Demographic and Clinical Characteristics of Regular GHB-Users with and without GHB-Induced Comas.

BACKGROUND: Gamma hydroxybutyric acid (GHB) has been used recreationally for nearly three decades and its chronic use is frequently associated with serious adverse events including GHB-intoxication with GHB-induced comas. Moreover, despite its low prevalence, the number of individuals with GHB-use disorders is steadily increasing. However, the risk-factors associated with chronic GHB-use or the development of a GHB-use disorders remain poorly understood. Purpose: This study aims to profile two types of GHB-users, those with and those without GHB-induced comas. Methods: We included 27 GHB users with ≥4 GHB-induced comas (GHB-Coma), 27 GHB users without a coma (GHB-NoComa), and 27 polydrug users who never used GHB (No-GHB). Participants completed self-reported questionnaires in order to assess their demographic and clinical features, and their use profile of GHB and other drugs. Results: The typical GHB user in our sample was young, single, living alone, well-educated, and a student. The GHB-Coma group had lower self-control and reported higher negative affect than the GHB-NoComa group. GHB-Coma participants were heavier GHB users and mostly used GHB alone at home, whereas the GHB-NoComa group mostly used GHB with friends and in nightclubs. Remarkably, the majority of participants were not concerned about potential neurocognitive impairments induced by GHB-intoxication and/or GHB-induced comas. Conclusion: In this assessment, different profiles for recreational users with and without GHB-induced comas were well expressed. Their description contributes to a better understanding of the risk factors associated with recreational GHB-use, GHB-induced coma, and the development of GHB-use disorders.

Recreational use of GHB is associated with alterations of resting state functional connectivity of the central executive and default mode networks.

Gamma-hydroxybutyrate acid (GHB) is a recreational drug with a high addictive potential. Severe side effects such as GHB-induced coma are common and linked to increased emergency room attendances. Task-based functional-imaging studies have revealed an association between the regular use of GHB and multiple GHB-induced comas, and altered neurocognitive function. However the effects of multiple GHB-induced comas and regular GHB-use on intrinsic brain connectivity during rest remain unknown. The study population consisted of 23 GHB-users with ≥4 GHB-induced comas (GHB-Coma), 22 GHB-users who never experienced a GHB-induced coma (GHB-NoComa) and 24 polydrug users who never used GHB (No-GHB). Resting-state scans were collected to assess resting-state functional-connectivity within and between the default mode network (DMN), the bilateral central executive network (CEN) and the salience network (SN). The GHB-NoComa group showed decreased rsFC of the right CEN with a region in the anterior cingulate cortex (pFWE = 0.048) and decreased rsFC between the right CEN and the DMN (pFWE = 0.048) when compared with the No-GHB group. These results suggest that regular GHB-use is associated with decreased rsFC within the right CEN and between the right CEN and the DMN. The presence of multiple GHB-induced comas is not associated with (additional) alterations in rsFC.

Influence of Gamma-Hydroxybutyric Acid-Use and Gamma-Hydroxybutyric Acid-Induced Coma on Affect and the Affective Network.

BACKGROUND: Gamma-hydroxybutyric acid (GHB) is a drug of abuse associated with increased emergency room attendances, due to GHB-induced comas. Withdrawal from GHB often increases social anxiety and is linked to alterations in emotion processing. However, little is known about the effects of GHB-use and GHB-induced comas on affect regulation in humans. OBJECTIVES: We aimed to assess the effect of GHB-use and GHB-induced comas on the affective network. METHOD: We recruited 27 GHB users with ≥4 GHB-induced comas (GHB-Coma), 27 GHB users without a GHB-induced coma (GHB-NoComa), and 27 polydrug users who never used GHB (No-GHB). Participants completed self-report questionnaires assessing negative affect (depression, anxiety and stress) and performed an emotional face matching task during functional magnetic resonance imaging to probe activity of the amygdala and the hippocampus. RESULTS: The GHB-Coma group reported higher levels of depression, anxiety, and stress; showed decreased activity of the hippocampus; and increased functional connectivity of the left hippocampus with the left fusiform gyrus and a cluster on the left temporal-parietal-occipital junction, when compared with the 2 other groups. The GHB-NoComa group showed decreased functional connectivity of the left hippocampus with the amygdala in comparison with the No-GHB group. CONCLUSIONS: GHB-use but in particular GHB-induced comas, are associated with altered emotion identification and hippocampal functioning. Awareness campaigns are required to raise consciousness about the adverse effects of GHB-induced comas on affect regulation, despite the absence of subjective side effects.

The Prenatal Environment in Twin Studies: A Review on Chorionicity.

A literature search was conducted to identify articles examining the association of chorionicity (e.g., whether twins share a single chorion and thus placenta or have separate chorions/placentas) and genetics, psychiatry/behavior, and neurological manifestations in humans twins and higher-order multiples. The main aim was to assess how frequently chorionicity has been examined in relation to heritability estimates, and to assess which phenotypes may be most sensitive to, or affected by, bias in heritability estimates because of chorionicity. Consistent with the theory that some chorionicity effects could lead to overestimation and others to underestimation of heritability, there were instances of each across the many phenotypes reviewed. However, firm conclusions should not be drawn since some of the outcomes were only examined in one or few studies and often sample sizes were small. While the evidence for bias due to chorionicity was mixed or null for many outcomes, results do, however, consistently suggest that heritability estimates are underestimated for measures of birth weight and early growth when chorionicity is not taken into account.

The Influence of Chorion Type on Health Measures at Birth and Dental Development in Australian and Dutch Twins: A Comparative Study.

Chorion type may significantly influence the prenatal environment of twins. This study explored the associations between chorion type and gestational age, birth weight, birth length, and the timing of emergence of the first primary tooth in two populations of twins, Australian and Dutch. Additionally, we investigated the relationship between chorion type and birth weight discordance (BWD) in order to determine whether a significant relationship existed between discordance in birth weight and discordance in the timing of emergence of the first primary tooth. The two study samples consisted of 409 Australian twin pairs and 301 Dutch twin pairs, all of European ancestry. Data were collected through a combination of questionnaires and recording charts administered to the parents and through linkage with biological databases. In the Australian sample, monozygotic monochorionic (MZMC) twins experienced the shortest mean gestation time (35 weeks), the lowest mean birth length (46 cm) and the lowest mean birth weight (2.3 kg) compared with other twin groups. For the same variables in the Dutch sample, these trends with MZMC twinning were not observed. Chorion type did not significantly affect the mean timing of emergence of the first primary tooth in either sample. Monochorionicity was found to be significantly associated with BWD in both samples, but there was a significant association between BWD in MZMC twin pairs and timing of emergence of the first primary tooth only in the Australian sample. Results from this study support previous findings that the timing of emergence of the first primary tooth is influenced strongly by genetic factors and is well protected from environmental disturbances.

Effects of Recreational GHB Use and Multiple GHB-Induced Comas on Brain Structure and Impulsivity.

BACKGROUND AND AIMS: The regular use of gamma-hydroxybutyrate acid (GHB) can induce GHB-induced comas. Other substance use disorders are associated with alterations in brain structure and impulsivity. Here we aim to investigate if these are also modulated by either regular GHB use or GHB-induced comas. METHODS: In a sample of human males, structural and diffusion neuroimaging data were collected for 27 GHB users with ≥4 GHB-induced comas (GHB-Coma), 27 GHB users without GHB-induced comas (GHB-NoComa), and 27 polydrug users who never used GHB (No-GHB). The structural brain parameters were analyzed macroscopically using voxel-based morphometry and microscopically using tract-based spatial statistics (TBSS) and tractography. Impulsivity was assessed with the Barrat Impulsivity Scale. RESULTS: In comparison to the other two groups, the GHB-Coma group showed a higher fractional anisotropy in the body of the corpus callosum and a lower mean diffusivity in the forceps minor (i.e., whole-brain TBSS analysis). No macrostructural differences nor microstructural differences, as assessed with tractography, were observed. The GHB-Coma group also reported higher impulsivity, which was more strongly associated with white matter volume and fractional anisotropy in tracts involved in impulse control (post-hoc analysis). GHB use per se was associated neither with differences in brain structure nor with impulsivity. CONCLUSIONS: The results suggest that multiple GHB-induced comas, but not GHB use per se, are associated with microstructural alterations in white matter and with higher self-reported impulsivity, which in turn was associated with white matter tracts involved in impulse control.

Effect of GHB-use and GHB-induced comas on dorsolateral prefrontal cortex functioning in humans.

BACKGROUND: Gamma-hydroxybutyric acid (GHB) is a recreational drug associated with increasing numbers of GHB-dependent patients and emergency attendances often related to GHB-induced comas. Working memory (WM) deficits have been reported in association with GHB use, and animal studies have shown that GHB induces oxidative stress in vulnerable WM-related brain areas such as the dorsolateral prefrontal cortex (DLPFC). However, the effects of chronic GHB use and multiple GHB-induced comas on WM-related brain function in humans remains unknown. METHODS: We recruited 27 GHB users with ≥4 GHB-induced comas (GHB-Coma), 27 GHB users who never experienced GHB-induced coma (GHB-NoComa), and 27 polydrug users who never used GHB (No-GHB). Participants performed an n-back WM task during functional magnetic resonance imaging (fMRI) to probe DLPFC functioning. RESULTS: The GHB-Coma group had lower premorbid IQ (p = .006) than the GHB-NoComa group despite comparable age and education level. There were also group differences in the use of other drugs than GHB. Therefore, all group comparisons were adjusted for IQ and drug use other than GHB. Compared with the GHB-NoComa and the No-GHB groups, the GHB-Coma group showed increased activity in the right DLPFC (pSVC = 0.028) and increased functional connectivity of the right DLPFC with a cluster comprising the left anterior cingulate and medial frontal gyrus (pFWE = 0.003). No significant fMRI differences were observed between the GHB-NoComa and No-GHB groups. Due to technical problems, no behavioural data were collected. DISCUSSION: These results suggest that multiple GHB-induced comas, but not GHB-use per se, are associated with alterations in WM-related brain function. Public awareness campaigns are required to minimize the potential adverse effects induced by GHB recreational use, and especially GHB-induced comas, even if no immediate side effects are experienced.

Adverse effects of GHB-induced coma on long-term memory and related brain function.

BACKGROUND: Gamma-Hydroxybutyric acid (GHB) is a drug of abuse associated with increasing numbers of GHB-dependent patients and emergency attendances often related to GHB-induced coma. Animal studies suggest that GHB induces oxidative stress in the hippocampus, resulting in memory impairments. However, the consequences of chronic GHB use and GHB-induced coma on human brain function and cognition are unknown. METHODS: We recruited 27 GHB users with ≥4 GHB-induced comas (GHB-Coma), 27 GHB users without a coma (GHB-NoComa), and 27 polydrug users who never used GHB (No-GHB). Participants completed verbal and spatial memory tests and an associative memory encoding task during functional magnetic resonance imaging (fMRI) to probe hippocampus functioning. RESULTS: The GHB-Coma group showed a lower premorbid IQ (p = 0.006) and performed worse on the verbal memory test (p = 0.017) compared to the GHB-NoComa group, despite exhibiting similar levels of education. Compared with the other two groups, the GHB-Coma group showed lower left hippocampus (pSVC = 0.044) and left lingual gyrus (pFWE = 0.017) activity, and a trend for lower hippocampal functional connectivity with the left superior temporal cortex during performance of the associative memory encoding task (pFWE = 0.063). No significant differences were observed between the GHB-NoComa group and the No-GHB group. CONCLUSIONS: These results suggest that multiple GHB-induced comas, but not the use of GHB per se, are associated with alterations of memory performance and memory-related brain, although no causal link can be inferred from this cross-sectional study. The results highlight the need for public awareness to minimize the negative health consequences of recreational GHB use, in particular when related with GHB-induced comas.

Layer-specific high-frequency action potential spiking in the prefrontal cortex of awake rats.

Cortical pyramidal neurons show irregular in vivo action potential (AP) spiking with high-frequency bursts occurring on sparse background activity. Somatic APs can backpropagate from soma into basal and apical dendrites and locally generate dendritic calcium spikes. The critical AP frequency for generation of such dendritic calcium spikes can be very different depending on cell type or brain area involved. Previously, it was shown in vitro that calcium electrogenesis can be induced in L(ayer) 5 pyramidal neurons of prefrontal cortex (PFC). It remains an open question whether somatic burst spiking and the resulting dendritic calcium electrogenesis also occur in morphologically more compact L2/3 pyramidal neurons. Furthermore, it is not known whether critical frequencies that trigger dendritic calcium electrogenesis occur in PFC under awake conditions in vivo. Here, we addressed these issues and found that pyramidal neurons in both PFC L2/3 and L5 in awake rats spike APs in short bursts but with different probabilities. The critical frequency (CF) for calcium electrogenesis in vitro was layer-specific and lower in L5 neurons compared to L2/3. Taking the in vitro CF as a predictive measure for dendritic electrogenesis during in vivo spontaneous activity, supracritical bursts in vivo were observed in a larger fraction of L5 neurons compared to L2/3 neurons but with similar incidence within these subpopulations. Together, these results show that in PFC of awake rats, AP spiking occurs at frequencies that are relevant for dendritic calcium electrogenesis and suggest that in awake rat PFC, dendritic calcium electrogenesis may be involved in neuronal computation.

Possible long-term effects of γ-hydroxybutyric acid (GHB) due to neurotoxicity and overdose.

In several countries, including the Netherlands, the use of GHB seems to be rising. GHB is regarded by recreational users as an innocent drug without any side effects. Recently, the number of patients in treatment due to GHB addiction sharply increased. In addition, various studies report incidents following risky GHB use or GHB overdosing. Other sedative drugs, like ketamine and alcohol have been shown to result in unintended neurotoxic harm at the level of memory and cognitive function. As outlined in the present review, GHB and ketamine have a common mode of action, which suggests that GHB may also lead to similar neurotoxicity as ketamine. GHB overdosing, as well as binge drinking (and high ketamine doses), induce profound coma which is probably neurotoxic for the brain especially in the maturing brain of young adults. It is therefore advocated to investigate possible long-term neurotoxic effects in recreational GHB users e.g. by studying the residual effects on cognition and memory.