gamma power changes were mainly driven by lateral DMN sites, while theta power displayed task-specific effects. During alternate uses task, theta changes did not show spatial differences within the DMN, while mind wandering was associated to an early lateral and late dorsomedial DMN engagement. Furthermore, causal manipulations of DMN regions using direct cortical stimulation preferentially decreased the originality of responses in the alternative uses task, without affecting fluency or mind wandering. Our results suggest that DMN activity is flexibly modulated as a function of specific cognitive processes and supports its causal role in divergent thinking. These findings shed light on the neural constructs supporting different forms of cognition and provide causal evidence for the role of DMN in the generation of original connections among concepts.

Delays in the diagnosis and surgical treatment of drug-resistant epilepsy: A cohort study.

OBJECTIVE: Delay in referral for epilepsy surgery of patients with drug-resistant epilepsy (DRE) is associated with decreased quality of life, worse surgical outcomes, and increased risk of sudden unexplained death in epilepsy (SUDEP). Understanding the potential causes of delays in referral and treatment is crucial for optimizing the referral and treatment process. We evaluated the treatment intervals, demographics, and clinical characteristics of patients referred for surgical evaluation at our level 4 epilepsy center in the U.S. Intermountain West. METHODS: We retrospectively reviewed the records of patients who underwent surgery for DRE between 2012 and 2022. Data collected included patient demographics, DRE diagnosis date, clinical characteristics, insurance status, distance from epilepsy center, date of surgical evaluation, surgical procedure, and intervals between different stages of evaluation. RESULTS: Within our cohort of 185 patients with epilepsy (99 female, 53.5%), the mean ± standard deviation (SD) age at surgery was 38.4 ± 11.9 years. In this cohort, 95.7% of patients had received definitive epilepsy surgery (most frequently neuromodulation procedures) and 4.3% had participated in phase 2 intracranial monitoring but had not yet received definitive surgery. The median (1st-3rd quartile) intervals observed were 10.1 (3.8-21.5) years from epilepsy diagnosis to DRE diagnosis, 16.7 (6.5-28.4) years from epilepsy diagnosis to surgery, and 1.4 (0.6-4.0) years from DRE diagnosis to surgery. We observed significantly shorter median times from epilepsy diagnosis to DRE diagnosis (p < .01) and epilepsy diagnosis to surgery (p < .05) in patients who traveled further for treatment. Patients with public health insurance had a significantly longer time from DRE diagnosis to surgery (p < .001). SIGNIFICANCE: Both shorter distance traveled to our epilepsy center and public health insurance were predictive of delays in diagnosis and treatment intervals. Timely referral of patients with DRE to specialized epilepsy centers for surgery evaluation is crucial, and identifying key factors that may delay referral is paramount to optimizing surgical outcomes.

Disparities in Access to Deep Brain Stimulation and Responsive Neurostimulation Approaches to Drug-Resistant Epilepsy.

BACKGROUND: Epilepsy affects 1% to 2% of the global population, and those who are resistant to medical treatment may be candidates for neuromodulation. In select populations, brain stimulation approaches including deep brain stimulation (DBS) and responsive neurostimulation (RNS) are used. Although studies have shown that patients from Black, Hispanic, lower income, and rural communities have less access to epilepsy care and have lower rates of epilepsy surgery, disparities in the use of brain stimulation for epilepsy treatment are currently not known. MATERIALS AND METHODS: We queried the US National Inpatient Sample data base from January 1, 2014 to December 31, 2019 for all patients discharged with an International Classification of Diseases (ICD) Ninth Revision or ICD Tenth Revision diagnosis of drug-resistant epilepsy. Among these patients discharged, the rates of brain stimulation treatment, including DBS and RNS, were reported in each subgroup of race, ethnicity, and insurance. To generate national estimates, all analyses were weighted. RESULTS: A total of 237,895 patients discharged with drug-resistant epilepsy were identified, of whom 4,925 (2.1%) received brain stimulation treatment for drug-resistant epilepsy. Black patients (n = 420, 0.9%, odds ratio [OR] = 0.51, 95% CI [0.40, 0.64]) were less likely to receive brain stimulation treatment than were White patients (n = 3300, 2.4%). There was no significant difference between Asian (n = 105, 2.3%, OR = 0.80, 95% CI [0.53, 1.33]) and Hispanic (n = 655, 2.6%, OR = 0.95, 95% CI [0.77, 1.17]) patients and White patients. No significant difference was observed between female (n = 2515, 2.1%, OR = 1.02, 95% CI [0.89, 1.17]) and male (n = 2410, 2.0%) patients either. Patients with Medicare (n = 1150, 1.2%, OR = 0.69, 95% CI [0.57, 0.84]) or Medicaid (n = 1150, 1.8%, OR = 0.52, 95% CI [0.44, 0.62]) were less likely to receive brain stimulation treatment than were those with private insurance as the primary payer (n = 2370, 3.9%). CONCLUSIONS: We discovered significant disparities in the use of brain stimulation treatments for drug-resistant epilepsy based on race and insurance status. More research will be required to determine the cause of these disparities.

Demographics of focused ultrasound thalamotomy for essential tremor and trends in deep brain stimulation surgery after its introduction in the USA.

Background: Essential tremor (ET) is a movement disorder that affects 4%-5% of adults >65 years. For patients with medically refractory ET, neurosurgical interventions such as deep brain stimulation (DBS) and unilateral MR-guided focused ultrasound thalamotomy (MRgFUS) are available. In this retrospective cohort study, we examined the demographics of patients with ET who have received MRgFUS and evaluated trends in DBS usage in the USA after the introduction of MRgFUS in 2016. Methods: We used multiple databases to examine the demographics of patients who received DBS and MRgFUS, and trends in DBS. To assess the demographics, we queried the TriNetX database from 2003 to 2022 to identify patients diagnosed with ET and stratify them by DBS or MRgFUS treatment by using Current Procedural Terminology codes. Patient demographics were reported as frequencies and percentages. To examine the trends in DBS for ET, the yearly frequency of DBS procedures done for ET between 2012 and 2019 was extracted from the National Inpatient Sample (NIS) database, and breakpoint analysis was performed. Additionally, the yearly frequency of MRgFUS procedures for ET was obtained from Insightec Exlabate. Results: Most of the patients (88.69%) in the cohort extracted from TriNetX database self-identified as white, followed by black or African American (2.40%) and Asian (0.52%). A higher percentage of black patients received MRgFUS treatment than DBS (4.10% vs 1.88%). According to the NIS database, from 2012 to 2020, 13 525 patients received DBS for ET. Conclusion: This study provides an overview of the characteristics of patients who undergo DBS or MRgFUS. We found notable differences in sex and race among patients who underwent each treatment type. Additionally, until at least the beginning of 2020, the number of DBS procedures for ET was not negatively affected after the introduction of MRgFUS.

Radiographic abnormalities and their clinical significance in patients with Parkinson disease who receive deep brain stimulation implants.

OBJECTIVE: Preoperative MR images obtained in patients with Parkinson disease (PD) undergoing deep brain stimulation (DBS) often reveal incidental radiographic abnormalities (RAs). These findings range from small changes to gross pathologies. The effect of these findings on patients' clinical outcomes is unknown. The authors characterized RAs in patients with PD who underwent DBS and assessed clinical outcomes. METHODS: Records of patients at the authors' institution with PD who underwent MRI for DBS electrode implantation from 2010 through 2022 were reviewed. RAs were identified from the official preoperative MRI reports. RAs were grouped into four general categories (ischemic changes, atrophy or degenerative changes [ADCs], structural abnormalities, and tumors) and correlated with clinical outcomes (including subjective clinical response, levodopa equivalent dose [LED], and Unified Parkinson's Disease Rating Scale Part III [UPDRS] score) at the 1-year and last available follow-ups. RESULTS: In this review, 160 patients were identified for initial analysis, with 135 presenting with ≥ 1 RAs. Of these 135 patients, 69.4% (111/160) had ischemic vascular changes, 39.4% (63/160) had ADCs, 16.9% (27/160) had structural changes, and 1.9% (3/160) had tumors. No differences in preoperative LED or UPDRS score were observed between these groups. After DBS, no differences in outcomes were observed between patients with RAs and those without RAs for both the 1-year and last follow-up time points, including mortality rates and times. Structural lesions were associated with lower mortality rates (OR 0.1, p = 0.04). ADCs were associated with a worse subjective clinical response at the 1-year (OR 0.50, p = 0.04) and last (OR 0.49, p = 0.03) follow-ups, but subjectively worse responses were not correlated with worse objective outcome measures. CONCLUSIONS: Most RAs have no significant effect on clinical outcomes in PD patients undergoing DBS. Generalized ADCs may be associated with poorer subjective responses and may warrant further discussion with the patient if diagnosed on preoperative MRI.

Disparities in the treatment of movement disorders using deep brain stimulation.

OBJECTIVE: Deep brain stimulation (DBS) is a well-established treatment for Parkinson's disease (PD) and essential tremor (ET). Although the prevalence of PD and ET can vary by sex and race, little is known about the accessibility of neurosurgical treatments for these conditions. In this nationwide study, the authors aimed to characterize trends in the use of DBS for the treatment of PD and ET and to identify disparities in the neurosurgical treatment of these diseases based on ethnic, racial, sex, insurance, income, hospital, and geographic factors. METHODS: Using the dates January 1, 2012, to December 31, 2019, the authors queried the National Inpatient Sample database for all discharges with an ICD-9 or ICD-10 diagnosis of PD or ET. Among these discharges, the DBS rates were reported for each subgroup of race, ethnicity, and sex. To develop national estimates, all analyses were weighted. RESULTS: Among 2,517,639 discharges with PD, 29,820 (1.2%) received DBS, and among 652,935 discharges with ET, 11,885 (1.8%) received DBS. Amid the PD cases, Black patients (n = 405 [0.2%], OR 0.16, 95% CI 0.12-0.20) were less likely than White patients (n = 23,975 [1.2%]) to receive DBS treatment, as were Hispanic patients (n = 1965 [1.1%], OR 0.76, 95% CI 0.65-0.88), whereas Asian/Pacific Islander patients (n = 855 [1.5%]) did not statistically differ from White patients. Amid the ET cases, Black (n = 230 [0.8%], OR 0.39, 95% CI 0.27-0.56), Hispanic (n = 215 [1.0%], OR 0.39, 95% CI 0.28-0.55), and Asian/Pacific Islander (n = 55 [1.0%], OR 0.51, 95% CI 0.28-0.93) patients were less likely than White patients (n = 10,440 [1.9%]) to receive DBS. Females were less likely than males to receive DBS for PD (OR 0.69, p < 0.0001) or ET (OR 0.70, p < 0.0001). CONCLUSIONS: The authors describe significant racial and sex-based differences in the utilization of DBS for the treatment of PD and ET. Further research is required to ascertain the causes of these disparities, as well as any differences in access to specialty neurosurgical care and referral for neuromodulation approaches.

Intracranial Directed Connectivity Links Subregions of the Prefrontal Cortex to Major Depression.

Understanding the neural basis of major depressive disorder (MDD) is vital to guiding neuromodulatory treatments. The available evidence supports the hypothesis that MDD is fundamentally a disease of cortical disinhibition, where breakdowns of inhibitory neural systems lead to diminished emotion regulation and intrusive ruminations. Recent research also points towards network changes in the brain, especially within the prefrontal cortex (PFC), as primary sources of MDD etiology. However, due to limitations in spatiotemporal resolution and clinical opportunities for intracranial recordings, this hypothesis has not been directly tested. We recorded intracranial EEG from the dorsolateral (dlPFC), orbitofrontal (OFC), and anterior cingulate cortices (ACC) in neurosurgical patients with MDD. We measured daily fluctuations in self-reported depression severity alongside directed connectivity between these PFC subregions. We focused primarily on delta oscillations (1-3 Hz), which have been linked to GABAergic inhibitory control and intracortical communication. Depression symptoms worsened when connectivity within the left vs. right PFC became imbalanced. In the left hemisphere, all directed connectivity towards the ACC, from the dlPFC and OFC, was positively correlated with depression severity. In the right hemisphere, directed connectivity between the OFC and dlPFC increased with depression severity as well. This is the first evidence that delta oscillations flowing between prefrontal subregions transiently increase intensity when people are experiencing more negative mood. These findings support the overarching hypothesis that MDD worsens with prefrontal disinhibition.

Beta activity in human anterior cingulate cortex mediates reward biases.

The rewards that we get from our choices and actions can have a major influence on our future behavior. Understanding how reward biasing of behavior is implemented in the brain is important for many reasons, including the fact that diminution in reward biasing is a hallmark of clinical depression. We hypothesized that reward biasing is mediated by the anterior cingulate cortex (ACC), a cortical hub region associated with the integration of reward and executive control and with the etiology of depression. To test this hypothesis, we recorded neural activity during a biased judgment task in patients undergoing intracranial monitoring for either epilepsy or major depressive disorder. We found that beta (12-30 Hz) oscillations in the ACC predicted both associated reward and the size of the choice bias, and also tracked reward receipt, thereby predicting bias on future trials. We found reduced magnitude of bias in depressed patients, in whom the beta-specific effects were correspondingly reduced. Our findings suggest that ACC beta oscillations may orchestrate the learning of reward information to guide adaptive choice, and, more broadly, suggest a potential biomarker for anhedonia and point to future development of interventions to enhance reward impact for therapeutic benefit.

Insula uses overlapping codes for emotion in self and others.

In daily life, we must recognize others' emotions so we can respond appropriately. This ability may rely, at least in part, on neural responses similar to those associated with our own emotions. We hypothesized that the insula, a cortical region near the junction of the temporal, parietal, and frontal lobes, may play a key role in this process. We recorded local field potential (LFP) activity in human neurosurgical patients performing two tasks, one focused on identifying their own emotional response and one on identifying facial emotional responses in others. We found matching patterns of gamma- and high-gamma band activity for the two tasks in the insula. Three other regions (MTL, ACC, and OFC) clearly encoded both self- and other-emotions, but used orthogonal activity patterns to do so. These results support the hypothesis that the insula plays a particularly important role in mediating between experienced vs. observed emotions.

Disruption of neural periodicity predicts clinical response after deep brain stimulation for obsessive-compulsive disorder.

Recent advances in surgical neuromodulation have enabled chronic and continuous intracranial monitoring during everyday life. We used this opportunity to identify neural predictors of clinical state in 12 individuals with treatment-resistant obsessive-compulsive disorder (OCD) receiving deep brain stimulation (DBS) therapy ( NCT05915741 ). We developed our neurobehavioral models based on continuous neural recordings in the region of the ventral striatum in an initial cohort of five patients and tested and validated them in a held-out cohort of seven additional patients. Before DBS activation, in the most symptomatic state, theta/alpha (9 Hz) power evidenced a prominent circadian pattern and a high degree of predictability. In patients with persistent symptoms (non-responders), predictability of the neural data remained consistently high. On the other hand, in patients who improved symptomatically (responders), predictability of the neural data was significantly diminished. This neural feature accurately classified clinical status even in patients with limited duration recordings, indicating generalizability that could facilitate therapeutic decision-making.

Prefrontal network engagement by deep brain stimulation in limbic hubs.

Prefrontal circuits in the human brain play an important role in cognitive and affective processing. Neuromodulation therapies delivered to certain key hubs within these circuits are being used with increasing frequency to treat a host of neuropsychiatric disorders. However, the detailed neurophysiological effects of stimulation to these hubs are largely unknown. Here, we performed intracranial recordings across prefrontal networks while delivering electrical stimulation to two well-established white matter hubs involved in cognitive regulation and depression: the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VC/VS). We demonstrate a shared frontotemporal circuit consisting of the ventromedial prefrontal cortex, amygdala, and lateral orbitofrontal cortex where gamma oscillations are differentially modulated by stimulation target. Additionally, we found participant-specific responses to stimulation in the dorsal anterior cingulate cortex and demonstrate the capacity for further tuning of neural activity using current-steered stimulation. Our findings indicate a potential neurophysiological mechanism for the dissociable therapeutic effects seen across the SCC and VC/VS targets for psychiatric neuromodulation and our results lay the groundwork for personalized, network-guided neurostimulation therapy.

Stereo-EEG-guided network modulation for psychiatric disorders: Surgical considerations.

BACKGROUND: Deep brain stimulation (DBS) and other neuromodulatory techniques are being increasingly utilized to treat refractory neurologic and psychiatric disorders. OBJECTIVE: /Hypothesis: To better understand the circuit-level pathophysiology of treatment-resistant depression (TRD) and treat the network-level dysfunction inherent to this challenging disorder, we adopted an approach of inpatient intracranial monitoring borrowed from the epilepsy surgery field. METHODS: We implanted 3 patients with 4 DBS leads (bilateral pair in both the ventral capsule/ventral striatum and subcallosal cingulate) and 10 stereo-electroencephalography (sEEG) electrodes targeting depression-relevant network regions. For surgical planning, we used an interactive, holographic visualization platform to appreciate the 3D anatomy and connectivity. In the initial surgery, we placed the DBS leads and sEEG electrodes using robotic stereotaxy. Subjects were then admitted to an inpatient monitoring unit for depression-specific neurophysiological assessments. Following these investigations, subjects returned to the OR to remove the sEEG electrodes and internalize the DBS leads to implanted pulse generators. RESULTS: Intraoperative testing revealed positive valence responses in all 3 subjects that helped verify targeting. Given the importance of the network-based hypotheses we were testing, we required accurate adherence to the surgical plan (to engage DBS and sEEG targets) and stability of DBS lead rotational position (to ensure that stimulation field estimates of the directional leads used during inpatient monitoring were relevant chronically), both of which we confirmed (mean radial error 1.2±0.9 mm; mean rotation 3.6±2.6°). CONCLUSION: This novel hybrid sEEG-DBS approach allows detailed study of the neurophysiological substrates of complex neuropsychiatric disorders.