Noninvasive Visualization of Serotonergically Mediated Pathophysiology

As described in the article MDMA (“Ecstasy”) and Its Predisposition to Cerebrovascular Accidents: Preliminary Results in this issue of the AJNR (page 1001), the acute and chronic morbidity associated with recreational serotonergic drug abuse seems to be escalating. At the same time, serotonergic drugs are becoming increasingly important for the treatment of several peripheral and central nervous system disorders. These factors suggest that neuroradiology could benefit from the development of imaging that can reveal the pathophysiologic changes mediated by serotonin.

Radiopharmaceuticals that behave like serotonergic drugs have a role in the research of 3,4-methylenedioxymethamphetamine (MDMA)-induced brain dysfunction. Reneman et al effectively used a serotonergic radioligand, iodine-123 [¹²³] labeled R91150, to show that there are subacute and chronic pathophysiologic consequences of abusing MDMA. The etiology may not be completely clear because several mechanisms of action probably contribute to MDMA-mediated axonal injury and death. It does seem certain, however, that a noninvasive technique for visualizing the adverse effects of MDMA on serotonergic neurons in the brain has been developed successfully. As a single-photon emission CT (SPECT) ligand, R91150 has the potential for use on existing equipment in most conventional medical facilities. This could greatly accelerate research, but will not be enough to understand the pharmacology of drugs like MDMA. Direct measurements of the other physiologic processes that the drugs influence are still needed.

Functional MR (fMR) imaging may be a nearly ideal technology for furthering this work. Changes in regional cerebral blood flow usually reflect changes in regional brain metabolism. The majority of the energy consumed by the brain reflects the work required to conduct neural transmission (1). It follows that changes in fMR imaging signals ultimately reflect drug-induced changes in neural transmission. Extrapolating in the opposite direction, the lack of appropriate changes in fMR imaging signals may reflect deranged neural transmission, including MDMA toxicity. Nonetheless, as the authors note, the relationships may not be completely straightforward.

A vast amount of literature shows that drug-induced changes in brain function and behavior are complex, and these changes sometimes are located far from areas of direct drug action. Indirect drug effects in distant areas are produced only occasionally by a direct drug action on the structures that the distant neurons reciprocally innervate. Distant effects can be complicated because the brain actively resists the perturbation of homeostasis caused by drugs. The introduction of foreign drug substances that bind receptors will perturb steady-state neurotransmitter tone, but the metabolic response by the brain can depend on many extraneous factors, such as the dose, rate, and frequency of administration. Agonists sometimes decrease the amount of work necessary to maintain neurotransmitter tone by providing artificial stimulation to the system. As a consequence, agonists can reduce blood flow in regions they bind directly, while increasing blood flow in distant target areas where they do not. Antagonists can have the opposite effect. These generalizations are, however, not laws of nature, but rather observations in some patients taking some drugs some of the time.

Investigators have noted that systemically administered drugs frequently have regionally specific effects that may be the opposite of their effects on other areas. Several mechanisms can produce this phenomenon. Most commonly, different neuroreceptor subtypes have different topographical distributions; however, the same receptor subtype will sometimes produce opposite effects in different regions of the brain (2). Selectively activating receptors in one region may inhibit the same receptors in another. As a result, it is not always clear if a drug is activating an inhibitory group of neurons or inhibiting an activating group. Many permutations of compensatory reflexes are possible.

The period between changes in neuronal transmission and changes in regional brainwork is rarely well known, which makes the usual assumption that changes in cerebral hemodynamics are instantaneous seem precarious. Advantages of [O-15] positron emission tomography (PET) and fMR imaging include the ability to make repeated measurements over short intervals during a single imaging session. Freeze-framed tracers, like fluorodeoxyglucose and all the currently available SPECT perfusion tracers, only allow one image of flow or metabolism to be acquired in a single session. This limitation obviates the ability to measure the time course of acute drug action. In contrast, fMR imaging, like [O-15] PET, has the potential to measure pharmacokinetic-equivalent curves. fMR imaging measurements can be made even faster than [O-15] PET, and without engendering more radiation dosimetry with each sampling, which makes fine temporal resolution possible. Within-session, within-subjects designs can still be confounded by the stressors that are inherent in almost any neuroimaging procedure. Since psychological perceptions of, and biological responses to, external stressors can be highly variable within subjects, it is essential to design studies in a way that allows subjects to acclimate to the scanner before making critical measurements.

Even then, true biological variability can make defining a normal response to a drug difficult. Some drugs appear to increase cerebral flow and metabolism as often as they decrease them. This tends to make the group mean response to some drugs zero, and makes single-image, cross-sectional designs of drug effects on blood flow particularly problematic regardless of the technique used to visualize perfusion or one of its surrogates.

There are also extracerebral effects of drugs that have an impact on brain function and can confound the understanding of their central mechanisms of action. For example, psychostimulants like MDMA frequently cause reduced food intake. There are powerful somatic responses to starvation that produce their own effects on the brain. Metabolic, as well as gonadal, hormone levels invariably are perturbed, which also produces effects on the brain. Whereas not many systematic investigations of somatic MDMA toxicity have been conducted, its capacity to produce fatal hyperthermia suggests that it may produce many systemic effects that could have an impact on brain function.

This report emphasizes yet another potentially confounding situation produced by the direct effects of MDMA on the vasculature. Serotonin clearly contributes to symptom formation in migraine, and, as the authors note, there is growing anecdotal evidence that suggests that MDMA abuse is associated with stroke. A drug effect that can lead to stroke in major vessels also may be capable of producing microscopic vascular disease. This could make it difficult to determine if chronic decreases in blood flow or one of its surrogate measures reflect changes in the vasculature, or represent down regulation because a neurotoxic effect has limited the amount of work performed by the neurons. It also makes it difficult to determine if changes in neuroreceptor ligand activity represent decreased delivery of the radiopharmaceutical secondary to vascular disease, decreased numbers of neurons secondary to ischemic damage, or pathophysiologic down regulation secondary to other drug effects on the neurons themselves.

These issues constitute challenges that sometimes appear formidable; however, the field has no choice but to attack them vigorously. The fact that patients with serotonergic drug abuse–related neuropsychiatric disorders sometimes suffer immense psychological anguish makes it morally imperative for medical research to push the field forward. The fact that society is economically, as well as culturally, impoverished by serotonergic drug abuse and its consequences makes further investigation pragmatic. On both levels, the authors have reported several major contributions to the field. They have shown that it seems possible to measure physiologic correlates of serotonergic drug abuse. Publicizing hard data that show persistent brain dysfunction resulting from abuse of MDMA may help prevent many people at risk from ever experimenting with the drug. It may not be important that complete characterization of the pathophysiologic processes that produce brain damage are not clear yet. What seems most relevant is demonstrating, as the authors have, that imaging technologies and scientific paradigms have been developed that validate social and political decisions to support research in this field.