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HILLYARD AND MARTA KUTAS To uncover the neural bases of a cognitive process it is extracellular fluid produce ERPs, the flow of synaptic cur- important both to identify the participating brain regions rent through neuronal processes produce ERFs, thereby giv- and determine the precise time course of information trans- ing rise to concentric magnetic fields surrounding the cell. Although neu- When a sufficient number of neurons having a similar ana- roimaging techniques based on cerebral blood flow or me- tomic configuration are synchronously active, their sum- tabolism (e. Noninvasive recordings of the lation of generator locations from surface field distributions electrical and magnetic fields generated by active neuronal is known as the inverse problem, which typically has no populations, however, can reveal the timing of brain activity unique solution. However, the validity of inverse source related to cognition with a very high, msec-level resolution. In general, sensory, motor, or cognitive events are known as event- the localization of active neural populations is more straight- related potentials (ERPs) and the corresponding magnetic forward with surface recordings of ERFs than with ERPs, field changes are termed event-related fields (ERFs). Both because magnetic fields, unlike electrical fields, are mini- ERPs and ERFs consist of precisely timed sequences of mally distorted by the physical properties of the intervening waves of varying field strength and polarity (Fig. The general research strategy has been to discover whereas others consider ERP/ERF components to be those the mapping between the components of the waveform and waveform features that are associated with a particular cog- specific cognitive processes that are engaged by a particular nitive process or manipulation (2). When an ERP/ERF component can be shown to be are generated primarily by the flow of ionic currents in a valid index of the neural activity underlying a cognitive elongated nerve cells during synaptic activity. Whereas syn- operation, that component can yield valuable information aptic currents flowing across nerve cell membranes into the about the presence or absence of that operation and its tim- ing with respect to other cognitive events. In many cases, such data have been related to psychological models of the Steven A. Hillyard: Department of Neurosciences, University of Califor- underlying processing operations and used to test alternative nia, San Diego, La Jolla, California. Marta Kutas: Department of Cognitive Science, University of California, theoretical positions. In addition, by localizing the neural San Diego, La Jolla, California. The characteristic waveform of the auditory event-re- latedpotentialfollowingabriefstim- ulus such as a click or tone. The indi- vidual components (peaks and troughs) are evoked with specific time delays (latencies) after stimulus onset. Note the logarithmic time base, which makes it possible to visu- alize the earliest waves (I–VI) gener- ated in the auditory brainstem path- ways. Longer latency negative (N) and positive (P) components are gen- erated in different cortical areas. Dashedlineshowsincreasednegativ- ityelicitedbyattendedsounds(nega- tive difference) or by deviant sounds (mismatch negativity), and dotted line shows N2 and P3 components to task-relevanttargetstimuli. The use of ERP/ERF recordings to evaluate cognitive disorders associated with The P50 and SensoryGating neurobehavioral and psychopathologic syndromes also is re- The refractory properties of the auditory P50 (P1) compo- viewed. In the standard paradigm, pairs of PREATTENTIVE SENSORY PROCESSING auditory stimuli are presented with an ISI of 0. In nents as well, represent sensory-evoked neural activity in general, schizophrenic subjects do not show as large a reduc- modality-specific cortical areas. These evoked components tion in the P50 amplitude to S2 relative to S1 as do normal vary with the physical parameters of the stimuli and in many controls. This refractory reduction of P50 amplitude to S2 cases are associated with the preattentive encoding of stimu- has been interpreted as a sign of preattentive sensory gating, lus features. In the visual modality, for example, the early which occurs because the initial S1 automatically activates C1 component (onset latency 50 to 60 msec) originates an inhibitory system that suppresses responsiveness to S2 (9, in retinotopically organized visual cortex (5) and varies in 10). This inhibitory system presumably prevents irrelevant amplitude according to the spatial frequency of the stimulus information from ascending to higher levels of cortical pro- (6). Similarly, the early auditory cortical components P50 cessing. The abnormally large S2/S1 amplitude ratio for and N100 (and their magnetic counterparts, M50 and P50 seen in schizophrenics was thus considered evidence M100) arise in part from generators in tonotopically organ- for impaired sensory gating, which was suggested to be the ized supratemporal auditory cortex and reflect the encoding principal sensory deficit of the disease process. This pattern of more rapid P50 recovery in schizophrenia In general, ERP amplitudes decrease when the time be- has been widely reported, but there have been some notable tween successive stimulus presentations is made shorter than exceptions that raise questions about the exact conditions the refractory or recovery period of the component under needed to produce the effect (13–15). Although the neural processes underlying ERP refrac- tion, however, is whether existing studies have, in fact, dem- tory effects are not well established, some candidate mecha- onstrated a reliably abnormal S2/S1 ratio of the auditory nisms include synaptic fatigue, active inhibition, and the P50 in schizophrenics. This concern stems from the way the Chapter 32: Event-Related Potentials and Magnetic Fields 429 P50 has typically been measured—as the maximal positive parator process that contrasts current auditory input against amplitude within a time window (e. Such peak measures may be features held in preperceptual sensory memory. This mis- artificially inflated by increased levels of background noise match detection process may represent an early stage in the in the EEG recordings, originating from either intracranial alerting and orienting of the organism toward novel and or extracranial sources. Thus, if a patient group has higher potentially important changes in the acoustic environment. This type of error is more the memory traces of the preceding sounds (23). Indeed, pronounced when measuring the P50 to S2, because its the maximal interstimulus interval (ISI) at which the MMN amplitude is diminished relative to the noise owing to re- can be maintained is of the order of 10 sec, corresponding fractory effects. Reports of increased variability and lower well with behavioral estimates of the duration of echoic reliability of P50 measures in schizophrenics (12,16) suggest memory (19,20). The MMN also can be used to study more that background noise levels are indeed higher in the patient permanent auditory memory traces, such as those for the groups. Further of the MMN originating in auditory cortex reflects the pre- studies are needed to determine whether the actual S2/S1 attentive sensory store and automatic change detection pro- amplitude ratio is reliably higher in schizophrenics, or cess, whereas a frontal component indexes the involuntary whether this reported effect is a product of noise-sensitive orienting of attention to the deviant event (24,25). There is little evidence cortex is the locus of language-specific auditory traces (19). Nor does it for the diagnosis and evaluation of a variety of neurobehav- appear that the amplitude of P50 to S2 is reduced only ioral and psychiatric disorders (24,26). Schizophrenic pa- when S2 is irrelevant (17), calling into question the hypoth- tients have reduced or prolonged MMNs to pitch or dura- esis that the P50 refractory effect reflects the selective gating tion deviants, with the degree of abnormality depending on of irrelevant versus relevant sensory inputs. In addition, it the specific parameters of the stimulus deviance (24,27,28).

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Thus cheap 20mg forzest mastercard, other mechanisms likely contribute that subunit who have less nicotine-induced dopamine re- to the rewarding properties of nicotine in the latter portion lease and do not self-administer nicotine as do wild-type of the daily cycle of smoking (49) generic forzest 20 mg mastercard. Nicotine increases or decreases brain serotonin levels discount forzest 20 mg visa, de- When nicotine binds to nicotine receptors order 20mg forzest with amex, allosteric pending on concentration and pattern of exposure (16). A changes lead to different functional states including a resting possible role for serotonin release in reward mechanisms is state, an activated state (channel open), and two desensitized suggested by selective serotonin (5-HT3) antagonists that states (channel closed) (10). Receptor change to the desensi- reduce nicotine reinforcing effects. Chronic exposure to nic- tized state probably accounts for tolerance and for the obser- otine results in reduced capacity to synthesize 5-HT in sero- vation that tolerance to nicotine is associated with increased tonergic terminals. Postmortem human studies indicate that numbers of nicotinic cholinergic receptors in animals dur- tobacco smoking is associated with reductions in hippocam- ing chronic nicotine treatment and in brains of human pal 5-HT and 5-hydroxyindole acetic acid (16). The mesolimbic dopamine system is assumed to release could result in anxiety and related symptoms com- mediate pleasurable and other rewards from nicotine as with mon during the early stages of nicotine withdrawal (49). Nicotinic receptors are on the nerve Nicotine-mediated release of norepinephrine plays a role terminal membranes in the nucleus accumbens and on in the release of adrenocorticotropic hormone (ACTH) and membranes of the dopamine-secreting neurons innervating cortisol. Nicotine, acting on -7 cholinergic receptors, re- nucleus accumbens located in the midbrain. Unlike cocaine leases glutamate, enhances fast excitatory synaptic trans- and amphetamine, which exert effects by binding to pre- mission possibly contributing to improved learning and synaptic dopamine transporters on nerve terminal mem- memory (28,36), and regulates dopaminergic function. As happens after with nicotine-increased burst firing an adaptive reaction to repeated exposure to other stimulants, repeated exposure to stressful situations (49). Activation of nicotinic cholinergic nicotine results in sensitization of its effects on dopamine receptors in the adrenal medulla releases epinephrine and release in the accumbens. In this the importance of sensory phenomena in cigarette smoking respect, some consequences of repeated nicotine exposure satisfaction and important in shaping conditioned aspects on these pathways are similar to those of other stimulant of smoking behaviors. For example, intravenous nicotine 1536 Neuropsychopharmacology: The Fifth Generation of Progress produces burst firing of locus ceruleus neurons before in- dicting drugs, including tobacco, has been hypothesized to jected nicotine reaches the brain (47). After an initial rapid result in a negative affect state with dysphoria, malaise, and onset, brief activation that can be blocked by a peripheral inability to experience pleasure that has been termed hedonic nicotine antagonist, a second longer-lasting activation, me- dysregulation (84). Smokers may be protected from such diated by central nicotinic receptors, occurs (31). Consistent with a notion that nicotine may be self-ad- ministered by some smokers to manage affective disorders is an uncontrolled study reporting that transdermal nicotine NATURAL HISTORY OF NICOTINE lessened depression in nonsmokers with major depression DEPENDENCE (56). Another intriguing connection is that cigarette smok- ing inhibits activity of brain monoamine oxidase (MAO) Most nicotine addicts begin smoking during adolescence. A and B as measured in the brains of smokers and nonsmok- Adolescent smoking has been increasing since the 1990s. Smokers have a 30% to 40% suppression of brain Each day, 6,000 more begin. Medications that inhibit MAO be dependent on nicotine within their first year of smoking. Conceivably, ciga- Adolescent daily smokers appear to inhale doses of nicotine rette smoking could have similar effects. Finally, some re- similar to doses inhaled by adults. When asked, about 50% searchers suggest that links between depression and cigarette report wanting to quit, and 71% report having tried and smoking result from a common genetic predisposition (42). Adolescents report withdrawal symptoms similar Schizophrenia is a risk factor for nicotine addiction; ap- to those reported by adults (32). An abnormality in neuronal nicotinic acetylcholine in adolescent smokers in the United States are comparable receptor expression or function may be involved in the neu- to those of addicted adult smokers. Young, still experiment- ropathophysiology of schizophrenia. Nonschizophrenic ing smokers are likely to become regular smokers; however, smokers have increased nicotinic receptor binding in post- the proportion of adolescents who go on to regular smoking mortem brain hippocampus, cortex, and caudate with in- and what influences the progression remain obscure. In contrast, schizophrenic smokers first symptoms of nicotine dependence occur within weeks have reduced nicotinic receptor levels, a finding suggesting of the onset of occasional use, often before daily smoking abnormal regulation of high-affinity neuronal nicotinic re- begins (7). As many as one-third to one-half of adolescents ceptors after nicotine use (43). One theory linking schizo- experimenting with cigarettes become regular smokers. Adolescents have less interest in treatment, high treat- diated by functions of the -7 nicotinic cholinergic receptor ment dropout rates, and low quitting rates (20). Cigarette smoking and nicotine improve abnormal of adolescent tobacco smoking conclude that better charac- sensory gating in humans and animals. The abnormality of terization of nicotine dependence (35) and assessment of sensory gating in schizophrenia has been linked to the gene pharmacotherapies are needed, given the almost epidemic also encoding the -7 subunit (45). Dependence on alcohol, heroin, cocaine, and other drugs frequently coexists with nicotine addiction (4). Alcohol and nicotine addiction have common heritability (46,60). Stim- RISK FACTORS ulant drug exposure may cross-sensitize to neurochemical effects of other stimulants, so nicotine and other stimulants Comorbidity enhance the effects of one another (14,48). Because all ad- Some smokers report that smoking helps relieve their dicting drugs release dopamine in the mesolimbic system, depression and other mood disorders. Others become se- drugs may be interacting or substituting for one another to verely depressed when they stop smoking (16,52). Smokers produce common changes in dopamine-related reinforce- are more likely to have experienced major depression, and ment. Several mechanisms may link smoking and depression (16). Genetics Depression sensitizes patients to the dysphoric effects of stressful stimuli. Nicotine-related decreases in 5-HT formation and cant proportion in the variation in the use of tobacco in release in the hippocampus could be a factor. Stopping ad- twin studies, with heritabilities estimated to be as high as Chapter 107: Therapeutics for Nicotine Addiction 1537 84% and 82% for liability to lifetime and current tobacco The alterations in synaptic function plausibly would ac- use, respectively (9), influencing both initiation and mainte- count for associated behavioral disruptions evident in hu- nance of tobacco smoking (60). Another twin pair study mans (98) and in animal models (1,62,89). The fetal effects of nicotine may be (72% versus 28%). Genetic factors also appeared important greater during the later stages of pregnancy, a finding sug- for the appearance of alcohol dependence (55% versus gesting the first trimester is the most desirable period for 45%), consistent with a common genetic vulnerability and NRT during pregnancy. Based on the rat data, it may be showing that nicotine and alcohol dependence occur to- preferable to introduce NRTs early in pregnancy to try to gether (60). Environmental factors more strongly deter- reduce the fetal exposure to nicotine before the second or mined age of first use of tobacco and alcohol, whereas la- third trimester. In the rat models, episodic nicotine delivery, tency between first use and patterns of regular use were as happens with smoking, is associated with less nicotine more genetically determined (54). A major genetic influence exposure to the fetus than continuous exposure from a nico- accounting for about 70% of the variance in risk in a group tine patch. Of course, fetal exposure to tobacco smoke pre- of Vietnam era twin pairs is consistent with other studies sents a host of other toxins besides nicotine. Cognitive defi- Genetically determined dopamine receptor functional cits, behavioral problems in childhood, particularly atten- differences and genetic variation in hepatic enzyme activity tion-deficit/hyperactivity disorders, conduct disorders, and important in metabolizing nicotine suggest possible mecha- substance abuse in the exposed children are associated with nisms. Individuals with TaqIA alleles (A1 and A2) and maternal smoking. Children whose mothers smoked ten or TaqIB (B1 and B2) of the D2 dopamine receptor gene had more cigarettes daily during pregnancy had a fourfold in- earlier onset of smoking, smoked more, and made fewer creased risk of prepubertal-onset conduct disorder in boys attempts to quit (58). Specific gene mutations, including and a fivefold risk in adolescent-onset drug dependence in those associated with dopamine D2 receptors (23) and do- girls (98). The outcomes are not explained by other risk pamine transporter proteins (95), have been implicated as factors. Maternal prenatal smoking appeared to be related possible determinants for nicotine addiction. People lacking to future criminal behavior in male children, with a a fully functional genetically variable enzyme CYP2A6 im- dose–response relationship between intensity of third portant in the metabolism of nicotine to cotinine are slow trimester smoking and arrest history of 34-year-old men nicotine metabolizers (30). This genotype may be important whose mothers smoked during pregnancy (63). Although in protecting against tobacco dependence because of im- such studies are limited by retrospective maternal reports paired nicotine metabolism and may be important as well of smoking behaviors during pregnancy, there is a consis- in determining dose and response to NRTs. Tobacco and Nicotine Exposure During Pregnancy MANAGEMENT AND THERAPEUTICS OF In the United States, about 25% of pregnant women smoke NICOTINE ADDICTION cigarettes, and so each year about 1 million babies are ex- posed in utero to tobacco smoke (89). Within those countries, smokers Tobacco smoking has long been known to present consider- have the lowest income, are the least educated, and have able fetal risks (59). Less well appreciated is that nicotine the poorest access to health care. Thus, from a world view, itself is a neuroteratogen (89). Nicotine given to rats during cost of therapeutics and access become important considera- gestation or adolescence at levels assumed to be consistent tions. Prevention is obviously an important strategy, but with those in human smokers alters gene expression and strategies to prevent tobacco addiction must deal with a produces long-lasting central nervous system cellular dam- politically powerful and wealthy multinational industry pro- age, by reducing cell number and impairing synaptic activity moting use of tobacco (64). The tobacco industry in the and cell signaling (62). Developing brain cells appear partic- United States alone spent 6 billion dollars in 1998 to market ularly vulnerable. In adult rats, similar exposure stimulates cigarettes, about 18 million dollars each day. More is spent nicotinic cholinergic receptors without lasting cellular promoting tobacco use elsewhere in the world. Individual or group behavioral treatments appear Contemporaneous reviews of tobacco addiction thera- almost equally effective. Intensive treatment programs are peutics (59,70–73) and an extensive report on tobacco ad- effective in assisting even very dependent smokers to stop diction pharmacology and therapeutics from the Royal Col- for a few months. However, as with other addictions, relapse lege of Physicians (49) offered similar conclusions. Initial quitting rates of 50% to 60% summary review from the Cochrane Tobacco Addiction Re- at 1 month typically decrease to 20% to 30% at 1 year. Details of the 20 None has proven clearly effective. Most tobacco addicts re- systematic reviews are available on the Internet in the Coch- peat the quitting process on average every 3. The reviews used a similar strategy and three or four times before finally stopping forever (66). In reviewed much the same literature on tobacco addiction that respect, stopping smoking is similar to overcoming ad- therapeutics as did the Public Health Service review. Tobacco addiction The Cochrane reviews considered the results from ran- treatment programs are cost-effective. Average treatment domized controlled trials having at least 6 months of follow- costs per year of life saved are $1,000 to $2,000 per year up (91).