Neuroethics overview

The reach of neuroscience is unusually broad. As the title of this book indicates, our present interest in neuroscience extends all the way from cells to cognition – from how neurons operate at the microscopic level to how people think, speak, perceive, and remember at the macroscopic level. Given that the brain is the most complex structure in the known universe, this breathtaking breadth may come as no surprise and makes it understandable why neuroscience is of compelling interest to engineers, physicians, computer scientists, and even to musicians.

The reach of our concerns is so great that it engages even philosophers, including those grappling with the most difficult – perhaps intractable – questions of them all, those touching on the question of human choice and free will. In this special chapter with which we lead off this book, the noted philosopher Patricia Churchland takes on the challenge of reconciling the seemingly deterministic neurological system underlying human choice behavior, the common belief in free will, and the question of who, if anyone, is responsible for the behavior of human beings. When people commit crimes or other ethical breeches, may they rightfully claim that “their neurons made them do it”? Or, is there lurking within their nervous systems an accountable agent that must take responsibility for decisions made?

Introduction

The language system is that aspect of mind/brain function that forms the basis for phonological, morphological, syntactic, and semantic computation. The “currencies” (or the ontology) of this central and abstract computational system are representations that are amodal, for example the concepts “feature” (phonology) or “affix” (morphology) or “phrase” (syntax) or “generalized quantifier” (semantics). Representation and computation with such concepts is typically considered independent of sensory modalities. Of course, the linguistic computational system is not isolated but interacts with other cognitive systems and with sensory–motor interface systems.

With regard to the input and output, the system has at least three modality-specific interfaces: an acoustic-articulatory system (speech perception and production), a visuo-motor system (reading/writing and sign), and a somatosensory interface (Braille). Speech and sign are the canonical interfaces and develop naturally; written language and Braille are explicitly taught: barring gross pathology, every child learns to speak or sign (rapidly, early, without explicit instruction, to a high level of proficiency), whereas learning to read/write Braille requires explicit instruction, is not universal, and occurs later in development.

In this chapter we focus on speech perception, specifically with regard to linguistic constraints and cortical organization. We first outline the key linguistic assumptions, including the concept of “distinctive feature,” and then discuss a functional-anatomic model that captures a range of empirical findings.

The linguistic basis of speech perception

The central importance of words for language use and understanding

An essential part of the cognitive ability underlying the linguistic behavior of a competent speaker of a language consists of knowing the words of the language or their constituents (roots).

Introduction

Although the past decade has witnessed many advances in the basic science and clinical practice of sleep medicine, perhaps none has been more significant than the discovery of the orexin (also called hypocretin) neuropeptides that are produced in the lateral hypothalamus (LH). Failure of orexin signaling causes narcolepsy–cataplexy in humans and animals. In this chapter, we briefly review current knowledge about orexins and the symptoms of narcolepsy–cataplexy in humans. We discuss the molecular genetic analysis of the narcolepsy–cataplexy syndrome through phenotypic characterization of rodents genetically modified to be deficient in orexins or orexin receptors. These studies point to the mechanisms by which orexins promote arousal and gate sleep in normal animals; they thus have important therapeutic implications for disorders of sleep and wakefulness. We conclude with recent data implicating melanin-concentrating hormone (MCH), a related hypothalamic neuropeptide system, in the modulation of arousal. Orexin and MCH may act in concert to stabilize vigilance states, suggesting a more significant role for the LH in sleep–wakefulness regulation than previously appreciated.

The orexin neuropeptide system

Orexins are two hypothalamically expressed neuropeptide sequences, the gene for which was described concurrently and independently by two groups using different biochemical and genetic approaches (de Lecea, This volume, de Lecea et al., 1998; Sakurai et al., 1998).

The chapter will summarize our current understanding of the neuronal and neurochemical basis of hypnogenesis. The hypothesis of the localization of a hypnogenic mechanism in the mammalian hypothalamic preoptic area (POA) was first proposed by von Economo more than 70 years ago (von Economo, 1930). This hypothesis has been confirmed by findings that experimental POA lesions suppress sleep, and that electrical, chemical, and thermal POA stimulation induce sleep (reviewed by McGinty & Szymusiak, 2001). Unit recording studies have identified POA neurons that exhibit increased activity during NREM sleep, REM sleep, or both. These sleep-active neurons are hypothesized to be the substrate of the hypnogenic mechanism. The past decade has seen substantial progress in the further description of this hypnogenic system; we summarize this progress in this chapter.

Localization of sleep-active neurons within the POA

Studies of sleep-active neuronal discharge across the sleep–wake cycle in freely moving animals provide important information about the hypnogenic process (see below) but, because of sampling limitations, are not suitable for systematic mapping of the exact locations of putative hypnogenic neurons. The application of the c-Fos immunoreactivity (IR) method to map sleep-active neurons has stimulated several advances. C-Fos IR is a marker of neuronal activation in most brain sites; immunohistochemically labeled neurons can be mapped systematically.

Seventy years ago Otto Loewi and Henry Dale shared the 1936 Nobel Prize for the discovery that acetylcholine (ACh) is a neurotransmitter. Loewi's Nobel Lecture provided the following historical context for their discovery (Loewi, 1936): “Up until the year 1921 it was not known how the stimulation of a nerve influenced the effector organ's function, in other words, in what way the stimulation was transmitted to the effector organ from the nerve-ending.” The significance of Loewi's and Dale's discovery is emphasized by the profound relevance of ACh for sensorimotor, autonomic, and arousal state control. At all neuromuscular junctions ACh is the transmitter. For the autonomic nervous system, all preganglionic sympathetic and parasympathetic nerves use ACh, as do postganglionic fibers of the parasympathetic nervous system. In the context of the present volume, the effector organ of sleep is the brain. Therefore, this chapter focuses on the role of cholinergic “nerve endings” through which “the effector organ” generates states of sleep and wakefulness. This chapter uses Loewi's synaptic perspective to review data from many laboratories demonstrating that cholinergic synaptic mechanisms (Fig. 5.1) regulate levels of arousal.

Blocking degradation of ACh activates the EEG and enhances REM sleep

The discovery of rapid eye movement (REM) sleep (Aserinsky & Kleitman, 1953) as a state of enhanced electroencephalographic (EEG) activity implied the existence of endogenous neurochemical mechanisms underlying rhythmic oscillations in brain excitability.

Introduction

Determining the underlying therapeutic mechanisms of a drug makes pharmacology a powerful tool for understanding biological phenomena. This chapter reviews the preclinical evidence of the impact of some neurotransmitter systems and related drugs on sleep and wakefulness.

GABA-A and sleep

A series of neurotransmitter systems are responsible for maintaining wakefulness, including norepinephrine (NE), serotonin (5-HT), acetylcholine (ACh), dopamine (DA), excitatory amino acids, hypocretins (i.e. orexins), and histamine (Mendelson 2001; Monti and Jantos 2004; Salin-Pascual et al. 1999; Ursin 2002; Sakurai 2005). Delta sleep, or non-REM sleep, is related to adenosine, GABA, and prostaglandins, among others (Ekimova and Pastukhov 2005; Hayaishi and Matsumura 1995; Johnston 2005; Koyama and Hayaishi 1994). Finally, ACh has a prominent role in rapid eye movement (REM) sleep, together with 5-HT, NE, and hypocretin; these three molecules inhibit cholinergic and cholinoceptive neurons, which are implicated in the initiation of this sleep stage (McCarley 2004; Reinoso-Suarez et al. 2001).

GABA, and molecules that act at GABA-A receptors, have been classically recognized as hypnotics (i.e. benzodiazepines) and anesthetics (i.e. barbiturates). Benzodiazepine (BZD) receptors, a modulatory site on the GABA-A receptor, were discovered in the 1970s. Like other sites on the GABA-A receptor complex, these receptors work allosterically, cooperatively modifying channel permeability to chloride ions.

Biosynthesis and metabolism of melatonin

Melatonin was isolated in 1958 by Lerner and his associates, its chemical nature being identified as N-acetyl-5-methoxytryptamine (Lerner et al. 1958, 1959) (Fig. 10.1). In vertebrates, melatonin is primarily secreted by the pineal gland. Synthesis also occurs in other cells and organs including the retina (Cardinali and Rosner 1971; Tosini and Menaker 1998; Liu et al. 2004), human and murine bone marrow cells (Conti et al. 2000), platelets (Champier et al. 1997), gastrointestinal tract (Bubenik 2002), skin (Slominski et al. 2005a,b), or lymphocytes (Carrillo-Vico et al. 2004). However, circulating melatonin is derived only from the pineal gland, as shown by its disappearance after pineal removal. Since there is no storage of melatonin in the pineal gland, and since the circulating melatonin is degraded rapidly by the liver, plasma levels of melatonin reflect pineal biosynthetic activity.

Melatonin secretion is synchronized to the light/dark (LD) cycle, with a nocturnal maximum (in young humans, about 200 pg/ml plasma) and low diurnal baseline levels (about 10 pg/ml plasma). Studies have supported the value of the exogenous administration of melatonin in circadian rhythm sleep disorders, insomnia, cancer, neurodegenerative diseases, disorders of the immune function, and oxidative damage (Karasek et al. 2002; Pandi-Perumal et al. 2005, 2006; Srinivasan et al. 2005a,b, 2006; Hardeland et al. 2006).

Although many questions remain about the complicated role of serotonin and its receptors in regulating sleep and waking, recent neurochemical, electrophysiological, and neuropharmacological studies have revealed much detailed information about this process.

Neural structures and neurotransmitters involved in the regulation of sleep and waking in laboratory animals

The neural structures involved in the promotion of the waking (W) state are located in the (1) brainstem [dorsal raphe nucleus (DRN), median raphe nucleus (MRN), locus coeruleus (LC), laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT), and medial-pontine reticular formation (mPRF)]; (2) hypothalamus [tuberomammillary nucleus (TMN) and lateral hypothalamus (LH)]; (3) basal forebrain (BFB) (medial septal area, nucleus basalis of Meynert); and (4) midbrain ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) (Pace-Schott & Hobson, 2002; Jones, 2003). The following neurotransmitters function to promote W: (1) acetylcholine (ACh: LDT/PPT, BFB); (2) noradrenaline (NA: LC); (3) serotonin (5-HT: DRN, MRN); (4) histamine (HA: TMN); (5) glutamate (GLU: mPRF, BFB, thalamus); (6) orexin (OX: LH); and (7) dopamine (DA: VTA, SNc) (Zoltoski et al., 1999; Monti, 2004).

The neural structures involved in the regulation of W give rise to mainly ascending projections. In this respect (1) NA-, 5-HT-, and HA-containing neurons send long ascending projections to the forebrain and cerebral cortex; (2) DA-containing cells project into the basal ganglia and the frontal cortex; (3) cholinergic neurons from the midbrain tegmentum project to the thalamus (ventromedial, intralaminar, and midline nuclei) and the BFB, and cholinergic BFB neurons have widespread rostral projections to the cerebral cortex and the hippocampus; (4) orexin-containing neurons from the LH project to the entire forebrain and brainstem arousal systems; and (5) glutamatergic neurons make up the projection neurons of the mPRF and thalamus (Baghdoyan & Lydic, 2002; Jones, 2003).

Neurochemistry of Sleep and Wakefulness focuses on the actions and interactions of neurotransmitters involved in the control and modulation of the behavioral states that we know as waking and sleeping. It presents results and emerging concepts that in recent years have challenged our understanding about the basic brain systems that are involved in sleep and wakefulness. As might be expected, these new findings are also having an effect on the practice of sleep medicine. In fact, once considered a minor sub-specialty, sleep medicine is developing into a significant and growing area of medicine; and much of this growth can be attributed to improved knowledge about brain neurochemistry and the drugs that have been developed as a result.

Thus, inevitably, the relationship between sleep and the chemistry of neurotransmission has become an area of intense medical, biological, and scientific interest. It seemingly affects all facets of our health and well-being. But this relationship is also complex because it involves fundamental, yet still incompletely understood mechanisms and functions in the brain, most notably the essential difference between sleep and wakefulness. Although this field of research in its current form began with the identification of specific chemical neurotransmitter systems in the brain some forty years ago, we can actually date the beginning of research into sleep neurochemistry to the onset of the twentieth century.