Multiple time courses of somatosensory responses in human cortex.

Here we show how anatomical and functional data recorded from patients undergoing stereo-EEG can be used to decompose the cortical processing following nerve stimulation in different stages characterized by specific topography and time course. Tibial, median and trigeminal nerves were stimulated in 96 patients, and the increase in gamma power was evaluated over 11878 cortical sites. All three nerve datasets exhibited similar clusters of time courses: phasic, delayed/prolonged and tonic, which differed in topography, temporal organization and degree of spatial overlap. Strong phasic responses of the three nerves followed the classical somatotopic organization of SI, with no overlap in either time or space. Delayed responses presented overlaps between pairs of body parts in both time and space, and were confined to the dorsal motor cortices. Finally, tonic responses occurred in the perisylvian region including posterior insular cortex and were evoked by the stimulation of all three nerves, lacking any spatial and temporal specificity. These data indicate that the somatosensory processing following nerve stimulation is a multi-stage hierarchical process common to all three nerves, with the different stages likely subserving different functions. While phasic responses represent the neural basis of tactile perception, multi-nerve tonic responses may represent the neural signature of processes sustaining the capacity to become aware of tactile stimuli.

Decomposing Tool-Action Observation: A Stereo-EEG Study.

A description of the spatiotemporal dynamics of human cortical activity during cognitive tasks is a fundamental goal of neuroscience. In the present study, we employed stereo-EEG in order to assess the neural activity during tool-action observation. We recorded from 49 epileptic patients (5502 leads) implanted with intracerebral electrodes, while they observed tool and hand actions. We deconstructed actions into 3 events-video onset, action onset, and tool-object contact-and assessed how different brain regions respond to these events. Video onset, with actions not yet visible, recruited only visual areas. Aligning the responses at action onset, yielded activity in the parietal-frontal manipulation circuit and, selectively for tool actions, in the left anterior supramarginal gyrus (aSMG). Finally, by aligning to the tool-object contact that signals the achievement of the main goal of the observed action, activations were found in SII and dorsal premotor cortex. In conclusion, our data show that during tool-action observation, in addition to the general action observation network there is a selective activation of aSMG, which exhibits internally different patterns of responsiveness. In addition, neural responses selective for the contact between the tool and the object were also observed.

Incomplete filling of lithium heparin tubes affects the activity of creatine kinase and gamma-glutamyltransferase.

This study aims to assess whether or not incomplete filling of primary lithium heparin tubes may influence the activity of creatine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT). Blood was drawn from 20 healthy volunteer using an identical sequence of tubes. First, a 6 mL, 13 x 100 mm 14 unit/mL lithium heparin Vacuette was filled and discharged. Then, three identical lithium heparin Vacuette tubes were filled, one to the nominal volume (i.e., full-draw tube), another with half of the nominal volume (half-draw tube) and the last with one-third of the nominal volume (low-draw tube). The plasma was separated and tested for CK (non-activated by N-acetylcysteine), AST and ALT on a Beckman Coulter Unicel DxC 800. Tests for CK were performed with a different reagent on a Beckman Coulter AU5800 (activated by N-acetylcysteine). Although the concentrations of ASL and ALT measured on the Unicel DxC and that of CK measured on the AU5800 did not change significantly across the different specimens, those of CK and GGT measured on the Unicel DxC 800 were significantly increased in the half-draw and low-draw tubes. The percentage bias of CK on the Unicel DxC 800 (using Bland Altman plots) was 3.3% and 7.9% for the half-draw and low-draw tubes, respectively, whereas that of GGT was 10.3% and 16.6% for the half-draw and low-draw tubes, respectively. These results suggest that short-draw lithium heparin tubes might be unsuitable for testing GGT and CK using specific combinations of reagents and instrumentation.

The web of laughter: frontal and limbic projections of the anterior cingulate cortex revealed by cortico-cortical evoked potential from sites eliciting laughter.

According to an evolutionist approach, laughter is a multifaceted behaviour affecting social, emotional, motor and speech functions. Albeit previous studies have suggested that high-frequency electrical stimulation (HF-ES) of the pregenual anterior cingulate cortex (pACC) may induce bursts of laughter-suggesting a crucial contribution of this region to the cortical control of this behaviour-the complex nature of laughter implies that outward connections from the pACC may reach and affect a complex network of frontal and limbic regions. Here, we studied the effective connectivity of the pACC by analysing the cortico-cortical evoked potentials elicited by single-pulse electrical stimulation of pACC sites whose HF-ES elicited laughter in 12 patients. Once these regions were identified, we studied their clinical response to HF-ES, to reveal the specific functional target of pACC representation of laughter. Results reveal that the neural representation of laughter in the pACC interacts with several frontal and limbic regions, including cingulate, orbitofrontal, medial prefrontal and anterior insular regions-involved in interoception, emotion, social reward and motor behaviour. These results offer neuroscientific support to the evolutionist approach to laughter, providing a possible mechanistic explanation of the interplay between this behaviour and emotion regulation, speech production and social interactions. This article is part of the theme issue 'Cracking the laugh code: laughter through the lens of biology, psychology and neuroscience'.

Simultaneous stereo-EEG and high-density scalp EEG recordings to study the effects of intracerebral stimulation parameters.

BACKGROUND: Cortico-cortical evoked potentials (CCEPs) recorded by stereo-electroencephalography (SEEG) are a valuable tool to investigate brain reactivity and effective connectivity. However, invasive recordings are spatially sparse since they depend on clinical needs. This sparsity hampers systematic comparisons across-subjects, the detection of the whole-brain effects of intracortical stimulation, as well as their relationships to the EEG responses evoked by non-invasive stimuli. OBJECTIVE: To demonstrate that CCEPs recorded by high-density electroencephalography (hd-EEG) provide additional information with respect SEEG alone and to provide an open, curated dataset to allow for further exploration of their potential. METHODS: The dataset encompasses SEEG and hd-EEG recordings simultaneously acquired during Single Pulse Electrical Stimulation (SPES) in drug-resistant epileptic patients (N = 36) in whom stimulations were delivered with different physical, geometrical, and topological parameters. Differences in CCEPs were assessed by amplitude, latency, and spectral measures. RESULTS: While invasively and non-invasively recorded CCEPs were generally correlated, differences in pulse duration, angle and stimulated cortical area were better captured by hd-EEG. Further, intracranial stimulation evoked site-specific hd-EEG responses that reproduced the spectral features of EEG responses to transcranial magnetic stimulation (TMS). Notably, SPES, albeit unperceived by subjects, elicited scalp responses that were up to one order of magnitude larger than the responses typically evoked by sensory stimulation in awake humans. CONCLUSIONS: CCEPs can be simultaneously recorded with SEEG and hd-EEG and the latter provides a reliable descriptor of the effects of SPES as well as a common reference to compare the whole-brain effects of intracortical stimulation to those of non-invasive transcranial or sensory stimulations in humans.

[Sensitivity and accuracy of health databases in determining incidence of lymphoid malignancies in an Italian population]. / Sensibilità ed accuratezza diagnostica dei flussi informativi del Servizio Sanitario Nazionale nella rilevazione dell'incidenza delle patologie linfoproliferative in una popolazione italiana.

We examined the sensitivity and the accuracy of three health databases (hospital discharge data, death certificates and pathologic records) between 1997 and 2001 in an Italian community, to evaluate their accuracy for the diagnosis of lymphoid malignancies and their ability to detect newly diagnosed patients affected by these diseases. Hospital discharge data showed the best sensitivity among the examined databases, though they exhibited an unexpectedly high number of diagnostic errors, even when limiting the analysis to patients with repeated hospital admissions over time. Overall, the pathologic registry and the death certificate file showed a higher diagnostic accuracy, though their sensitivity was considerably lower than hospital discharge data.

Smile and laughter elicited by electrical stimulation of the frontal operculum.

Laughter and smile are typical expressions of mirth and fundamental means of social communication. Despite their general interest, the current knowledge about the brain regions involved in the production of these expressions is still very limited, and the principal insights come from electrical stimulation (ES) studies in patients, in which, nevertheless, laughter or smile have been elicited very rarely. Previous studies showed that laughter is evoked by the stimulation of nodes of an emotional network encompassing the anterior cingulate, the superior frontal and basal temporal cortex. A common feature of these stimulation studies is that the facial expression was always accompanied by motor awareness and often by mirth, in line with the affective functions attributed to these regions. Little is known, in contrast, on the neural basis of the voluntary motor control of this expression. The objective of this study was to investigate the effect of ES of the frontal operculum (FO), which is considered a crucial node for the linkage of the voluntary motor system for emotional expression and limbic emotional network. We report the case of ES applied to the frontal operculum (FO) in four patients with drug-resistant focal epilepsy undergoing stereo-electroencephalographic (SEEG) implantation of intracerebral electrodes. In all patients, ES applied to the FO produced laughter or smile. Interestingly, in one patient, the production of a smiling expression was also clearly accompanied by the lack of motor awareness. Since the lack of motor awareness has been previously observed only after the stimulation of the voluntary motor network, we speculate that FO is involved in the voluntary control of facial expressions, and is placed at the interface with the emotional network, gating limbic information to the motor system.

MOPP/EBV/CAD hybrid chemotherapy with or without limited radiotherapy in advanced or unfavorably presenting Hodgkin's disease: a report from the Italian Lymphoma Study Group.

PURPOSE: We explored the feasibility, toxicity, and preliminary results of a chemotherapy (CT) regimen, mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/epidoxirubicin, bleomycin, and vinblastine (EBV)/lomustine (CCNU), doxorubicin, and vindesine (CAD), derived through hybridization, shortening, and intensification of a corresponding 10-drug alternating combination CAD/MOPP/doxorubicin, bleomycin, and vinblastine (ABV), effective in treatment of advanced Hodgkin's disease (HD). PATIENTS AND METHODS: Hybridization involved all drugs except CCNU and mechlorethamine, which were administered in alternating cycles; the length of therapy was reduced from nine to six cycles. The average projected drug doses during the six cycles were increased by 42%, with an overall 1.54 dose-intensification; epidoxorubicin was substituted for doxorubicin at equivalent tumoricidal doses. Radiotherapy (RT) was optional and its indications were limited. RESULTS: Eighty assessable patients with previously untreated, advanced or unfavorably presenting HD were treated in nine cooperating institutions between 1988 and 1991. RT was delivered to 22 patients. Remissions were complete (CR) in 75 patients (93%), partial in three (4%), and null in two (3%). The median relative dose-intensity was 0.71 for the overall regimen. Three of five patients who failed to achieve CR, and two of the four who relapsed, received lower relative dose-intensive cycles. Nonhematologic toxicity was acceptable, but there was considerable hematologic toxicity. Fatal gastrointestinal bleeding was seen in one patient. CONCLUSION: Caution is advised due to the short median follow-up period. Nevertheless, in addition to the excellent response rate, (1) the results were reached through abbreviation, intensification, and hybridization of an existing alternating regimen; (2) RT had limited use in this program, which may have contributed to lowering the risk of second tumors; and (3) the results were obtained in a multicenter study (a condition that often impairs results from clinical trials).

Vinblastine, bleomycin, and methotrexate chemotherapy plus extended-field radiotherapy in early, favorably presenting, clinically staged Hodgkin's patients: the Gruppo Italiano per lo Studio dei Linfomi Experience.

PURPOSE: To ascertain whether vinblastine, bleomycin, and methotrexate (VBM) (CT) combined with extended-field radiotherapy (EF RT) is effective enough to spare laparotomy in early, favorably presenting Hodgkin's disease (HD) patients. PATIENTS AND METHODS: Fifty patients with clinical stage IA or IIA HD with favorable histology and no bulky masses entered a prospective multicenter study started in January 1988. The median follow-up time was 38 months. RESULTS: All patients achieved a complete remission (CR). Five relapsed after 3 to 40 months and underwent successful salvage therapy. The actuarial remission rate was 0.89% at 3 years and 0.82% at 5 years. Two patients died in CR: one of severe pulmonary toxicity, the other of a second neoplasia (adenocarcinoma of the lung), 2 and 43 months after the end of therapy, respectively. The hematologic toxicity recorded during VBM CT was mild on the whole. Major toxicity was represented by pulmonary side effects and neurologic symptoms. Multiple regression analysis demonstrated that pulmonary toxicity was significantly related only to the amount of RT delivered to the mediastinum and not to the relative dose of bleomycin, to the dose-intensities of the three drugs in the regimen, or to patient age or sex. The same statistical technique showed that the only clinical factor related to grade of neurotoxicity was vinblastine dosage. CONCLUSION: VBM CT combined with EF RT is an effective treatment for early, clinically staged, favorable HD patients. However, the toxicity of this combination suggests that certain modifications should be evaluated.

ProMACE-cytaBOM versus MACOP-B in intermediate and high grade NHL. Preliminary results of a prospective randomized trial.

One hundred seventy-nine patients with intermediate or high-grade non-Hodgkin's lymphoma were randomized to receive either ProMACE-CytaBOM (P-C) or MACOP-B (M-B). At last follow-up 71 patients in the P-C arm and 78 in the M-B arm were assessable for response. Forty-one patients treated with P-C (58%) and 49 patients treated with M-B (63%) achieved a CR. Moreover 18 and 22 patients achieved PR with P-C and M-B, respectively. Twenty-five patients relapsed, 12 in the P-C arm and 13 in the M-B arm. Thirty-nine patients died, 32 from disease progression, 5 from treatment related causes, and 2 from other causes. No differences between the two treatment groups were observed as regard to relapse or death-rate. At 27 months the survival rate was of 71.9% for patients treated with P-C and 70.7% for those treated with M-B. At 2 years the RFD rate was 64% and 60% for patients in P-C and M-B arm, respectively. Patients treated with M-B experienced an high rate of methotrexate-related toxicity. ProMACE-CytaBOM and M-B seem provided with similar activity. However P-C seem less toxic and more manageable in an outpatient setting.

Development of simple equations for effective screening of spurious hemolysis in whole-blood specimens.

INTRODUCTION: We aimed to identify simple but reliable indices for effective screening of spurious hemolysis in whole-blood specimens. METHODS: Thirteen inpatient whole-blood samples were divided in two aliquots. The former was left untreated, whereas the latter was mechanically hemolyzed by forced aspiration with an insulin syringe. All aliquots were tested on Siemens Advia 2120 and Sysmex XE-2100. The hemolysis index (HI) was also assessed in centrifuged plasma. RESULTS: The mechanical hemolysis generated a 4-40% decrease in red blood cells (RBCs). A statistically significant decrease was observed for hematocrit (Ht) and mean corpuscular volume (MCV), whereas mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and platelet count were increased. The values of hemoglobin (Hb) and white blood cells remained substantially unchanged. Two specific equations ([Ht/Hb] × âˆšMCV and [Ht/Hb] × 100) were developed. Both equations displayed an area under the curve of ≥0.99 for identifying spurious hemolysis, much greater than that of both RBC ghosts and immature platelet fraction. A highly significant correlation was also observed between results of these equations and percentage reduction in RBCs or HI increase. CONCLUSION: Provided that these results will be confirmed in further studies, these equations may provide a reliable means for screening spurious hemolysis in whole-blood samples.

Anaplastic large cell lymphoma (CD30+/Ki-1+). Analysis of 35 cases followed at GISL centres.

Between January 1988 and June 1992, 35 patients with primary anaplastic large cell lymphoma (ALCL)CD30+ were referred to one of the institutions participating in GISL (Gruppo Italiano per lo Studio dei Linformi). 16 patients were treated with ProMACE-CytaBOM, two with MACOP-B, one with CHOP and one with LSA2-L2. As of November 1990, all newly diagnosed patients were treated with MOPP/EBV/CAD hybrid. 27 (77%) cases of ALCL CD30+ and 8 (23%) cases of Hodgkin's-related (HR) lymphoma CD30+ were diagnosed. Extranodal disease was present in 22 cases (63%), and 8 patients (23%) had primary bone marrow involvement. Twenty-three complete remissions (CR) (66%), six partial remissions (PR) (17%) and six no remissions (NR) (17%) were achieved with induction therapy. Results achieved with ProMACE-CytaBOM and MOPP/EBV/CAD hybrid were comparable. The overall response rate (CR+PR) was 85% for patients with classic ALCL CD30+ and 87% for those with HR lymphoma CD30+. The 3 year estimated overall survival rate was 66% and the 3 year relapse free survival rate was 65% for the entire group. The only significant favourable prognostic factor was the achievement of CR with initial therapy. Our findings suggest that ALCL (CD30+/Ki-1+) has a clinical outcome similar to aggressive non-Hodgkin's lymphoma (NHL). The use of an anthracycline-containing regimen will provide a change of cure in approximately 65% of cases.

Neurotransmitter and endocrine modulation of aggressive behavior and its components in normal humans.

Correlations between aggressiveness and its components and plasma concentrations of norepinephrine (NE), epinephrine (EPI), testosterone (T), cortisol (Cort) and prolactin (Prl) were studied in 158 physically and psychologically healthy male volunteers. Global aggressiveness, examined directly in the probands by the Buss-Durkee Hostility Inventory (BDHI), was not correlated with any of the biochemical parameters investigated, but reports by first-degree relatives and spouses showed positive correlations between global aggressiveness and NE and T levels. The BDHI scores for 'irritability' and 'resentment' were positively correlated with NE, T and Cort.

ProMECE-CytaBOM vs MACOP-B in advanced aggressive non-Hodgkin's lymphoma: long term results of a multicenter study of the Italian Lymphoma Study Group (GISL).

A randomized trial was designed in order to compare the efficacy and feasibility of ProMECE-CytaBOM (P-C) and MACOP-B (M-B) in patients with advanced, aggressive non Hodgkin's lymphoma (NHL). P-C and M-B were chosen due to their association with a very high complete remission rate when compared to other published protocols. The study was conducted on 210 patients with intermediate or high-grade NHL in stage I bulky, or stages II-IV, randomized to receive either 6 courses of P-C delivered every 28 days (106 patients), or 12 weeks of M-B chemotherapy (104 patients). In both regimens doxorubicin was replaced by a 20% higher dose of epidoxorubicin (i.e. 30 mg/m2 of the analog). At the end of induction therapy patients could receive additional radiotherapy to residual masses or to sites of previous bulky disease. The two groups of patients were compared for response rates, number and severity of therapy related side effects, overall survival, disease-free survival, and time to treatment failure. Sixty-five patients (62%) treated with P-C and 69 patients (67%) treated with M-B achieved a complete remission, with no significant differences between the two treatment arms (P = 0.13). The overall objective response rate (complete + partial remission) was 74% for patients treated with P-C, and 81% for patients treated with M-B, respectively. The 4-year relapse-free survival rate was 59% for P-C and 69% for M-B, respectively (P = 0.11).(ABSTRACT TRUNCATED AT 250 WORDS)

Hostility in heroin abusers subtypes: fluoxetine and naltrexone treatment.

1. Substance abusers subtypes have been identified considering underlying psychobiological disorder, familial factors, age of onset, legal problems and drug of choice. 2. In the present study the authors submitted 98 male heroin addicted individuals (age 19-28 y) to the Buss Durkee Hostility Inventory (Italian version) and a structured interview concerning social and clinical history; legal problems, age of onset of drug abuse, drug of choice. 3. Serotonergic system sensitivity was evaluated with fenfluramine challenge for PRL assay. 4. Thirty two patients (group A) showed high score for resentment and guilt at BDHI (hostility in), low rate of legal problems, late age of onset, preference for heroin and alcohol. Twenty nine patients (group B) showed high score for assault and irritability at BDHI (hostility out), high rate of legal problems, early age of onset, preference for heroin and cocaine. The other 37 patients (group C) showed aggression score in the normal range at BDHI, no legal problems, late onset of substance abuse, preference for heroin only. 5. PRL responses was blunted in group A (p < 0.001) and significantly decreased in group B (p < 0.05). PRL plasma levels were inversely correlated with HRSD scores. 6. All the patients were included in a treatment protocol with fluoxetine and naltrexone or placebo and naltrexone for 6 months. 7. The treatment was effective in group A with a significant improvement of BDHI results and decrease of craving score, lower level of drop out, lower level of positive urine controls. No significant differences between fluoxetine and placebo effects have been evidenced in patients of group B and C. The present findings suggest that psychopharmacological approach to addiction needs a diagnostic screening for specific subtypes.

Neurotransmitter-hormonal responses to psychological stress in peripubertal subjects: relationship to aggressive behavior.

The relationship between different degrees of normal aggressiveness (low, medium, high) and neurotransmitter-neuroendocrine responses to the administration of psychologically stressful tests (Mental Arithmetic, Stroop Color Word Interference task, Trial Social Stress test) was examined in thirty male peripubertal junior school adolescents. Plasma concentrations of norepinephrine (NE), epinephrine (EPI), ACTH, cortisol (CORT), growth hormone (GH), prolactin (PRL) and testosterone (T) were measured immediately before the beginning of the tests and at their end, 30 min later. High-normal aggressiveness have been found associated with significantly higher basal concentrations of NE, ACTH, PRL, and T and with a significant increase of GH responses to the stressful stimuli.

Intravenous flumazenil following prolonged exposure to lormetazepam in humans: lack of precipitated withdrawal.

The capacity of flumazenil to reverse benzodiazepine agonist effects has been widely demonstrated. In contrast, the role of flumazenil in precipitating withdrawal symptoms is unclear in humans: the inability of RO 15-1788 to induce benzodiazepine withdrawal seems to be related to the duration of exposure to the GABAergic drugs. In the present experiment we evaluated the effects of intravenous flumazenil or placebo in 36 healthy volunteers pretreated with lormetazepam for 30 days (2 mg/day) and 18 lormetazepam-dependent subjects (6-8 mg/day). Measurements of a balance task, subject- and observer-rated symptoms showed a reversal of lormetazepam effects induced by flumazenil without any significant withdrawal symptoms. Slight anxiety, increase in heart rate and perspiration were observed in a few subjects. Independent of benzodiazepine doses, long-term treatment seems to be responsible for tolerance development with consistent changes in GABA-benzodiazepine receptor sensitivity. Flumazenil could be able to normalize benzodiazepine receptor sensitivity and exert its weak agonist activity.

Flumazenil effects on growth hormone response to gamma-hydroxybutyric acid.

Gamma-hydroxybutyric acid (GHBA) has been recently introduced for alcohol detoxication but few data are available concerning the central mechanism of action of this gamma-aminobutyric acid (GABA) catabolite. GHBA ability to stimulate growth hormone (GH) and prolactin (PRL) secretion has been reported: the involvement of GABA, dopamine or serotonin systems acting on pituitary hormones has been hypothesized. In the present study we investigated GH and PRL responses to GHBA with or without flumazenil (a benzodiazepine receptor antagonist) i.v. pretreatment. Our study included nine male healthy volunteers (aged 23.2 +/- 2.5 years) who were submitted to three tests in random order: (1) oral GHB administration; (2) oral GHBA and i.v. flumazenil administration; (3) oral placebo and i.v. saline administration. Blood samples for GH and PRL assays were collected during the three tests at -15, 0, 15, 30, 45, 60 and 90 min. GHBA induced a significant increase in GH plasma levels; flumazenil pretreatment antagonized GHBA action on GH secretion. No changes were obtained with placebo and saline administration. A subpopulation of GABA receptors or GHBA-specific receptors seems to be involved in GHBA action. The benzodiazepine receptor antagonist flumazenil was able to influence the sensitivity and the neuroendocrine consequences of GHBA binding site stimulation.

Naloxone and metergoline effects on growth hormone response to gamma-hydroxybutyric acid.

Gamma-hydroxybutyric acid (GHB) has been recently used in alcohol detoxification, but conflicting data are available concerning the central mechanism of action of this GABA catabolite. GHB ability to stimulate growth hormone (GH) secretion has been reported. Our previous studies revealed the ability of flumazenil (a benzodiazepine antagonist) to counteract GHB effects on GH secretion. Other hypotheses, including an opioid or serotonergic role of GHB, have been considered. In the present study we investigated GH responses to GHB with or without naloxone (an opiate receptor antagonist) or metergoline (a serotonin receptor antagonist) pretreatment. This study included 10 male healthy volunteers (aged 24.3 +/- 2.9 years) who were submitted to four tests in random order: (A) oral GHB administration; (B) oral GHB and i.v. naloxone administration; (C) oral GHB and oral metergoline administration; and (D) oral placebo and i.v. saline administration. Blood samples for GH assay were collected during the three tests at -15, 0, 15, 30, 45, 60 and 90 min. GHB induced a significant increase in GH plasma levels; naloxone pretreatment did not antagonize GHB action on GH secretion; metergoline significantly decreased GH response to GHB (p < 0.05). No changes were obtained with placebo and saline administration. The opioid system does not seem to be involved in GHB effects on GH-secreting pituitary cells; GHB effects on the serotonergic system influencing GH secretion, on the other hand, cannot be excluded.