European Neuropsychopharmacology (v.12, #6)

For optimal function of the brain with its meticulous operations, an adequate and constant micro environment seems to be a prerequisite. This is secured by the blood–brain barrier which is impermeable to hydrophilic substances, with notable exceptions such as glucose, which cross the barrier by a mechanism of facilitated diffusion. A constant micro environment is further secured by the blood flow which is balanced to the metabolic demand of the cerebral tissue and which also contributes to the maintenance of a constant pH. During activation, blood flow and glucose consumption increase more than oxygen consumption in activated areas of the brain. The flow increase forms the physiological basis for measurement and mapping of functional activation using positron emission tomography and the changes in the metabolic pattern which has been called uncoupling of flow and oxygen metabolism is the basis for such measurements using functional magnetic resonance imaging.
Keywords: Blood–brain barrier; Cerebral blood flow; Cerebral metabolism; Glucose; Lactate; Oxygen; Functional activation; Microcirculation;

This paper reviews the contribution of human PET and SPECT neuroreceptor occupancy studies to the understanding of drug action in psychiatric illness, and how they can aid the development of new drugs. All effective antipsychotics show significant D2 receptor occupancy. However, at least for atypical antipsychotics, there is no clear relationship between occupancy and clinical response. The mechanisms underlying antipsychotic efficacy, and the minimal effective D2 occupancy, remain to be elucidated, particularly for drugs with modest or transient occupancy. The low liability of some atypical antipsychotics for extrapyramidal side effects does not appear to be explained by their 5-HT2A antagonism, and the muscarinic receptor occupancy of some drugs may be partly explanatory. Previous reports of apparent ‘limbic selectivity’ of atypical antipsychotics may be in error, and may be due to technical differences in radiotracers. For SSRIs, high occupancies at the serotonin transporter (SERT) are achieved at therapeutic doses, although the minimum SERT occupancy required for therapeutic response remains undefined. Previous attempts to augment the antidepressant effect of SSRIs by pindolol have generally used daily doses which result in inadequate 5-HT1A receptor occupancy. For benzodiazepines, clinical doses would appear to leave a wide margin of unoccupied receptors. For methylphenidate and cocaine, typical doses occupy more than 50% of dopamine transporters, and their profiles are extremely similar. In therapeutic drug development, these techniques may be used to assess receptor occupancy profiles, likely drug dosages and dosing intervals which cannot be reliably assessed in humans by other methods.
Keywords: Molecular imaging; Positron emission tomography; Single photon emission computed tomography;

Radioligand studies: imaging and quantitative analysis by Adriaan A Lammertsma (513-516).
Radioligand studies enable visualisation and measurement of molecular pathways and pharmacokinetic processes. Using positron emission tomography, accurate measurements of the time course of radioligand uptake and clearance can be obtained. A tracer kinetic model is needed to derive physiological or pharmacokinetic parameters from these tissue time–activity curves. In addition, an input function that indicates delivery to the tissue is required. Usually this will be the arterial plasma curve. For receptor studies, where binding potential is the parameter of interest, it might also be possible to avoid arterial sampling provided a tissue can be defined that is devoid of receptors.
Keywords: Positron emission tomography; Tracer kinetic modelling; Receptor studies;

Functional MRI experiments: acquisition, analysis and interpretation of data by N.F. Ramsey; H. Hoogduin; J.M. Jansma (517-526).
Functional MRI is widely used to address basic and clinical neuroscience questions. In the key domains of fMRI experiments, i.e. acquisition, processing and analysis, and interpretation of data, developments are ongoing. The main issues are sensitivity for changes in fMRI signal that are associated with brain function, and the design of tasks with which brain functions are invoked. In this paper we address these issues, in terms of strengths, weaknesses and future developments. Acquisition of data is commonly achieved with techniques that measure blood oxygen level-dependent (BOLD) signal changes. Although the mechanisms that affect BOLD signal are complex and not well understood, fMRI yields results that agree with known functional topography. Sensitivity for task-related brain activity is expected to benefit from technological advances in acquisition, i.e. SENSE or parallel imaging, and higher field scanners (3 T). Data analysis is geared towards modelling sources of signal variation, i.e. reducing noise in the data time-series, and the cerebrovascular response to task-related changes in neuronal activity. Analytical algorithms such as connectivity and component analysis contribute to the extraction of meaningful information from fMRI datasets. The choice of tasks, and consequently of the statistical evaluation procedures, is best guided by the specific questions that are formulated a priori. The future is expected to bring more sophisticated questions, and tasks that allow for accurate modelling of involved brain functions. An example of a hypothesis-driven experiment is presented, where we investigated whether practise of a working memory task caused a shift in the neuronal representation of working memory or not.
Keywords: Functional neuroimaging; fMRI; Methodology;

Neurophysiological studies of major depression performed using PET imaging have shown abnormalities of regional cerebral blood flow (CBF) and glucose metabolism in multiple prefrontal cortical and limbic structures that have been more generally implicated in emotional processing. The current study investigated the effects of antidepressant drug treatment in these regions using PET measures of glucose metabolism. Subjects with primary MDD (n=27) were imaged while unmedicated and depressed, and, of these, 20 were rescanned following chronic antidepressant drug treatment. Regional metabolism was compared between unmedicated depressives and controls and between the pre- and post-treatment conditions in regions-of-interest (ROI) where metabolism or flow had previously been shown to be abnormal in unmedicated depressives. At baseline, the mean metabolism was increased in the left and right lateral orbital cortex/ventrolateral prefrontal cortex (PFC), left amygdala, and posterior cingulate cortex, and decreased in the subgenual ACC and dorsal medial/dorsal anterolateral PFC in the unmedicated depressives relative to controls, consistent with the results of previous studies. Following treatment, metabolism significantly decreased in the left amygdala and left subgenual ACC, and corresponding changes in the orbital and posterior cingulate cortices approached significance. The metabolic reduction in the amygdala and right subgenual ACC appeared largely limited to those subjects who both responded to treatment and remained well at 6 months follow-up, in whom the reduction in amygdala metabolism tightly correlated with the reduction in HDRS scores. The magnitude of the treatment-associated, metabolic change in the amygdala also correlated positively with the change in the stressed plasma cortisol levels measured during scanning. These data converge with those from other PET studies to indicate that primary MDD is associated with abnormal metabolism in limbic and paralimbic structures of the mesiotemporal and prefrontal cortices. Chronic antidepressant drug treatment reduces metabolism in the amygdala and ventral ACC in subjects showing a persistent, positive treatment response. In contrast, the persistence of the abnormal metabolic deficits in the dorsomedial/dorsal anterolateral PFC in MDD during treatment may conceivably relate to the histopathological changes reported in these regions in post mortem studies of MDD.
Keywords: Antidepressant drug treatment; Positron emission tomography; Regional glucose metabolism;

Small animal PET by Ralph Myers; Susan Hume (545-555).
Positron emission tomography (PET) has well-established strengths which are commonly exploited in human clinical research. Not least of these are its dynamic and quantitative capabilities. The recent growth in small animal PET, spurred on by technological developments and an interest in the application of imaging to the field of genomics in mice, has seen impressive improvements in image spatial resolution. The availability of commercial small animal PET scanners has meant a broadening of the user base away from PET development environments and into experimental laboratories. This paper will review these developments and assess the impact on overall data quality.
Keywords: Small animal imaging; Positron emission tomography; Pharmacokinetics; Radioligand; Radiotracer;

Role of dopamine in the therapeutic and reinforcing effects of methylphenidate in humans: results from imaging studies by Nora D Volkow; Joanna S Fowler; Gene-Jack Wang; Yu-Shin Ding; Samuel J Gatley (557-566).
Methylphenidate is the most commonly prescribed drug for the treatment of ADHD. We have used positron emission tomography to assess the role that methylphenidate’s effects in brain dopamine have on its therapeutic and reinforcing effects. We have documented that in the human brain therapeutic doses of methylphenidate block more than 50% of the dopamine transporters and significantly enhance extracellular DA, an effect that appears to be modulated by the rate of DA release. Thus, we postulate that methylphenidate’s therapeutic effects are in part due to amplification of DA signals, that variability in responses is in part due to differences in DA tone and that methylphenidate’s effects are context dependent. Methylphenidate-induced increases in DA are also associated with its reinforcing effects but only when this occurs rapidly, as with intravenous administration. Moreover, abuse of methylphenidate is constrained by its long half-life, which we postulate limits the frequency at which it can be administered.
Keywords: Ritalin; PET; Stimulants; Cocaine; Routes of Administration; Pharmacokinetics; Abuse;

Receptor binding and drug modulation in anxiety by Andrea L Malizia (567-574).
Anxiety is an emotion that allows an individual to prepare for, or respond to, changes in the environment. For many people, however, this emotion is expressed inappropriately and impairs their lives causing considerable distress and disability. These disorders cause a great deal of personal distress, result in reduced life expectancy and, in the UK alone, have an estimated cost of approximately £5 billion per year. Despite a great deal of research, an adequate account of the mechanisms that underlie these human disorders is still lacking. An understanding of the brain substrates underlying these disorders is likely to provide such adequate explanations, but one of the principal challenges facing the investigators has been the reciprocal mapping of pre-clinical and clinical knowledge. Altogether, the last 10 years have seen a consolidation of imaging techniques. These are now mature in many areas and are likely to provide fundamental contributions in our understanding of human psychopharmacology.
Keywords: Receptor binding; Drug modulation; Anxiety;

In vivo imaging of neuroinflammation by Annachiara Cagnin; Alexander Gerhard; Richard B Banati (581-586).
We briefly outline the rationale for employing positron emission tomography (PET), using the ligand [11C](R)-PK11195, the binding site for which is highly expressed by activated microglia, in order (a) to detect in vivo neuroinflammatory changes occurring in a variety of brain diseases and at different disease stages and (b) to monitor the progression of neuroinflammation as a generic in vivo marker of ‘disease activity’. The use of [11C](R)-PK11195 PET is described as a systematic attempt at measuring the emerging phenomenology of tissue pathology itself—as opposed to measuring, for example, the loss of neuronal function or structure—and as a proof of principle for the clinical utility of imaging glial cells in vivo.
Keywords: Neuroinflammation; Positron emission tomography; [11C](R)-PK11195;

Architectonics of the human cerebral cortex and transmitter receptor fingerprints: reconciling functional neuroanatomy and neurochemistry by K. Zilles; N. Palomero-Gallagher; C. Grefkes; F. Scheperjans; C. Boy; K. Amunts; A. Schleicher (587-599).
The density of transmitter receptors varies between different locations in the human cerebral cortex. We hypothesized that this variation may reflect the cyto- and myeloarchitectonical as well as the functional organisation of the cortex. We compared data from different imaging modalities (postmortem studies: cyto- and myeloarchitecture, quantitative in vitro receptor autoradiography; in vivo studies: PET receptor neuroimaging) in order to test our hypothesis. The regional and laminar distribution of the densities of numerous receptor types representing all classical transmitter systems as well as the adenosine system are visualized and measured in different cortical areas. The receptor distribution patterns segregate motor, primary sensory, unimodal sensory, multimodal association and other functionally identified cortical areas from each other. Areas of similar function show similar receptor fingerprints and differ from those with other properties. Thus, receptor distribution patterns reflect an organisational structure strictly correlated with the architectonics and functions of the human cerebral cortex.
Keywords: Human brain; Cerebral cortex; Neuroanatomy; Neuroimaging; Glutamate; GABA; Acetylcholine; Dopamine; Noradrenaline; Serotonin; Adenosine;

The use of functional magnetic resonance imaging (fMRI) to follow random or serial sequences of neural activity is explored and illustrated with examples that include auditory hallucinations and a short-term memory paradigm. Despite the availability of ultra-high-speed fMRI sequences, the inherent latency of the haemodynamic response limits the time resolution of fMRI studies. To access finer time-scales, it can be combined with electromagnetic techniques (MEG or EEG). Functional magnetic resonance spectroscopy (MRS) studies, in which infusion of [1-13C]glucose enables rates of the tricarboxylic acid cycle to be determined, demonstrates substantial (50%) increases in this flux on visual activation. Not only does this provide a quantitative estimate of the energy cost of brain activation, it also shows that the extra glucose is consumed essentially oxidatively. In the same studies, measurements of the rate of glutamine synthesis, enable the rate of recycling of neurotransmitter glutamate to be estimated.
Keywords: Functional magnetic resonance imaging (fMRI); Magnetic resonance spectroscopy (MRS); MEG; Cerebral metabolism; Glutamate;

Author Index (609-612).

Keyword Index (613-622).

Volume Contents (623-627).