The role of placebo in the diagnosis and treatment of functional neurologic disorders.

Placebo therapy can produce meaningful, clinical relief for a variety of conditions. While placebos are not without their ethically fraught history, they continue to be used, largely covertly, even today. Because the prognosis for psychogenic disorders is often poor and recovery may be highly dependent on the patient's belief in the diagnosis and treatment regimen, some physicians find placebo therapy for psychogenic disorders compelling, but also particularly contentious. Yet placebos also have a long tradition of being used for provocative diagnosis (wherein placebo is used to elicit and/or terminate the symptoms as a way of diagnosing symptoms as "psychogenic"). In this chapter we discuss cases describing placebo as therapy for psychogenic disorders and the challenges related to embedded Cartesian beliefs in Western medicine. The legitimate ethical reservations against placebo therapy, in general, have been related to assumptions about their "inertness" and a requirement for deception, both which are being refuted by emerging data. In this chapter, we also re-evaluate the concerns associated with placebo therapy for psychogenic disorders by asking, "Are we harming patients by withholding placebo treatment?"

Guidelines for the ethical use of neuroimages in medical testimony: report of a multidisciplinary consensus conference.

SUMMARY: With rapid advances in neuroimaging technology, there is growing concern over potential misuse of neuroradiologic imaging data in legal matters. On December 7 and 8, 2012, a multidisciplinary consensus conference, Use and Abuse of Neuroimaging in the Courtroom, was held at Emory University in Atlanta, Georgia. Through this interactive forum, a highly select group of experts-including neuroradiologists, neurologists, forensic psychiatrists, neuropsychologists, neuroscientists, legal scholars, imaging statisticians, judges, practicing attorneys, and neuroethicists-discussed the complex issues involved in the use of neuroimaging data entered into legal evidence and for associated expert testimony. The specific contexts of criminal cases, child abuse, and head trauma were especially considered. The purpose of the conference was to inform the development of guidelines on expert testimony for the American Society of Neuroradiology and to provide principles for courts on the ethical use of neuroimaging data as evidence. This report summarizes the conference and resulting recommendations.

Light and electron microscopic localization of alpha-1 adrenergic receptor immunoreactivity in the rat striatum and ventral midbrain.

Electrophysiological and pharmacological studies have demonstrated that alpha-1 adrenergic receptor (alpha1AR) activation facilitates dopamine (DA) transmission in the striatum and ventral midbrain. However, because little is known about the localization of alpha1ARs in dopaminergic regions, the substrate(s) and mechanism(s) underlying this facilitation of DA signaling are poorly understood. To address this issue, we used light and electron microscopy immunoperoxidase labeling to examine the cellular and ultrastructural distribution of alpha1ARs in the caudate putamen, nucleus accumbens, ventral tegmental area, and substantia nigra in the rat. Analysis at the light microscopic level revealed alpha1AR immunoreactivity mainly in neuropil, with occasional staining in cell bodies. At the electron microscopic level, alpha1AR immunoreactivity was found primarily in presynaptic elements, with scarce postsynaptic labeling. Unmyelinated axons and about 30-50% terminals forming asymmetric synapses contained the majority of presynaptic labeling in the striatum and midbrain, while in the midbrain a subset of terminals forming symmetric synapses also displayed immunoreactivity. Postsynaptic labeling was scarce in both striatal and ventral midbrain regions. On the other hand, only 3-6% of spines displayed alpha1AR immunoreactivity in the caudate putamen and nucleus accumbens. These data suggest that the facilitation of dopaminergic transmission by alpha1ARs in the mesostriatal system is probably achieved primarily by pre-synaptic regulation of glutamate and GABA release.

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice.

Although Parkinson's disease (PD) is characterized primarily by loss of nigrostriatal dopaminergic neurons, there is a concomitant loss of norepinephrine (NE) neurons in the locus coeruleus. Dopaminergic lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are commonly used to model PD, and although MPTP effectively mimics the dopaminergic neuropathology of PD in mice, it fails to produce PD-like motor deficits. We hypothesized that MPTP is unable to recapitulate the motor abnormalities of PD either because the behavioral paradigms used to measure coordinated behavior in mice are not sensitive enough or because MPTP in the absence of NE loss is insufficient to impair motor control. We tested both possibilities by developing a battery of coordinated movement tests and examining motor deficits in dopamine beta-hydroxylase knockout (Dbh-/-) mice that lack NE altogether. We detected no motor abnormalities in MPTP-treated control mice, despite an 80% loss of striatal dopamine (DA) terminals. Dbh-/- mice, on the other hand, were impaired in most tests and also displayed spontaneous dyskinesias, despite their normal striatal DA content. A subset of these impairments was recapitulated in control mice with 80% NE lesions and reversed in Dbh-/- mice, either by restoration of NE or treatment with a DA agonist. MPTP did not exacerbate baseline motor deficits in Dbh-/- mice. Finally, striatal levels of phospho-ERK-1/2 and DeltaFosB/FosB, proteins which are associated with PD and dyskinesias, were elevated in Dbh-/- mice. These results suggest that loss of locus coeruleus neurons contributes to motor dysfunction in PD.

Norepinephrine: The redheaded stepchild of Parkinson's disease.

Parkinson's disease (PD) affects approximately 1% of the world's aging population. Despite its prevalence and rigorous research in both humans and animal models, the etiology remains unknown. PD is most often characterized by the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc), and models of PD generally attempt to mimic this deficit. However, PD is a true multisystem disorder marked by a profound but less appreciated loss of cells in the locus coeruleus (LC), which contains the major group of noradrenergic neurons in the brain. Historic and more recent experiments exploring the role of norepinephrine (NE) in PD will be analyzed in this review. First, we examine the evidence that NE is neuroprotective and that LC degeneration sensitizes DA neurons to damage. The second part of this review focuses on the potential contribution of NE loss to the behavioral symptoms associated with PD. We propose that LC loss represents a crucial turning point in PD progression and that pharmacotherapies aimed at restoring NE have important therapeutic potential.