Objective markers of drug effects on brain function from recordings of scalp potential in healthy volunteers

In order to stress the importance of P300 responses in drug development, we describe the spatiotemporal characteristics of this objective, evoked event-related potential. These brain activations reflect mnemonic function, in which limbic structures play a role. It is demonstrated that a pharmacological challenge concerning, for example, the cholinergic system in young healthy volunteers induces modifications in P300 reminiscent of the aging brain. We use this type of observation to build a model in which it can be verified whether the deterioration can be counteracted by treatment with "cognition-enhancing" drugs. If we accept the extrapolation of the pharmacological effects to symptomatology, scalp potential analysis offers an appropriate tool for the study of drug interactions in early proof-of-concept models.

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Human models as tools in the development of psychotropic drugs

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2002.4.4/cgilles ◽

2002 ◽

Vol 4 (4) ◽

pp. 377-387

Keyword(s):

Drug Development ◽

Healthy Volunteers ◽

Phase 1 ◽

High Rate ◽

Proof Of Concept ◽

Human Models ◽

Pharmacodynamic Profile ◽

Early Proof ◽

Financial Expenditure ◽

Patient Studies

Despite the growing means devoted to research and development (R α D) and refinements in the preclinical stages, the efficiency of central nervous system (CMS) drug development is disappointing. Many drugs reach patient studies with an erroneous therapeutic indication andlor in incorrect doses. Apart from the first clinical studies, which are conducted in healthy volunteers and focus only on safety, iolerability, and pharmacokinetics, drug development mostly relies on patient studies. Psychiatric disorders are characterized by heterogeneity and a high rate of comorbidity. It is becoming increasingly difficult to recruit patients for clinical trials and there are many confounding factors in this population, for example, those related to treatments. In order to keep patient exposure and financial expenditure to a minimum, it is important to avoid ill-designed and inconclusive studies. This risk could be minimized by gathering pharmacodynamic data earlier in development and considering that the goal of a phase 1 plan is to reach patient studies with clear ideas about the compound's pharmacodynamic profile, its efficacy in the putative indication (proof of concept), and pharmacokinetic/pharmacodynamic relationships, in addition to safety, tolerability, and pharmacokinetics. Human models in healthy volunteers may be useful tools for this purpose, but their use necessitates a global adaptation of the phase scheme, favoring pharmacodynamic assessments without neglecting safety. We are engaged in an R α D program aimed to adapt existing models and develop new paradigms suitable for early proof of concept substantiation.

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Imaging and Cognitive Genetics: The Norwegian Cognitive NeuroGenetics Sample

Twin Research and Human Genetics ◽

10.1017/thg.2012.8 ◽

2012 ◽

Vol 15 (3) ◽

pp. 442-452 ◽

Cited By ~ 28

Author(s):

Thomas Espeseth ◽

Andrea Christoforou ◽

Astri J. Lundervold ◽

Vidar M. Steen ◽

Stephanie Le Hellard ◽

...

Keyword(s):

Sample Size ◽

Cognitive Aging ◽

Brain Function ◽

Large Scale ◽

Adult Life ◽

Aging Brain ◽

Adult Life Span ◽

Cross Sectional ◽

A Genome ◽

Effects Of Aging

Data collection for the Norwegian Cognitive NeuroGenetics sample (NCNG) was initiated in 2003 with a research grant (to Ivar Reinvang) to study cognitive aging, brain function, and genetic risk factors. The original focus was on the effects of aging (from middle age and up) and candidate genes (e.g., APOE, CHRNA4) in cross-sectional and longitudinal designs, with the cognitive and MRI-based data primarily being used for this purpose. However, as the main topic of the project broadened from cognitive aging to imaging and cognitive genetics more generally, the sample size, age range of the participants, and scope of available phenotypes and genotypes, have developed beyond the initial project. In 2009, a genome-wide association (GWA) study was undertaken, and the NCNG proper was established to study the genetics of cognitive and brain function more comprehensively. The NCNG is now controlled by the NCNG Study Group, which consists of the present authors. Prominent features of the NCNG are the adult life-span coverage of healthy participants with high-dimensional imaging, and cognitive data from a genetically homogenous sample. Another unique property is the large-scale (sample size 300–700) use of experimental cognitive tasks focusing on attention and working memory. The NCNG data is now used in numerous ongoing GWA-based studies and has contributed to several international consortia on imaging and cognitive genetics. The objective of the following presentation is to give other researchers the information necessary to evaluate possible contributions from the NCNG to various multi-sample data analyses.

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Differential drug effects on latent inhibition in healthy volunteers

Schizophrenia Research ◽

10.1016/s0920-9964(00)90660-1 ◽

2000 ◽

Vol 41 (1) ◽

pp. 148-149 ◽

Cited By ~ 1

Author(s):

D. McCartan ◽

C. Campbell ◽

R. Bell ◽

J.F. Green ◽

K. Trimble ◽

...

Keyword(s):

Healthy Volunteers ◽

Latent Inhibition ◽

Drug Effects

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The role of sedation tests in identifying sedative drug effects in healthy volunteers and their power to dissociate sedative-related impairments from memory dysfunctions

Journal of Psychopharmacology ◽

10.1177/0269881106071550 ◽

2006 ◽

Vol 21 (6) ◽

pp. 579-587 ◽

Cited By ~ 20

Author(s):

E. Wezenberg ◽

B.G.C. Sabbe ◽

W. Hulstijn ◽

G.S.F. Ruigt ◽

R.J. Verkes

Keyword(s):

Healthy Volunteers ◽

Drug Effects ◽

Sedative Drug

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Acute Pharmacological Effects and Oral Fluid Concentrations of the Synthetic Cannabinoids JWH-122 and JWH-210 in Humans After Self-Administration: An Observational Study

Frontiers in Pharmacology ◽

10.3389/fphar.2021.705643 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lucia Martínez ◽

Nunzia La Maida ◽

Esther Papaseit ◽

Clara Pérez-Mañá ◽

Lourdes Poyatos ◽

...

Keyword(s):

Blood Pressure ◽

Observational Study ◽

Oral Fluid ◽

Short Form ◽

Subjective Effects ◽

Synthetic Cannabinoids ◽

Drug Effects ◽

Pharmacological Effects ◽

Self Administration ◽

Potential Health

Synthetic cannabinoids (SCs) are a group of new psychoactive drugs used recreationally with potential health risks. They are monitored by the EU Early Warning System since 2010 due to severe adverse effects on consumers. JWH-122 and JWH-210 are naphthoylindole SCs and potent cannabinoid receptor CB1 and CB2 agonists. Information about the effects of SCs usually is available from intoxication cases and surveys, and few studies on humans after controlled administration or observational/naturalistic studies using standardized measures of cardiovascular and subjective effects are available. The aim of this study was to evaluate the acute pharmacological effects of JWH-122 and JWH-210 recreational consumption in a 4 h observational study and assess their disposition in oral fluid (OF). Sixteen volunteers self-administered 1 mg dose of JWH-122 (n = 8) or 2.25 mg mean dose of JWH-210 (range 2–3 mg, n = 8) by inhalation (smoking). Physiological parameters including blood pressure (systolic and diastolic), heart rate (HR), and cutaneous temperature were measured. A set of visual analog scales, the 49-item short-form version of the Addiction Research Center Inventory (ARCI), and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) were used for the evaluation of subjective effects. OF was collected at baseline and at 10, 20, and 40 min and 1, 2, 3, and 4 h after self-administration. Statistically significant increases in systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR were observed after JWH-122 self-administration but not after JWH-210 self-administration. JWH-210 self-administration produced significant changes in subjective drug effects, similar to those induced by THC (intensity, high, good effects, and hunger). The subjective effects following JWH-122 consumption were minimal. The maximal effects were mostly observed 20 min after intake. JWH-122 and JWH 210 OF concentration reached a peak 20 min after administration and could not be detected after 3 h. The results demonstrated a different pattern of effects of these two SCs. Due to the limitations of our observational study, further research with a larger sample and controlled studies are needed to better define the acute pharmacological effect and health risk profile of JWH-122 and JWH-210.

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The Impact of Cannabidiol on Human Brain Function: A Systematic Review

Frontiers in Pharmacology ◽

10.3389/fphar.2020.618184 ◽

2021 ◽

Vol 11 ◽

Author(s):

Albert Batalla ◽

Julian Bos ◽

Amber Postma ◽

Matthijs G. Bossong

Keyword(s):

Systematic Review ◽

Psychiatric Disorder ◽

Human Brain ◽

Healthy Volunteers ◽

Resting State ◽

Brain Function ◽

Brain Activity ◽

Autism Spectrum ◽

Cognitive Tasks ◽

Therapeutic Effects

Background: Accumulating evidence suggests that the non-intoxicating cannabinoid compound cannabidiol (CBD) may have antipsychotic and anxiolytic properties, and thus may be a promising new agent in the treatment of psychotic and anxiety disorders. However, the neurobiological substrates underlying the potential therapeutic effects of CBD are still unclear. The aim of this systematic review is to provide a detailed and up-to-date systematic literature overview of neuroimaging studies that investigated the acute impact of CBD on human brain function.Methods: Papers published until May 2020 were included from PubMed following a comprehensive search strategy and pre-determined set of criteria for article selection. We included studies that examined the effects of CBD on brain function of healthy volunteers and individuals diagnosed with a psychiatric disorder, comprising both the effects of CBD alone as well as in direct comparison to those induced by ∆9-tetrahydrocannabinol (THC), the main psychoactive component of Cannabis.Results: One-ninety four studies were identified, of which 17 met inclusion criteria. All studies investigated the acute effects of CBD on brain function during resting state or in the context of cognitive tasks. In healthy volunteers, acute CBD enhanced fronto-striatal resting state connectivity, both compared to placebo and THC. Furthermore, CBD modulated brain activity and had opposite effects when compared to THC following task-specific patterns during various cognitive paradigms, such as emotional processing (fronto-temporal), verbal memory (fronto-striatal), response inhibition (fronto-limbic-striatal), and auditory/visual processing (temporo-occipital). In individuals at clinical high risk for psychosis and patients with established psychosis, acute CBD showed intermediate brain activity compared to placebo and healthy controls during cognitive task performance. CBD modulated resting limbic activity in subjects with anxiety and metabolite levels in patients with autism spectrum disorders.Conclusion: Neuroimaging studies have shown that acute CBD induces significant alterations in brain activity and connectivity patterns during resting state and performance of cognitive tasks in both healthy volunteers and patients with a psychiatric disorder. This included modulation of functional networks relevant for psychiatric disorders, possibly reflecting CBD’s therapeutic effects. Future studies should consider replication of findings and enlarge the inclusion of psychiatric patients, combining longer-term CBD treatment with neuroimaging assessments.

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Automated pupillometry to detect command following in neurological patients: a proof-of-concept study

PeerJ ◽

10.7717/peerj.6929 ◽

2019 ◽

Vol 7 ◽

pp. e6929 ◽

Cited By ~ 5

Author(s):

Alexandra Vassilieva ◽

Markus Harboe Olsen ◽

Costanza Peinkhofer ◽

Gitte Moos Knudsen ◽

Daniel Kondziella

Keyword(s):

Brain Injury ◽

Healthy Volunteers ◽

Neurological Disorders ◽

Mental Arithmetic ◽

Proof Of Concept ◽

Icu Patients ◽

Wide Range ◽

Level Of Consciousness ◽

Neurological Patients ◽

Command Following

Background Levels of consciousness in patients with acute and chronic brain injury are notoriously underestimated. Paradigms based on electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) may detect covert consciousness in clinically unresponsive patients but are subject to logistical challenges and the need for advanced statistical analysis. Methods To assess the feasibility of automated pupillometry for the detection of command following, we enrolled 20 healthy volunteers and 48 patients with a wide range of neurological disorders, including seven patients in the intensive care unit (ICU), who were asked to engage in mental arithmetic. Results Fourteen of 20 (70%) healthy volunteers and 17 of 43 (39.5%) neurological patients, including 1 in the ICU, fulfilled prespecified criteria for command following by showing pupillary dilations during ≥4 of five arithmetic tasks. None of the five sedated and unconscious ICU patients passed this threshold. Conclusions Automated pupillometry combined with mental arithmetic appears to be a promising paradigm for the detection of covert consciousness in people with brain injury. We plan to build on this study by focusing on non-communicating ICU patients in whom the level of consciousness is unknown. If some of these patients show reproducible pupillary dilation during mental arithmetic, this would suggest that the present paradigm can reveal covert consciousness in unresponsive patients in whom standard investigations have failed to detect signs of consciousness.

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Behavioral and Physiological Effects of Remifentanil and Alfentanil in Healthy Volunteers

Anesthesiology ◽

10.1097/00000542-199903000-00013 ◽

1999 ◽

Vol 90 (3) ◽

pp. 718-726 ◽

Cited By ~ 35

Author(s):

Matthew L. Black ◽

Joanna L. Hill ◽

James P. Zacny

Keyword(s):

Healthy Volunteers ◽

Dose Range ◽

Subjective Effects ◽

Cold Pressor Test ◽

Drug Effects ◽

Cold Pressor ◽

Psychomotor Tests ◽

Potency Ratio ◽

Psychomotor Effects ◽

Double Blinded

Background The subjective and psychomotor effects of remifentanil have not been evaluated. Accordingly, the authors used mood inventories and psychomotor tests to characterize the effects of remifentanil in healthy, non-drug-abusing volunteers. Alfentanil was used as a comparator drug. Methods Ten healthy volunteers were enrolled in a randomized, double-blinded, placebo-controlled, crossover trial in which they received an infusion of saline, remifentanil, or alfentanil for 120 min. The age- and weight-adjusted infusions (determined with STANPUMP, a computer modeling software package) were given to achieve three predicted constant plasma levels for 40 min each of remifentanil (0.75, 1.5, and 3 ng/ml) and alfentanil (16, 32, and 64 ng/ml). Mood forms and psychomotor tests were completed, and miosis was assessed, during and after the infusions. In addition, analgesia was tested at each dose level using a cold-pressor test. Results Remifentanil had prototypic micro-like opioid subjective effects, impaired psychomotor performance, and produced analgesia. Alfentanil at the dose range tested had more mild effects on these measures, and the analgesia data indicated that a 40:1 potency ratio, rather than the 20:1 ratio we used, may exist between remifentanil and alfentanil. A psychomotor test administered 60 min after the remifentanil infusion was discontinued showed that the volunteers were still impaired, although they reported feeling no drug effects. Conclusions The notion that the pharmacodynamic effects of remifentanil are extremely short-lived after the drug is no longer administered must be questioned given our findings that psychomotor effects were still apparent 1 h after the infusion was discontinued.

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