Insular Stimulation Produces Mental Clarity and Bliss.

For the first time, an ecstatic aura has been evoked through the electrical stimulation of the dorsal anterior insula during presurgical invasive intracerebral monitoring in a patient who did not suffer from an ecstatic form of epilepsy. This case provides more evidence that the anterior insula is the major generator of such a mystical-type experience even in individuals with no underlying brain network changes related to a preexisting ecstatic epilepsy. ANN NEUROL 2022;91:289-292.

Exercise-induced euphoria and anxiolysis do not depend on endogenous opioids in humans.

A runner's high describes a sense of well-being during endurance exercise characterized by euphoria and anxiolysis. It has been a widespread belief that the release of endogenous opioids, such as endorphins, underlie a runner's high. However, exercise leads to the release of two classes of rewarding molecules, endocannabinoids (eCBs) and opioids. In mice, we have shown that core features of a runner's high depend on cannabinoid receptors but not opioid receptors. In the present study, we aimed to corroborate in humans that endorphins do not play a significant role in the underlying mechanism of a runner's high. Thus, we investigated whether the development of two core features of a runner's high, euphoria and reduced anxiety levels, depend on opioid signaling by using the opioid receptor antagonist naltrexone (NAL) in a double-blind, randomized, placebo (PLA)-controlled experiment. Participants (N = 63) exhibited increased euphoria and decreased anxiety after 45 min of running (RUN) on a treadmill in a moderate-intensity range compared to walking (WALK). RUN led to higher plasma levels of the eCBs anandamide (AEA) and 2-arachidonoglycerol (2-AG). Opioid blockade did not prevent the development of euphoria and reduced anxiety as well as elevation of eCB levels following exercise. Moreover, the fraction of participants reporting a subjective runner's high was comparable in the NAL and PLA-treated group. Therefore, this study indicates that the development of a runner's high does not depend on opioid signaling in humans, but makes eCBs strong candidates in humans, as previously shown in mice.

Provider Perspectives of Battlefield Acupuncture: Advantages, Disadvantages and Its Potential Role in Reducing Opioid Use for Pain.

OBJECTIVES: Nonpharmacological options to treat pain are in demand, in part to address the opioid crisis. One such option is acupuncture. Battlefield acupuncture (BFA) is an auricular needling protocol currently used to treat pain in the Veterans Health Administration. We aimed to identify the advantages and disadvantages of BFA from providers' perspectives. METHODS: We rely on an inductive qualitative approach to explore provider perceptions through thematic analysis of semistructured interviews with 43 BFA providers across the nation. RESULTS: We identified the following themes. Disadvantages included: (1) clinical guidelines are insufficient; (2) patients often request multiple BFA visits from providers; (3) BFA can be uncomfortable; (4) BFA may not be an effective treatment option unless it can be provided "on demand"; and (5) BFA can promote euphoria, which can have deleterious consequences for patient self-care. Perceived advantages included: (1) BFA can simultaneously effectively control pain while reducing opioid use; (2) BFA may alleviate the pain that has been unsuccessfully treated by conventional methods; (3) BFA gives providers a treatment option to offer patients with substance use disorder; (4) BFA helps build a trusting patient-provider relationship; (5) BFA can create the opportunity for hope. CONCLUSIONS: Providers perceive BFA to have many benefits, both clinical and relational, including ways in which it may have utility in addressing the current opioid crisis. BFA is easy to deliver and has potential clinical and relational utility. Efforts to better understand effectiveness are warranted.

In an exploratory randomized, double-blind, placebo-controlled, cross-over study, psychoactive doses of intravenous delta-9-tetrahydrocannabinol fail to produce antinociceptive effects in healthy human volunteers.

RATIONALE: Animal studies and anecdotal human reports suggest that cannabinoids have antinociceptive effects. Controlled human studies have produced mixed results. OBJECTIVES: We sought to reduce existing variability by investigating the effects of intravenous delta-9-tetrahydrocannabinol (THC) in several pain paradigms within the same human subjects, addressing some of the limitations to the published literature. METHODS: In this exploratory randomized, double-blind, placebo-controlled, cross-over study, healthy human subjects received 0.01 mg/kg or 0.03 mg/kg intravenous THC or placebo (ethanol vehicle) infused over 10 min on three test days, each separated by at least 72 h. Capsaicin (250 µg) was injected intradermally to induce chemical pain and hyperalgesia. Four other forms of acute pain were induced: mechanical (von Frey filament), hot and cold (thermode), and electrical (pulse generator). Pain ratings were obtained before drug administration, at peak drug effects, and 2 h after drug administration and included both objective and subjective measures. THC drug effects and vital signs were also collected during experimental sessions. Nonparametric analysis with repeated measures was performed. RESULTS: THC induced euphoria, perceptual and cognitive alterations, and tachycardia in a dose-related manner, but failed to have significant effects in experimentally induced acute chemical, mechanical, thermal, or electrical pain and capsaicin-induced hyperalgesia. CONCLUSIONS: In this exploratory controlled study, intravenous THC lacked significant antinociceptive properties in experimental models of acute pain and capsaicin-induced hyperalgesia in healthy human subjects. Continued study of THC and other cannabinoids through high-quality, controlled studies in both healthy volunteers and patients with pain conditions is warranted to inform the growing demand for the clinical application of cannabinoids in pain management.

Subjective responses to amphetamine in young adults with previous mood elevation experiences.

RATIONALE: One risk factor for alcohol and substance misuse is hypomanic experiences, or periods of mood elevation. Young people who report hypomanic states are more likely to develop bipolar disorder (BP), and BP and other mood disorders increase the risk of addiction. We recently reported that young adults with a history of mood elevation experience less subjective effects from a low dose of alcohol, which may be predictive of future alcohol use. The finding with alcohol raised the question of whether this dampened response to a drug also applies to other drugs, such as amphetamine. OBJECTIVE: This study assessed responses of d-amphetamine in healthy young adults with varying experiences of mood elevation, as measured by the Mood Disorders Questionnaire (MDQ). METHODS: Healthy 18-19-year-olds (N = 30) with a range of MDQ scores participated in three 4-h laboratory sessions in which they received placebo, 10 mg, or 20 mg d-amphetamine. They completed mood questionnaires and cardiovascular measures. RESULTS: Individuals with higher MDQ scores reported less stimulation and euphoria after 10 mg, but not 20 mg, d-amphetamine, than individuals with lower scores. MDQ scores were not related to cardiovascular responses to the drug. CONCLUSIONS: A history of mood elevation experiences or hypomania states is related to dampened response to a low dose of a psychostimulant drug, extending previous findings with dampened response to alcohol. This phenotype for mood disorders of dampened responses to drugs may contribute to risk for subsequent drug use or misuse.

The Transcriptional Signature of a Runner's High.

INTRODUCTION: Endorphins, endocannabinoids, monoamines, and neurotrophins have all been implicated in the euphoric response to endurance running, known as a runner's high (RH). The epitranscriptional mechanisms regulating this effect have not been defined. Here, we investigate peripheral micro-ribonucleic acid (miRNA) changes unique to athletes experiencing postrun euphoria, yielding insights into gene networks that control an RH. METHODS: A cohort study involving 25 collegiate runners (48% females, age = 20 ± 1 yr) examined salivary RNA levels before and after a long-distance run. Participants were divided into RH and nonrunner's high (NRH) groups based on surveys of four criteria (mood, lost sense of time, run quality, and euphoria). Physiological measures were also recorded (temperature, heart rate, blood pressure, pupillary dilatation, and salivary serotonin). Levels of miRNAs and their messenger RNA targets were compared across pre- and postrun samples from RH and NRH groups with two-way ANOVA. Representation of opioid, gamma-aminobutyic acid (GABA), endocannabinoid, neurotrophin, serotonergic, and dopaminergic pathways was assessed in DIANA miRPath. Pearson's correlation analyses examined relationships between miRNAs and RH indices. RESULTS: RH participants (n = 13) demonstrated postrun mydriasis (P = 0.046) and hypothermia (P = 0.043) relative to NRH participants (n = 12) but had no difference in serotonin dynamics (P = 0.88). Six miRNAs (miR-194-5p, miR-4676-3p, miR-4254, miR-4425, miR-1273-3p, miR-6743-5p) exhibited significant effects (false discovery rate P value < 0.05) across pre- or postrun and RH/NRH groups. These miRNAs displayed target enrichment for opioid (P = 2.74E-06) and GABA (P = 0.00016) pathways. miR-1237-3p levels were related with lost sense of time (R = 0.40). Mitogen-activated protein kinase (MAPK11), an endocannabinoid target of miR-1273-3p, was nominally elevated in RH participants (false discovery rate P value = 0.11). CONCLUSIONS: Unique dynamics in miRNA concentration occur in athletes with subjective/objective evidence of RH, targeting genes implicated endorphin, endocannabinoid, and GABAergic signaling.

Pediatric Mania: The Controversy between Euphoria and Irritability.

Pediatric Bipolar Disorder (BD) is a highly morbid pediatric psychiatric disease, consistently associated with family psychiatric history of mood disorders and associated with high levels of morbidity and disability and with a great risk of suicide. While there is a general consensus on the symptomatology of depression in childhood, the phenomenology of pediatric mania is still highly debated and the course and long-term outcome of pediatric BD still need to be clarified. We reviewed the available studies on the phenomenology of pediatric mania with the aim of summarizing the prevalence, demographics, clinical correlates and course of these two types of pediatric mania. Eighteen studies reported the number of subjects presenting with either irritable or elated mood during mania. Irritability has been reported to be the most frequent clinical feature of pediatric mania reaching a sensitivity of 95-100% in several samples. Only half the studies reviewed reported on number of episodes or cycling patterns and the described course was mostly chronic and ultra-rapid whereas the classical episodic presentation was less common. Few long-term outcome studies have reported a diagnostic stability of mania from childhood to young adult age. Future research should focus on the heterogeneity of irritability aiming at differentiating distinct subtypes of pediatric psychiatric disorders with distinct phenomenology, course, outcome and biomarkers. Longitudinal studies of samples attending to mood presentation, irritable versus elated, and course, chronic versus episodic, may help clarify whether these are meaningful distinctions in the course, treatment and outcome of pediatric onset bipolar disorder.

The evolution of extreme cooperation via shared dysphoric experiences.

Willingness to lay down one's life for a group of non-kin, well documented historically and ethnographically, represents an evolutionary puzzle. Building on research in social psychology, we develop a mathematical model showing how conditioning cooperation on previous shared experience can allow individually costly pro-group behavior to evolve. The model generates a series of predictions that we then test empirically in a range of special sample populations (including military veterans, college fraternity/sorority members, football fans, martial arts practitioners, and twins). Our empirical results show that sharing painful experiences produces "identity fusion" - a visceral sense of oneness - which in turn can motivate self-sacrifice, including willingness to fight and die for the group. Practically, our account of how shared dysphoric experiences produce identity fusion helps us better understand such pressing social issues as suicide terrorism, holy wars, sectarian violence, gang-related violence, and other forms of intergroup conflict.

Neuropsychiatric syndromes of multiple sclerosis.

Neuropsychiatric signs and symptoms occur frequently in individuals with multiple sclerosis (MS), either as the initial presenting complaint prior to a definitive neurological diagnosis or more commonly with disease progression. However, the pathogenesis of these comorbid conditions remains unclear and it remains difficult to accurately elucidate if neuropsychiatric symptoms or conditions are indicators of MS illness severity. Furthermore, both the disease process and the treatments of MS can adversely impact an individual's mental health. In this review, we discuss the common neuropsychiatric syndromes that occur in MS and describe the clinical symptoms, aetiology, neuroimaging findings and management strategies for these conditions.

Left medial orbitofrontal cortex volume correlates with skydive-elicited euphoric experience.

The medial orbitofrontal cortex has been linked to the experience of positive affect. Greater medial orbitofrontal cortex volume is associated with greater expression of positive affect and reduced medial orbital frontal cortex volume is associated with blunted positive affect. However, little is known about the experience of euphoria, or extreme joy, and how this state may relate to variability in medial orbitofrontal cortex structure. To test the hypothesis that variability in euphoric experience correlates with the volume of the medial orbitofrontal cortex, we measured individuals' (N = 31) level of self-reported euphoria in response to a highly anticipated first time skydive and measured orbitofrontal cortical volumes with structural magnetic resonance imaging. Skydiving elicited a large increase in self-reported euphoria. Participants' euphoric experience was predicted by the volume of their left medial orbitofrontal cortex such that, the greater the volume, the greater the euphoria. Further analyses indicated that the left medial orbitofrontal cortex and amygdalo-hippocampal complex independently explain variability in euphoric experience and that medial orbitofrontal cortex volume, in conjunction with other structures within the mOFC-centered corticolimbic circuit, can be used to predict individuals' euphoric experience.

Segregation of information about emotional arousal and valence in horse whinnies.

Studying vocal correlates of emotions is important to provide a better understanding of the evolution of emotion expression through cross-species comparisons. Emotions are composed of two main dimensions: emotional arousal (calm versus excited) and valence (negative versus positive). These two dimensions could be encoded in different vocal parameters (segregation of information) or in the same parameters, inducing a trade-off between cues indicating emotional arousal and valence. We investigated these two hypotheses in horses. We placed horses in five situations eliciting several arousal levels and positive as well as negative valence. Physiological and behavioral measures collected during the tests suggested the presence of different underlying emotions. First, using detailed vocal analyses, we discovered that all whinnies contained two fundamental frequencies ("F0" and "G0"), which were not harmonically related, suggesting biphonation. Second, we found that F0 and the energy spectrum encoded arousal, while G0 and whinny duration encoded valence. Our results show that cues to emotional arousal and valence are segregated in different, relatively independent parameters of horse whinnies. Most of the emotion-related changes to vocalizations that we observed are similar to those observed in humans and other species, suggesting that vocal expression of emotions has been conserved throughout evolution.

GC-MS-based plasma metabolomic investigations of morphine dependent rats at different states of euphoria, tolerance and naloxone-precipitated withdrawal.

Long-term or excessive application of morphine leads to tolerance and addiction, which hindered its conventional applications as a drug. Although tremendous progress has been made on the mechanisms of morphine, crucial evidence elaborating the neurobiological basis of tolerance and dependence is still lacking. To further explore the physiological adaptions during morphine's application, a systematic screening of small molecules in blood has been carried out. The plasma of morphine dependent rats was collected at different time points with or without naloxone treatment, and was analyzed by gas chromatography-mass spectrometry (GC-MS). Partial least squares discriminate analysis (PLS-DA) and the Student's t Tests with the false discovery rate (FDR) correction were conducted on the normalized data for the distinction of groups and the identification of the most contributed metabolites. Clear separation is observed between different treatments, and 29 out of 41 metabolites changes significantly compared with the corresponding controls. The concentration of threonine, glycine, serine, beta-d-glucose and oxalic acid are consistently changed in all morphine treated groups compared with controls. Through this experiment we find characteristic metabolites in different dependent states and discuss the possible compensation effects. The interpretation of these metabolites would throw light on the biological effects of morphine and reveal the possibilities to become marker of morphine addiction.

Changing definitions of euphoria in multiple sclerosis: A short report.

A recent interest in euphoria in multiple sclerosis (MS) has resulted in a wealth of literature on this topic. However, a marked change in the definition of this symptom appears to have taken place since its first descriptions in the mid-19(th) century. This short report will demonstrate that the 'euphoria' being studied today may not be the same state as that originally observed and described in MS patients and some implications of this possibility are discussed.

Smile without euphoria induced by deep brain stimulation: a case report.

Poststroke central pain (PSCP) can be a debilitating medication-refractory disorder. We report a single case where right unilateral ventral capsule/ventral striatum (VC/VS) deep brain stimulation was used to treat PSCP and inadvertently induced a smile without euphoria. The patient was a 69 year-old woman who had a stroke with resultant dysesthesia and allodynia in her left hemibody and also a painful left hemibody dystonia. In her case, VC/VS stimulation induced a smile phenomenon, but without a euphoric sensation. This phenomenon was different from the typical smile responses we have observed in obsessive-compulsive disorder cases. This difference was considered to be possibly attributable to impairment in the emotional smile pathway.

Neuronal oscillations and functional interactions between resting state networks.

Functional magnetic imaging (fMRI) studies showed that resting state activity in the healthy brain is organized into multiple large-scale networks encompassing distant regions. A key finding of resting state fMRI studies is the anti-correlation typically observed between the dorsal attention network (DAN) and the default mode network (DMN), which - during task performance - are activated and deactivated, respectively. Previous studies have suggested that alcohol administration modulates the balance of activation/deactivation in brain networks, as well as it induces significant changes in oscillatory activity measured by electroencephalography (EEG). However, our knowledge of alcohol-induced changes in band-limited EEG power and their potential link with the functional interactions between DAN and DMN is still very limited. Here we address this issue, examining the neuronal effects of alcohol administration during resting state by using simultaneous EEG-fMRI. Our findings show increased EEG power in the theta frequency band (4-8 Hz) after administration of alcohol compared to placebo, which was prominent over the frontal cortex. More interestingly, increased frontal tonic EEG activity in this band was associated with greater anti-correlation between the DAN and the frontal component of the DMN. Furthermore, EEG theta power and DAN-DMN anti-correlation were relatively greater in subjects who reported a feeling of euphoria after alcohol administration, which may result from a diminished inhibition exerted by the prefrontal cortex. Overall, our findings suggest that slow brain rhythms are responsible for dynamic functional interactions between brain networks. They also confirm the applicability and potential usefulness of EEG-fMRI for central nervous system drug research.

Amphetamine induced dopamine release increases anxiety in individuals recovered from anorexia nervosa.

OBJECTIVE: Genetic, pharmacologic, and physiological data suggest that individuals with anorexia nervosa (AN) have altered striatal dopamine (DA) function. METHOD: We used an amphetamine challenge and positron emission tomography [(11) C]raclopride paradigm to explore DA striatal transmission in 10 recovered (REC) AN compared with 9 control women (CW). RESULTS: REC AN and CW were similar for baseline, postamphetamine [(11) C]raclopride binding potential (BP(ND) ) and change (Δ) in BP(ND) for all regions. In CW, ventral striatum Δ BP(ND) was associated with euphoria (r = -0.76; p = 0.03), which was not found for REC AN. Instead, REC AN showed a significant relationship between anxiety and Δ BP(ND) in the precommissural dorsal caudate (r = -0.62, p = 0.05). DISCUSSION: REC AN have a positive association between endogenous DA release and anxiety in the dorsal caudate. This finding could explain why food-related DA release produces anxiety in AN, whereas feeding is pleasurable in healthy participants.

Behavioral evidence for the significance of serotoninergic (5-HT) receptors in cocaine addiction.

Cocaine addiction has somatic, psychological, psychiatric, socio-economic and legal implications in the developed world. Presently, there is no medication approved for the treatment of cocaine addiction. In recent years, data from the literature (pre-clinical studies and clinical trials) have provided several lines of evidence that serotonin (5-HT) and 5-HT receptors play a modulatory role in the mechanisms of action of cocaine. Here we review the contribution of 5-HT receptor subtypes to cocaine sensitization, discrimination, conditioned place preference, self-administration, reinstatement of seeking behavior and withdrawal symptoms in laboratory animals. Additionally, the consequences of chronic cocaine exposure on particular 5-HT receptor-assigned functions in pre-clinical studies are presented.

Hypomania with hypersexuality following bilateral anterior limb stimulation in obsessive-compulsive disorder.

This 28-year-old Chinese man was referred for deep brain stimulation (DBS) evaluation for an 8-year history of refractory obsessive-compulsive disorder. After the patient had signed an informed consent, the authors implanted DBS leads. Hypomania with hypersexuality was noted on stimulation at Contact 2 and became aggravated with a higher voltage (> or = 3 V) during chronic bilateral DBS. After the voltage was decreased to 1 V, the patient's hypomanic symptoms subsided and his libido returned to baseline.