Focused Ultrasound for Noninvasive, Focal Pharmacologic Neurointervention.

A long-standing goal of translational neuroscience is the ability to noninvasively deliver therapeutic agents to specific brain regions with high spatiotemporal resolution. Focused ultrasound (FUS) is an emerging technology that can noninvasively deliver energy up the order of 1 kW/cm2 with millimeter and millisecond resolution to any point in the human brain with Food and Drug Administration-approved hardware. Although FUS is clinically utilized primarily for focal ablation in conditions such as essential tremor, recent breakthroughs have enabled the use of FUS for drug delivery at lower intensities (i.e., tens of watts per square centimeter) without ablation of the tissue. In this review, we present strategies for image-guided FUS-mediated pharmacologic neurointerventions. First, we discuss blood-brain barrier opening to deliver therapeutic agents of a variety of sizes to the central nervous system. We then describe the use of ultrasound-sensitive nanoparticles to noninvasively deliver small molecules to millimeter-sized structures including superficial cortical regions and deep gray matter regions within the brain without the need for blood-brain barrier opening. We also consider the safety and potential complications of these techniques, with attention to temporal acuity. Finally, we close with a discussion of different methods for mapping the ultrasound field within the brain and describe future avenues of research in ultrasound-targeted drug therapies.

Socioeconomic Predictors of Pituitary Surgery.

BACKGROUND: There exists a lack of data on the effect of socioeconomic status (SES) on outcomes for pituitary tumors, which have been associated with significant morbidity. The goal of this population-level study is to investigate the role of SES on receiving treatment and survival in patients with pituitary tumors. METHODS: The Surveillance, Epidemiology, and End Results (SEER) program database from the National Cancer Institute was used to identify patients diagnosed with pituitary tumors between 2003 and 2012. SES was determined using a validated composite index. Race was categorized as Caucasian and non-Caucasian. Treatment received included surgery, radiation, and radiation with surgery. Odds of receiving surgery and survival probability were analyzed using multivariate logistic regression and Cox proportional hazards model, respectively. RESULTS: A total of 25,802 patients with pituitary tumors were identified for analysis. High SES tertile (odds ratio (OR) = 1.095; 95% confidence interval (CI) [1.059, 1.132]) and quintile (OR = 1.052; 95% CI [1.031, 1.072]) were associated with higher odds of receiving surgery (p<0.0001). Caucasian patients had higher odds of receiving surgery when compared to non-Caucasian patients (OR = 1.064; 95% CI [1.000, 1.133]; p<0.05). Neither SES nor race were significant predictors of survival probability. CONCLUSION: Socioeconomic status and race were found to be associated with higher odds of receiving surgery for pituitary tumors, and thus serve as independent predictors of surgical management. Further studies are required to investigate possible causes for these findings.

Hand function, not proximity, biases visuotactile integration later in object processing: An ERP study.

Behavioral studies document a functional hand proximity effect: objects near the palm, but not the back of the hand, affect visual processing. Although visuotactile bimodal neurons integrate visual and haptic inputs, their receptive fields in monkey cortex encompass the whole hand, not just the palm. Using ERPs, we investigated whether hand function influenced the topology of integrated space around the hand. In a visual detection paradigm, target and non-target stimuli appeared equidistantly in front or in back of the hand. Equivalent N1 amplitudes were found for both conditions. P3 target versus non-target amplitude differences were greater for palm conditions. Hand proximity biased processing of visual targets equidistant from the hand early in processing. However, hand function biases emerged later when targets were selected for potential action. Thus, early hand proximity effects on object processing depend on sensory-reliant neural responses, whereas later multisensory integration depend more on the hand's functional expertise.

Deep Brain Stimulation for Chronic Cluster Headache: A Review.

OBJECTIVES: Cluster headaches are a set of episodic and chronic pain syndromes that are sources of significant morbidity for patients. The standard of care for cluster headaches remains medication therapy, however a minority of patients will remain refractory to treatment despite changes to dosage and therapeutic combinations. In these patients, functional neuromodulation using Deep Brain Stimulation (DBS) presents the opportunity to alleviate the significant pain that is experienced by targeting the neurophysiological substrates that mediate pain. MATERIAL AND METHODS: We review the literature on chronic cluster headache, including the growing number of DBS case reports and series that describe the alleviation of pain in a majority of patients through conventional or endoventricular targeting of the posterior hypothalamus and ventral tegmental area, with a minimal side effect profile. RESULTS: In this review, the history and outcomes of DBS use for medication-refractory cluster headaches are examined, with discussion on future directions for improving this novel treatment modality and providing efficacious, longer-lasting pain relief in headache patients. CONCLUSION: In patients with chronic cluster headache, functional neuromodulation using DBS presents the opportunity to alleviate the significant pain that is experienced by targeting the neurophysiological substrates that mediate pain.

Noninvasive Ultrasonic Drug Uncaging Maps Whole-Brain Functional Networks.

Being able to noninvasively modulate brain activity, where and when an experimenter desires, with an immediate path toward human translation is a long-standing goal for neuroscience. To enable robust perturbation of brain activity while leveraging the ability of focused ultrasound to deliver energy to any point of the brain noninvasively, we have developed biocompatible and clinically translatable nanoparticles that allow ultrasound-induced uncaging of neuromodulatory drugs. Utilizing the anesthetic propofol, together with electrophysiological and imaging assays, we show that the neuromodulatory effect of ultrasonic drug uncaging is limited spatially and temporally by the size of the ultrasound focus, the sonication timing, and the pharmacokinetics of the uncaged drug. Moreover, we see secondary effects in brain regions anatomically distinct from and functionally connected to the sonicated region, indicating that ultrasonic drug uncaging could noninvasively map the changes in functional network connectivity associated with pharmacologic action at a particular brain target.

Feeling but not seeing the hand: Occluded hand position reduces the hand proximity effect in ERPs.

The hand proximity effect (nearby hands influence visual processing) reflects the integration of vision and proprioception for upcoming action; it is reduced when hand position is occluded. In an ERP study, we investigate whether hand proximity, without vision of the hand, accentuates the processing of stimuli requiring actions (targets) early (N1) and later (P3) in processing. In a go/no-go paradigm, participants viewed stimuli between two panels with hands placed near or far from stimuli. Occlusion of the hand eliminated near-hand target vs. non-target differentiation of the N1; amplification of near-hand target amplitudes emerged at the P3. Visual hand location appears necessary to draw visual attention to intended-action objects to integrate body and visual information early in processing. The integration of visual stimulus information and hand position from proprioception appears later in processing, indicating greater reliance on cognitive systems for discriminating the task-relevance of a stimulus.

Holistic processing for bodies and body parts: New evidence from stereoscopic depth manipulations.

Although holistic processing has been documented extensively for upright faces, it is unclear whether it occurs for other visual categories with more extensive substructure, such as body postures. Like faces, body postures have high social relevance, but they differ in having fine-grain organization not only of basic parts (e.g., arm) but also subparts (e.g., elbow, wrist, hand). To compare holistic processing for whole bodies and body parts, we employed a novel stereoscopic depth manipulation that creates either the percept of a whole body occluded by a set of bars, or of segments of a body floating in front of a background. Despite sharing low-level visual properties, only the stimulus perceived as being behind bars should be holistically "filled in" via amodal completion. In two experiments, we tested for better identification of individual body parts within the context of a body versus in isolation. Consistent with previous findings, recognition of body parts was better in the context of a whole body when the body was amodally completed behind occluders. However, when the same bodies were perceived as floating in strips, performance was significantly worse, and not significantly different, from that for amodally completed parts, supporting holistic processing of body postures. Intriguingly, performance was worst for parts in the frontal depth condition, suggesting that these effects may extend from gross body organization to a more local level. These results provide suggestive evidence that holistic representations may not be "all-or-none," but rather also operate on body regions of more limited spatial extent.