Chemogenetic studies with the ligand clozapine N-oxide (CNO) are predicated upon the assumption that CNO is devoid of actions at natural neuroreceptors. However, recent evidence shows that CNO may be converted back to clozapine (CLZ) in vivo , which could yield plasma concentrations that may be sufficient to occupy inter alia dopamine D 2/3 and serotonin 5HT 2A receptors in living brain. To test this phenomenon, we measured striatal dopamine D 2/3 receptor occupancy with [ 18 F]fallypride PET and serotonin 5HT 2A occupancy ex vivo using [ 18 F]MH.MZ. We found a CNO dose-dependent effect on the availability of both neuroreceptor sites. In parallel MR spectroscopy experiments, we found that CNO reduced creatine + phosphcreatine (Cr+PCr) and increased N -acetylaspartate + N -acetylaspartylglutamate (NAA+NAAG) signals in the prefrontal cortex, and also reduced the glutamate signal in dorsal striatum, with peak effect at 2 mg/kg. Thus, our findings suggest that conversion of CNO to CLZ in living rats imparts significant occupancy at endogenous neuroreceptors and significant changes to neurometabolite levels.

Background Although B waves were introduced as a concept in the analysis of intracranial pressure (ICP) recordings nearly 60 years ago, there is still a lack consensus on precise definitions, terminology, amplitude, frequency or origin. Several competing terms exist, addressing either their probable physiological origin or their physical characteristics. To better understand B wave characteristics and ease their detection, a literature review was carried out. Methods A systematic review protocol including search strategy and eligibility criteria was prepared in advance. A literature search was carried out using PubMed/MEDLINE, with the following search terms: B waves + review filter, slow waves + review filter, ICP B waves, slow ICP waves, slow vasogenic waves, Lundberg B waves, MOCAIP. Results In total, 19 different terms were found, B waves being the most common. These terminologies appear to be interchangeable and seem to be used indiscriminately, with some papers using more than five different terms. Definitions and etiologies are still unclear, which makes systematic and standardized detection difficult. Conclusions Two future lines of action are available for automating macro-pattern identification in ICP signals: achieving strict agreement on morphological characteristics of “traditional” B waveforms, or starting a new with a fresh computerized approach for recognition of new clinically relevant patterns.

Intracranial pressure (ICP) B‐waves are defined as short, repeating elevations of ICP of up to 50 mmHg with a frequency of 0.5–2 waves/min. The presence of B‐waves in overnight recordings is regarded as a pathological phenomenon. However, the physiology of B‐waves is still not fully understood and studies with transcranial Doppler, as a surrogate marker for ICP, have suggested that B‐waves could be a normal physiological phenomenon. We present four patients without known structural neurological disease other than a coincidentally found unruptured intracranial aneurysm. One of the patients had experienced well‐controlled epilepsy for several years, but was included because ICP under these conditions is unlikely to be abnormal. Following informed consent, all four patients had a telemetric ICP probe implanted during a prophylactic operation with closure of the aneurysm. They underwent overnight ICP monitoring with simultaneous polysomnography (PSG) sleep studies at 8 weeks after the operation. These patients exhibited nocturnal B‐waves, but did not have major structural brain lesions. Their ICP values were within the normal range. Nocturnal B‐waves occurred in close association with sleep‐disordered breathing (SDB) in rapid eye movement (REM) and non‐REM sleep stages. SDB during REM sleep was associated with ramp‐type B‐waves; SDB during non‐REM sleep was associated with the sinusoidal type of B‐wave. We propose that B‐waves are a physiological phenomenon associated with SDB and that the mechanical changes during respiration could have an essential and previously unrecognised role in the generation of B‐waves.