Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain.

Aberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a region near the posterior inferior frontal sulcus of the right dorsolateral prefrontal cortex (piDLPFC) in migraine patients during acute pain and cognitive task performance. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this piDLPFC region, and diffusion weighted imaging verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.

Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain.

Aberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a lateral aspect of the right dorsolateral prefrontal cortex (latDLPFC) in migraine patients. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this latDLPFC region, and diffusion weighted imaging (DWI) verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.

The mouse claustrum synaptically connects cortical network motifs.

Spatially distant areas of the cerebral cortex coordinate their activity into networks that are integral to cognitive processing. A common structural motif of cortical networks is co-activation of frontal and posterior cortical regions. The neural circuit mechanisms underlying such widespread inter-areal cortical coordination are unclear. Using a discovery based functional magnetic resonance imaging (fMRI) approach in mouse, we observe frontal and posterior cortical regions that demonstrate significant functional connectivity with the subcortical nucleus, the claustrum. Examining whether the claustrum synaptically supports such frontoposterior cortical network architecture, we observe cortico-claustro-cortical circuits reflecting the fMRI data: significant trans-claustral synaptic connectivity from frontal cortices to posteriorly lying sensory and sensory association cortices contralaterally. These data reveal discrete cortical pathways through the claustrum that are positioned to support cortical network motifs central to cognitive control functions and add to the canon of major extended cortico-subcortico-cortical systems in the mammalian brain.

Not just a hijack: Imaginary worlds can enhance individual and group-level fitness.

Why has fiction been so successful over time? We make the case that fiction may have properties that enhance both individual and group-level fitness by (a) allowing risk-free simulation of important scenarios, (b) effectively transmitting solutions to common problems, and (c) enhancing group cohesion through shared consumption of fictive worlds.

A role for the claustrum in cognitive control.

Early hypotheses of claustrum function were fueled by neuroanatomical data and yielded suggestions that the claustrum is involved in processes ranging from salience detection to multisensory integration for perceptual binding. While these hypotheses spurred useful investigations, incompatibilities inherent in these views must be reconciled to further conceptualize claustrum function amid a wealth of new data. Here, we review the varied models of claustrum function and synthesize them with developments in the field to produce a novel functional model: network instantiation in cognitive control (NICC). This model proposes that frontal cortices direct the claustrum to flexibly instantiate cortical networks to subserve cognitive control. We present literature support for this model and provide testable predictions arising from this conceptual framework.

Experimenters' sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor.

We show that the sex of human experimenters affects mouse behaviors and responses following administration of the rapid-acting antidepressant ketamine and its bioactive metabolite (2R,6R)-hydroxynorketamine. Mice showed aversion to the scent of male experimenters, preference for the scent of female experimenters and increased stress susceptibility when handled by male experimenters. This human-male-scent-induced aversion and stress susceptibility was mediated by the activation of corticotropin-releasing factor (CRF) neurons in the entorhinal cortex that project to hippocampal area CA1. Exposure to the scent of male experimenters before ketamine administration activated CA1-projecting entorhinal cortex CRF neurons, and activation of this CRF pathway modulated in vivo and in vitro antidepressant-like effects of ketamine. A better understanding of the specific and quantitative contributions of the sex of human experimenters to study outcomes in rodents may improve replicability between studies and, as we have shown, reveal biological and pharmacological mechanisms.

Illustrating routine outcomes monitoring at different points in a patient's journey: Inpatient then daypatient treatment of a patient with depressive and borderline symptoms.

Routine outcomes monitoring (ROM), combined with a psychotherapeutic intervention, can improve outcomes by assisting therapists in supporting patients who are off track to achieve a better treatment endpoint. While many ROM systems are suitable for particular clinical contexts, psychotherapy delivered in a hospital setting presents unique challenges. People can be treated as inpatients and daypatients, and psychotherapy may be delivered in multiple formats (e.g., closed and open groups; group and individual). The present case study will illustrate the adaptation of ROM to this environment with an 18-year-old woman with Borderline Personality Disorder. The patient was successfully treated with Dialectical Behavior Therapy as both an inpatient and daypatient. The case demonstrates the use of ROM systems and illustrate they are sufficiently flexible to accommodate these complexities of routine care.

(R)-Ketamine exerts antidepressant actions partly via conversion to (2R,6R)-hydroxynorketamine, while causing adverse effects at sub-anaesthetic doses.

BACKGROUND AND PURPOSE: (R)-Ketamine (arketamine) may have utility as a rapidly acting antidepressant. While (R)-ketamine has lower potency than (R,S)-ketamine to inhibit NMDA receptors in vitro, the extent to which (R)-ketamine shares the NMDA receptor-mediated adverse effects of (R,S)-ketamine in vivo has not been fully characterised. Furthermore, (R)-ketamine is metabolised to (2R,6R)-hydroxynorketamine (HNK), which may contribute to its antidepressant-relevant actions. EXPERIMENTAL APPROACH: Using mice, we compared (R)-ketamine with a deuterated form of the drug (6,6-dideutero-(R)-ketamine, (R)-d2 -ketamine), which hinders its metabolism to (2R,6R)-HNK, in behavioural tests predicting antidepressant responses. We also examined the actions of intracerebroventricularly infused (2R,6R)-HNK. Further, we quantified putative NMDA receptor inhibition-mediated adverse effects of (R)-ketamine. KEY RESULTS: (R)-d2 -Ketamine was identical to (R)-ketamine in binding to and functionally inhibiting NMDA receptors but hindered (R)-ketamine's metabolism to (2R,6R)-HNK. (R)-Ketamine exerted greater potency than (R)-d2 -ketamine in several antidepressant-sensitive behavioural measures, consistent with a role of (2R,6R)-HNK in the actions of (R)-ketamine. There were dose-dependent sustained antidepressant-relevant actions of (2R,6R)-HNK following intracerebroventricular administration. (R)-Ketamine exerted NMDA receptor inhibition-mediated behaviours similar to (R,S)-ketamine, including locomotor stimulation, conditioned-place preference, prepulse inhibition deficits, and motor incoordination, with approximately half the potency of the racemic drug. CONCLUSIONS AND IMPLICATIONS: Metabolism of (R)-ketamine to (2R,6R)-HNK increases the potency of (R)-ketamine to exert antidepressant-relevant actions in mice. Adverse effects of (R)-ketamine require higher doses than those necessary for antidepressant-sensitive behavioural changes in mice. However, our data revealing that (R)-ketamine's adverse effects are elicited at sub-anaesthetic doses indicate a potential risk for sensory dissociation and abuse liability.

Saving inventory - Revised: Psychometric performance across the lifespan.

BACKGROUND: The Saving Inventory - Revised (SI-R) is the most widely used self-report measure of hoarding symptom severity. The goal of this study is to establish a firm empirical basis for a cutoff score on the SI-R and to examine the functioning of the SI-R as a screening tool and indicator of hoarding symptom severity across the lifespan. METHODS: This study used archival data from 1,116 participants diagnosed with a clinical interview in 14 studies conducted by research groups who focus on hoarding. We used receiver operating characteristic (ROC) analysis and the Youden's J statistic to determine optimal cutoff scores for classifying participants who would be likely to receive a hoarding diagnosis. RESULTS: Overall, the discriminant performance of the SI-R Total score and each of the three subscales was high, confirming the status of the SI-R is an excellent screening tool for differentiating hoarding from non-hoarding cases. The optimal SI-R Total cutoff score is 39, although analyses suggested that older adults require a significantly lower cutoff and adults younger than 40 years require a significantly higher cutoff score. LIMITATIONS: The confidence interval around the optimal cutoff for the SI-R Total score for oldest age group was wide in comparison to those reported for the younger groups, creating more uncertainty around the optimal cutoff score for this group. CONCLUSIONS: This paper provides investigators and clinicians with the data necessary to select evidence-based cutoff scores on the SI-R that optimally suit their relative need for sensitivity and specificity in different age groups.

(2R,6R)-hydroxynorketamine exerts mGlu2 receptor-dependent antidepressant actions.

Currently approved antidepressant drugs often take months to take full effect, and ∼30% of depressed patients remain treatment resistant. In contrast, ketamine, when administered as a single subanesthetic dose, exerts rapid and sustained antidepressant actions. Preclinical studies indicate that the ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a rapid-acting antidepressant drug candidate with limited dissociation properties and abuse potential. We assessed the role of group II metabotropic glutamate receptor subtypes 2 (mGlu2) and 3 (mGlu3) in the antidepressant-relevant actions of (2R,6R)-HNK using behavioral, genetic, and pharmacological approaches as well as cortical quantitative EEG (qEEG) measurements in mice. Both ketamine and (2R,6R)-HNK prevented mGlu2/3 receptor agonist (LY379268)-induced body temperature increases in mice lacking the Grm3, but not Grm2, gene. This action was not replicated by NMDA receptor antagonists or a chemical variant of ketamine that limits metabolism to (2R,6R)-HNK. The antidepressant-relevant behavioral effects and 30- to 80-Hz qEEG oscillation (gamma-range) increases resultant from (2R,6R)-HNK administration were prevented by pretreatment with an mGlu2/3 receptor agonist and absent in mice lacking the Grm2, but not Grm3-/-, gene. Combined subeffective doses of the mGlu2/3 receptor antagonist LY341495 and (2R,6R)-HNK exerted synergistic increases on gamma oscillations and antidepressant-relevant behavioral actions. These findings highlight that (2R,6R)-HNK exerts antidepressant-relevant actions via a mechanism converging with mGlu2 receptor signaling and suggest enhanced cortical gamma oscillations as a marker of target engagement relevant to antidepressant efficacy. Moreover, these results support the use of (2R,6R)-HNK and inhibitors of mGlu2 receptor function in clinical trials for treatment-resistant depression either alone or in combination.

Monitoring and Follow-Up of High Radiation Dose Cases in Interventional Radiology.

RATIONALE AND OBJECTIVES: To assess the implementation of radiation dose monitoring software, create a process for clinical follow-up and documentation of high-dose cases, and quantify the number of patient reported radiation-induced tissue reactions in fluoroscopically guided interventional radiology (IR) and neuro-interventional radiology (NIR) procedures. MATERIALS AND METHODS: Web-based radiation dose monitoring software was installed at our institution and a process to flag all procedures with reference point air kerma (Ka,r) > 5000 mGy was implemented. The entrance skin dose was estimated and formal reports generated, allowing for physician-initiated clinical follow-up. To evaluate our process, we reviewed all IR and NIR procedures performed at our hospital over a 1-year period. For all procedures with Ka,r > 5000 mGy, retrospective medical chart review was performed to evaluate for patient reported tissue reactions. RESULTS: Three thousand five hundred eighty-two procedures were performed over the 1-year period. The software successfully transferred dose data on 3363 (93.9%) procedures. One thousand three hundred ninety-three (368 IR and 1025 NIR) procedures were further analyzed after excluding 2189 IR procedures with Ka,r < 2000 mGy. Ten of 368 (2.7%) IR and 52 of 1025 (5.1%) NIR procedures exceeded estimated skin doses of 5000 mGy. All 10 IR cases were abdominal/pelvic trauma angiograms with/without embolization; there were no reported tissue reactions. Of 52 NIR cases, 49 were interventions and 3 were diagnostic angiograms. Five of 49 (10.2%) NIR patients reported skin/hair injuries, all of which were temporary. CONCLUSION: Software monitoring and documentation of radiation dose in interventional procedures can be successfully implemented. Radiation-induced tissue reactions are relatively uncommon.

Cause of Cambrian Explosion - Terrestrial or Cosmic?

We review the salient evidence consistent with or predicted by the Hoyle-Wickramasinghe (H-W) thesis of Cometary (Cosmic) Biology. Much of this physical and biological evidence is multifactorial. One particular focus are the recent studies which date the emergence of the complex retroviruses of vertebrate lines at or just before the Cambrian Explosion of ∼500 Ma. Such viruses are known to be plausibly associated with major evolutionary genomic processes. We believe this coincidence is not fortuitous but is consistent with a key prediction of H-W theory whereby major extinction-diversification evolutionary boundaries coincide with virus-bearing cometary-bolide bombardment events. A second focus is the remarkable evolution of intelligent complexity (Cephalopods) culminating in the emergence of the Octopus. A third focus concerns the micro-organism fossil evidence contained within meteorites as well as the detection in the upper atmosphere of apparent incoming life-bearing particles from space. In our view the totality of the multifactorial data and critical analyses assembled by Fred Hoyle, Chandra Wickramasinghe and their many colleagues since the 1960s leads to a very plausible conclusion - life may have been seeded here on Earth by life-bearing comets as soon as conditions on Earth allowed it to flourish (about or just before 4.1 Billion years ago); and living organisms such as space-resistant and space-hardy bacteria, viruses, more complex eukaryotic cells, fertilised ova and seeds have been continuously delivered ever since to Earth so being one important driver of further terrestrial evolution which has resulted in considerable genetic diversity and which has led to the emergence of mankind.

APHAKIC PHACOEMULSIFICATION AND AUTOMATED ANTERIOR VITRECTOMY, AND POSTRETURN MONITORING OF A REHABILITATED HARBOR SEAL (PHOCA VITULINA RICHARDSI) PUP.

A female harbor seal pup rescued along the coast of San Diego on 13 June 2012 was diagnosed with bilateral mature cataracts, apparently congenital, in association with vitreal herniation in the anterior chamber of each eye. The cataracts were surgically removed on 1 August 2012 with single-port aphakic phacoemulsification and automated anterior vitrectomy. Postoperative monitoring during the next several weeks indicated that vision had been functionally repaired and that she could visually orient to and capture live fish in three different environments and in the presence of other animals. Consequently, we equipped the seal with a satellite-linked radio transmitter and returned her to the Pacific Ocean on 21 November 2012, and then monitored her movements until radio contact ended on 2 March 2013. She remained along the San Diego coast from 21 November until 5 December 2012 when she relocated to the Coronado Islands and remained there until 26 December. She then traveled directly to San Clemente Island and remained foraging in the near-shore kelp beds there through 2 March 2013, when radio contact ended. To our knowledge, this is the first published report of cataract treatment in a marine mammal using high-frequency ultrasound to emulsify the lenses followed by suction removal of the emulsified microfragments (i.e., phacoemulsification). Moreover, the rapid postoperative recovery of the seal and its quick acclimation, orientation, navigation, and foraging in marine habitats after return to the Pacific Ocean indicates that these surgical procedures can be safe and effective treatments for cataracts in seals, with substantially reduced postsurgical complications relative to other types of lens fragmentation and removal procedures.

Estimated skin dose look-up tables and their effect on dose awareness in the fluoroscopy-guided imaging suite.

OBJECTIVE: The displayed air kerma during a fluoroscopy-guided procedure often does not represent the entrance skin dose. The purpose of this work is to develop a system-specific air kerma-to-entrance skin dose look-up table (LUT) for immediate reference and to evaluate its clinical utility. MATERIALS AND METHODS: Physicists are often involved in retrospective dosimetry and risk estimates. Conservative dosimetry conversion factors, represented by the total conversion factor, prospectively estimate the maximum potential skin dose from the displayed air kerma. Air kerma-to-skin dose LUTs with corresponding tissue reactions and approximate time-of-onset can be posted for reference. By developing skin dose LUTs, physicians can actively evaluate during the procedure the potential for deterministic skin reactions. System user surveys evaluated the impact of LUTs on dose awareness. RESULTS: The range of the total conversion factor to the displayed air kerma for the nine systems evaluated was 0.8-1.6 for frontal x-ray tubes. Skin dose LUTs were posted in all imaging suites, and two surveys reported user feedback. Radiology technologists indicated that LUTs improved user dose awareness. Twelve of 14 physician respondents indicated an understanding that entrance skin dose is not equal to the displayed air kerma. CONCLUSION: Our efforts focused on educating fluoroscopy users about differences between displayed air kerma and the entrance skin dose while increasing dose awareness using an accessible and easy-to-understand tool. Skin dose LUTs provide physicians and staff an immediate reference for the maximum estimated entrance skin dose and the associated deterministic skin effects, allowing appropriate patient management.

Impact of incremental increase in CT image noise on detection of low-contrast hypodense liver lesions.

RATIONALE AND OBJECTIVES: To determine the impact of incremental increases in computed tomography (CT) image noise on detection of low-contrast hypodense liver lesions. MATERIAL AND METHODS: We studied 50 CT examinations acquired at image noise index (NI) of 15 and hypodense liver lesions and 50 examinations with no lesions. Validation of a noise addition tool to be used in the evaluation of the CT examinations was performed with a liver phantom. Using this tool, three 100-image sets were assembled: an NI of 17.4 (simulating 75% of the original patient radiation dose), 21.2 (simulating 50% dose), and 29.7 (simulating 25%). Three readers scored certainty of lesion presence using a five-point Likert scale. RESULTS: For original images (NI 15) plus images with NI of 17.4 and 21.2, sensitivity was >90% threshold (range, 95%-98%). For images with NI of 29.7, sensitivity was just below the threshold (89%). Reader Az values for receiver operating characteristic curves were good for original, NI 17.4, and NI 21.2 images (0.976, 0.973, and 0.96, respectively). For NI of 29.7, the Az decreased to 0.913. Detection sensitivity was <90% for both lesion size < 10 mm (85%) and lesion-to-liver contrast <60 Hounsfield units (85%) only at NI 29.7. CONCLUSIONS: For low-contrast lesion detection in liver CT, image noise can be increased up to NI 21.2 (a 50% patient radiation dose reduction) without substantial reduction in sensitivity.

Genomic evolution and polymorphism: segmental duplications and haplotypes at 108 regions on 21 chromosomes.

We describe here extensive, previously unknown, genomic polymorphism in 120 regions, covering 19 autosomes and both sex chromosomes. Each contains duplication within multigene clusters. Of these, 108 are extremely polymorphic with multiple haplotypes. We used the genomic matching technique (GMT), previously used to characterise the major histocompatibility complex (MHC) and regulators of complement activation (RCA). This genome-wide extension of this technique enables the examination of many underlying cis, trans and epistatic interactions responsible for phenotypic differences especially in relation to individuality, evolution and disease susceptibility. The extent of the diversity could not have been predicted and suggests a new model of primate evolution based on conservation of polymorphism rather than de novo mutation.

Radiation-induced complications in endovascular neurosurgery: incidence of skin effects and the feasibility of estimating risk of future tumor formation.

BACKGROUND: The incidence of radiation-induced complications is increasingly part of the informed consent process for patients undergoing neuroendovascular procedures. Data guiding these discussions in the era of modern radiation-minimizing equipment is lacking. OBJECTIVE: To quantify the rates of skin and hair effects at a modern high-volume neurovascular center, and to assess the feasibility of accurately quantifying the risk of future central nervous system (CNS) tumor formation. METHODS: We reviewed a prospectively collected database of endovascular procedures performed at our institution in 2008. The entrance skin dose and brain dose were calculated. Patients receiving skin doses >2 Gy were contacted to inquire about skin and hair changes. We reviewed several recent publications from leading radiation physics bodies to evaluate the feasibility of accurately predicting future cancer risk from neurointerventional procedures. RESULTS: Seven hundred two procedures were included in the study. Of the patients receiving >2 Gy, 39.6% reported subacute skin or hair changes following their procedure, of which 30% were permanent. Increasing skin dose was significantly associated with permanent hair loss. We found substantial methodological difficulties in attempting to model the risk of future CNS tumor formation given the gaps in our current understanding of the brain's susceptibility to low-dose ionizing radiation. CONCLUSION: Radiation exposures exceeding 2 Gy are common in interventional neuroradiology despite modern radiation-minimizing technology. The incidence of side effects approaches 40%, although the majority is self-limiting. Gaps in current models of brain tumor formation after exposure to radiation preclude accurately quantifying the risk of future CNS tumor formation.