Neural correlates of the LSD experience revealed by multimodal neuroimaging

Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD’s marked effects on the visual cortex did not significantly correlate with the drug’s other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of “ego-dissolution” and “altered meaning,” implying the importance of this particular circuit for the maintenance of “self” or “ego” and its processing of “meaning.” Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.Lysergic acid diethylamide (LSD) is a potent serotonergic hallucinogen or “psychedelic” that alters consciousness in a profound and characteristic way. First synthesized in 1938, its extraordinary psychological properties were not discovered until 1943 (1). LSD would go on to have a major effect on psychology and psychiatry in the 1950s and 1960s; however, increasing recreational use and its influence on youth culture provoked the drug’s being made illegal in the late 1960s. As a consequence, human research with LSD has been on pause for half a century. However, inspired by a revival of research with other psychedelics, such as psilocybin and ayahuasca, a small number of new reports on the psychological effects of LSD have recently been published (2–6).LSD has a high affinity for a range of different neurotransmitter receptors, but its characteristic psychological effects are thought to be mediated by serotonin 2A receptor (5-HT_2AR) agonism (7). Previous neurophysiological research with LSD is limited to electroencephalography (EEG) studies in the 1950s and 1960s. These reported reductions in oscillatory power, predominantly in the lower-frequency bands, and an increase in the frequency of alpha rhythms (8). Broadband decreases in cortical oscillatory power have been observed in modern EEG and magnetoencephalography (MEG) studies with psilocybin (9, 10), with EEG and the dimethyltryptamine-containing brew “ayahuasca” (11), and with rodent brain local-field potential recordings and a range of different 5-HT_2AR agonists (12–14).The effects of psychedelics (other than LSD) on human brain activity have also previously been investigated with positron emission tomography (PET) (15) and functional magnetic resonance imaging (fMRI) (16). fMRI studies with psilocybin revealed decreased cerebral blood flow (CBF) and blood oxygen level-dependent (BOLD) signal in connector hubs (16), decreased resting state functional connectivity (RSFC) in major resting state networks (RSNs) such as the default-mode network (DMN) (17), and the emergence of novel patterns of communication (18, 19), whereas increased cortical glucose metabolism was found with PET (15). Notably, the spatial locations of the PET-, fMRI-, EEG-, and MEG-measured effects of psychedelics are relatively consistent; for example, high-level cortical regions, such as the posterior cingulate cortex (PCC), and some of the principal effects of psilocybin revealed by fMRI (e.g., decreased DMN RSFC) were recently replicated by a separate team working with ayahuasca (20).Consistent with a prior hypothesis (17), these studies suggest that an “entropic” effect on cortical activity is a key characteristic of the psychedelic state. However, a putative excitation of hippocampal/parahippocampal gyri activity has also been observed with fMRI and psychedelics in humans (19) and animals (14). Moreover, depth EEG studies in the 1950s reported activations in medial temporal lobe regions during psychosis-like states under LSD and other psychedelics (21, 22). Further, patients with epilepsy with resection of the medial temporal lobes showed attenuated LSD effects postsurgery (23), and electrical stimulation of medial temporal lobe circuitry produces visual hallucinations of somewhat similar nature to those produced by psychedelics [e.g., distorted visual perception (24) and dreamlike “visions” (25)].The present study sought to investigate the acute brain effects of LSD in healthy volunteers, using a comprehensive placebo-controlled neuroimaging design incorporating ASL, BOLD signal measures, and MEG resting state scans. It was predicted that major RSNs (e.g., the DMN) and hippocampal/parahippocampal gyri circuitry would be implicated in the drug’s mechanism of action.Twenty healthy participants attended two scanning days (LSD and placebo) at least 2 wk apart in a balanced-order, within-subjects design. Sessions included an fMRI followed by a MEG scan, each lasting 75 min. Data were acquired during eye-closed, task-free, “resting state” conditions. Drug/placebo were administered in solution and injected i.v. over the course of 2 min. Two resting state ASL scans totaling 16 min were completed 100 min after i.v. administration of LSD (75 µg in 10 mL saline) or placebo (10 mL saline), corresponding to the initial phase of the peak subjective effects of LSD (peak effects were reached ∼120–150 min postinfusion). Two resting state BOLD scans totaling 14 min were completed 135 min postinfusion, and two resting state MEG scans totaling 14 min were completed 225 min postinfusion. All analyses applied multiple comparison correction (SI Appendix) and two-tailed hypothesis testing unless particularly strong prior hypotheses were held.     

Soluble kit receptor in human serum

c-kit encodes the transmembrane receptor tyrosine kinase (Kit) for the recently described ligand stem cell factor (SCF). We have developed an enzyme-linked immunosorbent assay for measuring soluble human Kit and we have used the assay to show high levels of soluble Kit in human serum. The distribution of soluble Kit levels was investigated among 112 normal human serum donors. The mean serum level (+/- SD) was found to be 324 +/- 105 ng/mL with the values falling between 163 ng/mL and 788 ng/mL. No correlation between soluble Kit levels and the sexes or ages of the donors was found. Partial purification using immunoaffinity chromatography allowed us to characterize the soluble Kit from pooled human serum. Antibodies generated to a 497-amino acid recombinant human soluble Kit corresponding to the N-terminal extracellular domain of the receptor recognized the serum-derived soluble Kit by immunoblotting. We found that the serum-derived soluble Kit is glycosylated, with mostly N- linked but also O-linked carbohydrate, and with terminal sialic acid residues. When compared with the recombinant human soluble Kit, the serum-derived material was similar both in size and glycosylation pattern. CNBr cleavage of the isolated serum-derived material followed by amino terminal sequencing confirmed the presence of five peptides expected for the extracellular portion of the Kit molecule. The immunoaffinity purified serum-derived soluble Kit inhibited binding of [125I]SCF to membrane-bound receptor in an in vitro assay. These results indicate that soluble Kit could modulate the activity and functions of SCF in vivo.     

An update on lower urinary tract tuberculosis

Tuberculosis of the genitourinary tract presents with atypical manifestations. Only 20% to 30% of patients with genitourinary tuberculosis have a history of pulmonary infection. Tuberculosis often affects the lower genitourinary system rather than the kidney. Tuberculosis of the lower genitourinary tract most commonly affects the epididymis and the testis, followed by bladder, ureter, prostate, and penis. Use of bacillus Calmette-Guérin therapy for bladder cancer can cause symptomatic tubercular infections of the lower genitourinary tract. Tuberculosis of the lower genitourinary tract can present with irritative voiding symptoms, hematuria, epididymo-orchitis, prostatitis, and fistulas. Tuberculosis of the seminal vesicles, vas, fallopian tubes, and the uterus can cause infertility. Urinalysis may demonstrate sterile pyuria, hematuria, or albuminuria. Identification of acid-fast bacilli in culture or tissue or by polymerase chain reaction studies is diagnostic. Medical treatment may not result in resolution of symptoms. Surgical intervention and reconstruction of the urinary tract are frequently indicated.     

Reduced tocopherol content of B cells from patients with chronic lymphocytic leukemia

The tocopherol content of lymphocytes, erythrocytes, and plasma from patients with chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), and normal subjects was measured by a sensitive high performance liquid chromatographic method. Lymphocytes from patients with CLL had lower values of tocopherol (1.7 +/- 1.0 micrograms/10(9) cells) than lymphocytes from normal subjects (3.8 +/- 0.7 micrograms/10(9) cells). Mononuclear cells from patients with HCL had an increased tocopherol content of 6.2 +/- 1.0 micrograms/10(9) cells. Subfractionation of the lymphocytes from patients with CLL into T- and B-cell subgroups showed that the tocopherol content of T cells was the same as in normal subjects (4.1 +/- 0.5 micrograms/10(9) cells versus 3.5 +/- 1.2), but that the tocopherol content of the B cells was markedly reduced compared to normals (2.6 +/- 1.0 versus 6.0 +/- 1.3).     

Stereological evaluation of Sertoli cell ontogeny during fetal and neonatal life in two diverse breeds of swine

Chinese Meishan (MS) boars have smaller testes due to fewer Sertoli cells compared with White Composite (WC) boars. The objective was to describe Sertoli cell development relative to circulating FSH concentrations in fetal and neonatal MS and WC boars. Testes and blood samples were collected on days 60, 75, 90 and 105 postcoitum (dpc) and 1, 7, 14 and 25 postpartum (dpp). One testis was immunostained for GATA4 or Ki67 antigen to evaluate total and proliferating Sertoli cell numbers respectively. Testicular size was greater (P<0.01) in WC than MS boars at all ages, associated with a greater mass of interstitial tIssue. Tubular mass (P<0.01) was greater in prenatal WC boars, but postnatally increased more rapidly (P<0.001) in MS boars, exceeding WC boars by 25 dpp. Sertoli cell numbers increased with age, was greater (P<0.001) in WC than MS boars during prenatal development but increased rapidly (P<0.01) by 1 dpp in MS and thereafter was similar in both breeds. The proportion of Ki67-positive Sertoli cells was maximal at 90 dpc, declining thereafter, did not differ between breeds through 7 dpp, but was greater (P<0.05) in WC than MS boars at 14 and 25 dpp. Plasma FSH concentrations were greater (P<0.05) in WC than MS boars at 75 dpc. FSH concentrations were elevated at 105 dpc (MS) and 1 dpp (WC) but declined thereafter with advancing postnatal age in both breeds. This study illustrates that late gestation represents the period of maximal Sertoli cell proliferation. Despite asynchronous Sertoli cell population growth between breeds during early postnatal life, differential mature Sertoli cell numbers and testicular size are probably due to differences in duration of the proliferative period after 25 dpp, potentially regulated by Sertoli cell maturation and blood-testis barrier formation. These events were not associated with fetal or early postnatal changes in FSH secretion.     

The role of hypoxia in the maintenance of hematopoietic stem cells

Bone marrow cell liquid cultures were incubated at various oxygen concentrations ranging from 0% to 18% (air). The total number of cells in culture (CT) at the end of a 6-day incubation was found to be directly proportional to the oxygen concentration. As compared with air- incubated controls, cells recovered from severely hypoxic (1% oxygen) day-5 liquid cultures showed (1) the same day-7 colony-formation efficiency in semisolid culture (neutrophilic/monocytic colonies) or in spleen; (2) a higher day-14 spleen colony-formation efficiency; (3) an enhanced radio-protection ability; and (4) an increased marrow repopulation ability, as measured by determining either total cell number in recipient marrow MRAcell, or the capacity of the latter of generating day-7 neutrophilic/monocytic colonies in secondary in vitro assays (MRACFU-NM). Taking into account CT, the absolute numbers of progenitors in culture were also computed. The results showed that, with respect to time 0, incubation in air produced an increase in the number of day-7 CFUs and a decrease in the number of the other progenitors, whereas in hypoxic cultures all types of progenitors decreased. However, as compared with air-incubated controls, all progenitors, except cells sustaining MRACFU-NM, were reduced in hypoxic cultures. The degree of reduction paralleled the position of the progenitor in the hematopoietic hierarchy, being maximum for day-7 CFUs and null for cells sustaining MRACFU-NM, which, in fact, were better preserved in hypoxic cultures.     

Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats

Background: There has been some difficulty getting standard laboratory rats to voluntarily consume large amounts of ethanol without the use of initiation procedures. It has previously been shown that standard laboratory rats will voluntarily consume high levels of ethanol if given intermittent‐access to 20% ethanol in a 2‐bottle‐choice setting [ Wise, Psychopharmacologia 29 (1973), 203 ]. In this study, we have further characterized this drinking model. Methods: Ethanol‐naïve Long–Evans rats were given intermittent‐access to 20% ethanol (three 24‐hour sessions per week). No sucrose fading was needed and water was always available ad libitum. Ethanol consumption, preference, and long‐term drinking behaviors were investigated. Furthermore, to pharmacologically validate the intermittent‐access 20% ethanol drinking paradigm, the efficacy of acamprosate and naltrexone in decreasing ethanol consumption were compared with those of groups given continuous‐access to 10 or 20% ethanol, respectively. Additionally, ethanol consumption was investigated in Wistar and out‐bred alcohol preferring (P) rats following intermittent‐access to 20% ethanol. Results: The intermittent‐access 20% ethanol 2‐bottle‐choice drinking paradigm led standard laboratory rats to escalate their ethanol intake over the first 5 to 6 drinking sessions, reaching stable baseline consumption of high amounts of ethanol (Long–Evans: 5.1 ± 0.6; Wistar: 5.8 ± 0.8 g/kg/24 h, respectively). Furthermore, the cycles of excessive drinking and abstinence led to an increase in ethanol preference and increased efficacy of both acamprosate and naltrexone in Long–Evans rats. P‐rats initiate drinking at a higher level than both Long–Evans and Wistar rats using the intermittent‐access 20% ethanol paradigm and showed a trend toward a further escalation in ethanol intake over time (mean ethanol intake: 6.3 ± 0.8 g/kg/24 h). Conclusion: Standard laboratory rats will voluntarily consume ethanol using the intermittent‐access 20% ethanol drinking paradigm without the use of any initiation procedures. This model promises to be a valuable tool in the alcohol research field.