Augmented Reality Registration System for Visualization of Skull Landmarks.

BACKGROUND: Augmented reality (AR) is an emerging technology in neurosurgery with the potential to become a strategic tool in the delivery of care and education for trainees. Advances in technology have demonstrated promising use for improving visualization and spatial awareness of critical neuroanatomic structures. In this report, we employ a novel AR registration system for the visualization and targeting of skull landmarks. METHODS: A markerless AR system was used to register 3-dimensional reconstructions of suture lines onto the head via a head-mounted display. Participants were required to identify craniometric points with and without AR assistance. Targeting error was measured as the Euclidian distance between the user-defined location and the true craniometric point on the subjects' heads. RESULTS: All participants successfully registered 3-dimensional reconstructions onto the subjects' heads. Targeting accuracy was significantly improved with AR (3.59 ± 1.29 mm). Across all target points, AR increased accuracy by an average of 19.96 ± 3.80 mm. Posttest surveys revealed that participants felt the technology increased their confidence in identifying landmarks (4.6/5) and that the technology will be useful for clinical care (4.2/5). CONCLUSIONS: While several areas of improvement and innovation can further enhance the use of AR in neurosurgery, this report demonstrates the feasibility of a markerless headset-based AR system for visualizing craniometric points on the skull. As the technology continues to advance, AR is expected to play an increasingly significant role in neurosurgery, transforming how surgeries are performed and improving patient care.

Thermal Damage Estimate Artifact Following Antecedent Biopsy: A Case Report.

MR-guided laser interstitial therapy (MRgLITT) is becoming more commonly used for minimal access approaches to intracranial lesions of all etiologies. The short-term safety profile of MRgLITT is favorable compared with sweeping incisions and open craniotomies, especially for lesions located in deep, periventricular, and highly eloquent areas. The Visualase software (Medtronic Inc., Minneapolis, MN, USA) has multiple adaptations to assist with this safety margin, including the thermal damage estimate (TDE), which applies predictive mathematical modeling to a two-dimensional (2D) graphical representation. TDE has been shown to highly correlate with actual tissue destruction in a priori MRgLITT cases and to anecdotally be imprecise when MRgLITT is combined with biopsy. We present a case regarding a 17-year-old male patient with intractable focal epilepsy. He underwent stereotactic biopsy and then ablation where it was shown that TDE is ~35% larger in the coronal plane than in the actual ablation zone. Air may have caused this artifact in the biopsy cavity, which affected the proton resonance frequency (PRF) and caused TDE pigment deposition. We believe in the need for a more comprehensive understanding and investigation regarding this TDE artifact. Future prospective studies into MRgLITT should attend carefully in cases where it is combined with biopsy.

Validation of the Benefits of Ambulation Within 8 Hours of Elective Cervical and Lumbar Surgery: A Michigan Spine Surgery Improvement Collaborative Study.

BACKGROUND: Early ambulation is considered a key element to Enhanced Recovery After Surgery protocol after spine surgery. OBJECTIVE: To investigate whether ambulation less than 8 hours after elective spine surgery is associated with improved outcome. METHODS: The Michigan Spine Surgery Improvement Collaborative database was queried to track all elective cervical and lumbar spine surgery between July 2018 and April 2021. In total, 7647 cervical and 17 616 lumbar cases were divided into 3 cohorts based on time to ambulate after surgery: (1) <8 hours, (2) 8 to 24 hours, and (3) >24 hours. RESULTS: For cervical cases, patients who ambulated 8 to 24 hours (adjusted odds ratio [aOR] 1.38; 95% CI 1.11-1.70; P = .003) and >24 hours (aOR 2.20; 95% CI 1.20-4.03; P = .011) after surgery had higher complication rate than those who ambulated within 8 hours of surgery. Similar findings were noted for lumbar cases with patients who ambulated 8 to 24 hours (aOR 1.31; 95% CI 1.12-1.54; P < .001) and >24 hours (aOR 1.96; 95% CI 1.50-2.56; P < .001) after surgery having significantly higher complication rate than those ambulated <8 hours after surgery. Analysis of secondary outcomes for cervical cases demonstrated that <8-hour ambulation was associated with home discharge, shorter hospital stay, lower 90-day readmission, and lower urinary retention rate. For lumbar cases, <8-hour ambulation was associated with shorter hospital stay, satisfaction with surgery, lower 30-day readmission, home discharge, and lower urinary retention rate. CONCLUSION: Ambulation within 8 hours after surgery is associated with significant improved outcome after elective cervical and lumbar spine surgery.

Atypical presentation of rotational vertebral artery insufficiency: illustrative case.

BACKGROUND: Rotational vertebral artery insufficiency (RVAI), also known as bow hunter's syndrome, is an uncommon cause of vertebrobasilar insufficiency that leads to signs of posterior circulation ischemia during head rotation. RVAI can be subdivided on the basis of the anatomical location of vertebral artery compression into atlantoaxial RVAI (pathology at C1-C2) or subaxial RVAI (pathology below C2). Typically, RVAI is only seen with contralateral vertebral artery pathologies, such as atherosclerosis, hypoplasia, or morphological atypia. OBSERVATIONS: The authors present a unique case of atlantoaxial RVAI due to rotational instability, causing marked subluxation of the C1-C2 facet joints. This case is unique in both the mechanism of compression and the lack of contralateral vertebral artery pathology. The patient was successfully treated with posterior C1-C2 instrumentation and fusion. LESSONS: When evaluating patients for RVAI, neurosurgeons should be aware of the variety of pathological causes, including rotational instability from facet joint subluxation. Due to the heterogeneous nature of the pathologies causing RVAI, care must be taken to decide if conservative management or surgical correction is the right course of action. Because of this heterogeneous nature, there is no set guideline for the treatment or management of RVAI.

Time cells in the human hippocampus and entorhinal cortex support episodic memory.

The organization of temporal information is critical for the encoding and retrieval of episodic memories. In the rodent hippocampus and entorhinal cortex, evidence accumulated over the last decade suggests that populations of "time cells" in the hippocampus encode temporal information. We identify time cells in humans using intracranial microelectrode recordings obtained from 27 human epilepsy patients who performed an episodic memory task. We show that time cell activity predicts the temporal organization of retrieved memory items. We also uncover evidence of ramping cell activity in humans, which represents a complementary type of temporal information. These findings establish a cellular mechanism for the representation of temporal information in the human brain needed to form episodic memories.

Manipulations of Central Amygdala Neurotensin Neurons Alter the Consumption of Ethanol and Sweet Fluids in Mice.

The central nucleus of the amygdala plays a significant role in alcohol use and other affective disorders; however, the genetically-defined neuronal subtypes and projections that govern these behaviors are not well known. Here we show that neurotensin neurons in the central nucleus of the amygdala of male mice are activated by in vivo ethanol consumption and that genetic ablation of these neurons decreases ethanol consumption and preference in non-ethanol-dependent animals. This ablation did not impact preference for sucrose, saccharin, or quinine. We found that the most robust projection of the central amygdala neurotensin neurons was to the parabrachial nucleus, a brain region known to be important in feeding behaviors, conditioned taste aversion, and alarm. Optogenetic stimulation of projections from these neurons to the parabrachial nucleus is reinforcing, and increases ethanol drinking as well as consumption of sucrose and saccharin solutions. These data suggest that this central amygdala to parabrachial nucleus projection influences the expression of reward-related phenotypes and is a novel circuit promoting consumption of ethanol and palatable fluids.SIGNIFICANCE STATEMENT Alcohol use disorder (AUD) is a major health burden worldwide. Although ethanol consumption is required for the development of AUD, much remains unknown regarding the underlying neural circuits that govern initial ethanol intake. Here we show that ablation of a population of neurotensin-expressing neurons in the central amygdala decreases intake of and preference for ethanol in non-dependent animals, whereas the projection of these neurons to the parabrachial nucleus promotes consumption of ethanol as well as other palatable fluids.

Coordination of Brain-Wide Activity Dynamics by Dopaminergic Neurons.

Several neuropsychiatric conditions, such as addiction and schizophrenia, may arise in part from dysregulated activity of ventral tegmental area dopaminergic (THVTA) neurons, as well as from more global maladaptation in neurocircuit function. However, whether THVTA activity affects large-scale brain-wide function remains unknown. Here we selectively activated THVTA neurons in transgenic rats and measured resulting changes in whole-brain activity using stimulus-evoked functional magnetic resonance imaging. Applying a standard generalized linear model analysis approach, our results indicate that selective optogenetic stimulation of THVTA neurons enhanced cerebral blood volume signals in striatal target regions in a dopamine receptor-dependent manner. However, brain-wide voxel-based principal component analysis of the same data set revealed that dopaminergic modulation activates several additional anatomically distinct regions throughout the brain, not typically associated with dopamine release events. Furthermore, explicit pairing of THVTA neuronal activation with a forepaw stimulus of a particular frequency expanded the sensory representation of that stimulus, not exclusively within the somatosensory cortices, but brain-wide. These data suggest that modulation of THVTA neurons can impact brain dynamics across many distributed anatomically distinct regions, even those that receive little to no direct THVTA input.

Loss of UBE3A from TH-expressing neurons suppresses GABA co-release and enhances VTA-NAc optical self-stimulation.

Motivated reward-seeking behaviours are governed by dopaminergic ventral tegmental area projections to the nucleus accumbens. In addition to dopamine, these mesoaccumbal terminals co-release other neurotransmitters including glutamate and GABA, whose roles in regulating motivated behaviours are currently being investigated. Here we demonstrate that loss of the E3-ubiquitin ligase, UBE3A, from tyrosine hydroxylase-expressing neurons impairs mesoaccumbal, non-canonical GABA co-release and enhances reward-seeking behaviour measured by optical self-stimulation.

Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Regulate Feeding and Reward.

The overconsumption of calorically dense, highly palatable foods is thought to be a major contributor to the worldwide obesity epidemic; however, the precise neural circuits that directly regulate hedonic feeding remain elusive. Here, we show that lateral hypothalamic area (LHA) glutamatergic neurons, and their projections to the lateral habenula (LHb), negatively regulate the consumption of palatable food. Genetic ablation of LHA glutamatergic neurons increased daily caloric intake and produced weight gain in mice that had access to a high-fat diet, while not altering general locomotor activity. Anterior LHA glutamatergic neurons send a functional glutamatergic projection to the LHb, a brain region involved in processing aversive stimuli and negative reward prediction outcomes. Pathway-specific, optogenetic stimulation of glutamatergic LHA-LHb circuit resulted in detectable glutamate-mediated EPSCs as well as GABA-mediated IPSCs, although the net effect of neurotransmitter release was to increase the firing of most LHb neurons. In vivo optogenetic inhibition of LHA-LHb glutamatergic fibers produced a real-time place preference, whereas optogenetic stimulation of LHA-LHb glutamatergic fibers had the opposite effect. Furthermore, optogenetic inhibition of LHA-LHb glutamatergic fibers acutely increased the consumption of a palatable liquid caloric reward. Collectively, these results demonstrate that LHA glutamatergic neurons are well situated to bidirectionally regulate feeding and potentially other behavioral states via their functional circuit connectivity with the LHb and potentially other brain regions. SIGNIFICANCE STATEMENT: In this study, we show that the genetic ablation of LHA glutamatergic neurons enhances caloric intake. Some of these LHA glutamatergic neurons project to the lateral habenula, a brain area important for generating behavioral avoidance. Optogenetic stimulation of this circuit has net excitatory effects on postsynaptic LHb neurons. This is the first study to characterize the functional connectivity and behavioral relevance of this circuit within the context of feeding and reward-related behavior.

Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors.

Optimally orchestrating complex behavioral states, such as the pursuit and consumption of food, is critical for an organism's survival. The lateral hypothalamus (LH) is a neuroanatomical region essential for appetitive and consummatory behaviors, but whether individual neurons within the LH differentially contribute to these interconnected processes is unknown. Here, we show that selective optogenetic stimulation of a molecularly defined subset of LH GABAergic (Vgat-expressing) neurons enhances both appetitive and consummatory behaviors, whereas genetic ablation of these neurons reduced these phenotypes. Furthermore, this targeted LH subpopulation is distinct from cells containing the feeding-related neuropeptides, melanin-concentrating hormone (MCH), and orexin (Orx). Employing in vivo calcium imaging in freely behaving mice to record activity dynamics from hundreds of cells, we identified individual LH GABAergic neurons that preferentially encode aspects of either appetitive or consummatory behaviors, but rarely both. These tightly regulated, yet highly intertwined, behavioral processes are thus dissociable at the cellular level.

Considerations when using cre-driver rodent lines for studying ventral tegmental area circuitry.

The use of Cre-driver rodent lines for targeting ventral tegmental area (VTA) cell types has generated important and novel insights into how precise neurocircuits regulate physiology and behavior. While this approach generally results in enhanced cellular specificity, an important issue has recently emerged related to the selectivity and penetrance of viral targeting of VTA neurons using several Cre-driver transgenic mouse lines. Here, we highlight several considerations when utilizing these tools to study the function of genetically defined neurocircuits. While VTA dopaminergic neurons have previously been targeted and defined by the expression of single genes important for aspects of dopamine neurotransmission, many VTA and neighboring cells display dynamic gene expression phenotypes that are partially consistent with both classically described dopaminergic and non-dopaminergic neurons. Thus, in addition to varying degrees of selectivity and penetrance, distinct Cre lines likely permit targeting of partially overlapping, but not identical VTA cell populations. This Matters Arising Response paper addresses the Lammel et al. (2015) Matters Arising paper, published concurrently in Neuron.

Optical suppression of drug-evoked phasic dopamine release.

Brief fluctuations in dopamine concentration (dopamine transients) play a key role in behavior towards rewards, including drugs of abuse. Drug-evoked dopamine transients may result from actions at both dopamine cell bodies and dopamine terminals. Inhibitory opsins can be targeted to dopamine neurons permitting their firing activity to be suppressed. However, as dopamine transients can become uncoupled from firing, it is unknown whether optogenetic hyperpolarization at the level of the soma is able to suppress dopamine transients. Here, we used in vivo fast-scan cyclic voltammetry to record transients evoked by cocaine and raclopride in nucleus accumbens (NAc) of urethane-anesthetized rats. We targeted halorhodopsin (NpHR) specifically to dopamine cells by injecting Cre-inducible virus into ventral tegmental area (VTA) of transgenic rats that expressed Cre recombinase under control of the tyrosine hydroxylase promoter (TH-Cre(+) rats). Consistent with previous work, co-administration of cocaine and raclopride led to the generation of dopamine transients in NAc shell. Illumination of VTA with laser strongly suppressed the frequency of transients in NpHR-expressing rats, but not in control rats. Laser did not have any effect on amplitude of transients. Thus, optogenetics can effectively reduce the occurrence of drug-evoked transients and is therefore a suitable approach for studying the functional role of such transients in drug-associated behavior.

Inhibition of projections from the basolateral amygdala to the entorhinal cortex disrupts the acquisition of contextual fear.

The development of excessive fear and/or stress responses to environmental cues such as contexts associated with a traumatic event is a hallmark of post-traumatic stress disorder (PTSD). The basolateral amygdala (BLA) has been implicated as a key structure mediating contextual fear conditioning. In addition, the hippocampus has an integral role in the encoding and processing of contexts associated with strong, salient stimuli such as fear. Given that both the BLA and hippocampus play an important role in the regulation of contextual fear conditioning, examining the functional connectivity between these two structures may elucidate a role for this pathway in the development of PTSD. Here, we used optogenetic strategies to demonstrate that the BLA sends a strong glutamatergic projection to the hippocampal formation through the entorhinal cortex (EC). Next, we photoinhibited glutamatergic fibers from the BLA terminating in the EC during the acquisition or expression of contextual fear conditioning. In mice that received optical inhibition of the BLA-to-EC pathway during the acquisition session, we observed a significant decrease in freezing behavior in a context re-exposure session. In contrast, we observed no differences in freezing behavior in mice that were only photoinhibited during the context re-exposure session. These data demonstrate an important role for the BLA-to-EC glutamatergic pathway in the acquisition of contextual fear conditioning.

Activation of prefrontal cortical parvalbumin interneurons facilitates extinction of reward-seeking behavior.

Forming and breaking associations between emotionally salient environmental stimuli and rewarding or aversive outcomes is an essential component of learned adaptive behavior. Importantly, when cue-reward contingencies degrade, animals must exhibit behavioral flexibility to extinguish prior learned associations. Understanding the specific neural circuit mechanisms that operate during the formation and extinction of conditioned behaviors is critical because dysregulation of these neural processes is hypothesized to underlie many of the maladaptive and pathological behaviors observed in various neuropsychiatric disorders in humans. The medial prefrontal cortex (mPFC) participates in the behavioral adaptations seen in both appetitive and aversive-cue-mediated responding, but the precise cell types and circuit mechanisms sufficient for driving these complex behavioral states remain largely unspecified. Here, we recorded and manipulated the activity of parvalbumin-positive fast spiking interneurons (PV+ FSIs) in the prelimbic area (PrL) of the mPFC in mice. In vivo photostimulation of PV+ FSIs resulted in a net inhibition of PrL neurons, providing a circuit blueprint for behavioral manipulations. Photostimulation of mPFC PV+ cells did not alter anticipatory or consummatory licking behavior during reinforced training sessions. However, optical activation of these inhibitory interneurons to cues associated with reward significantly accelerated the extinction of behavior during non-reinforced test sessions. These data suggest that suppression of excitatory mPFC networks via increased activity of PV+ FSIs may enhance reward-related behavioral flexibility.

Obsessive-compulsive-like behaviors in house mice are attenuated by a probiotic (Lactobacillus rhamnosus GG).

Two experiments examined probiotic pretreatment (Lactobacillus rhamnosus GG) on obsessive-compulsive disorder (OCD)-like behavior induction by RU 24969 in BALB/cJ house mice. In the first experiment, two groups were defined by their daily pretreatment by oral gavage of either (a) L. rhamnosus (1×109 CFU/day) or (b) the saline vehicle. Both a 2- and 4-week probiotic pretreatment attenuated OCD-like behavior induction (increased perseverative open-field locomotion, stereotypic turning, and marble burying) relative to saline pretreatment. Experiment 2 re-examined the 2-week probiotic pretreatment while also comparing it to a 4-week fluoxetine pretreatment. Again, groups were defined by daily pretreatment of either (a) L. rhamnosus for 2 weeks, (b) the saline vehicle for 2 weeks, or (c) fluoxetine (10 mg/kg) for 4 weeks. Pretreatment by either L. rhamnosus or fluoxetine blocked the induction of OCD-like behavior compared with saline pretreatment. Thus the 2-week probiotic pretreatment was again effective. Although side effects of fluoxetine or L. rhamnosus on androgen-dependent behaviors could not be demonstrated, L. rhamnosus treatment appeared comparable to fluoxetine treatment in attenuating mouse OCD-like behaviors.