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The Adolescent Brain Cognitive Development (ABCD) Study® is a 10-year longitudinal study of children recruited at ages 9 and 10. A battery of neuroimaging tasks are administered biennially to track neurodevelopment and identify individual differences in brain function. This study reports activation patterns from functional MRI (fMRI) tasks completed at baseline, which were designed to measure cognitive impulse control with a stop signal task (SST; N = 5,547), reward anticipation and receipt with a monetary incentive delay (MID) task (N = 6,657) and working memory and emotion reactivity with an emotional N-back (EN-back) task (N = 6,009). Further, we report the spatial reproducibility of activation patterns by assessing between-group vertex/voxelwise correlations of blood oxygen level-dependent (BOLD) activation. Analyses reveal robust brain activations that are consistent with the published literature, vary across fMRI tasks/contrasts and slightly correlate with individual behavioral performance on the tasks. These results establish the preadolescent brain function baseline, guide interpretation of cross-sectional analyses and will enable the investigation of longitudinal changes during adolescent development. This paper reports activation patterns for fMRI tasks assessing response inhibition, working memory and reward processing obtained at baseline in the longitudinal ABCD Study, providing a reference for research into adolescent brain development.

Commentary: Recognizing the increasing diversity of cannabis products and their expanded use, Freeman & Lorenzetti propose a standard unit dose of 5 mg 9‐tetrahydrocannabinol (THC) to be used for all cannabis products, regardless of method of administration. They argue that a standard dose would help to guide consumers towards safer patterns of cannabis use. The National Institute on Drug Abuse (NIDA) strongly supports the need for a standardized measure to facilitate research, and this was a key recommendation from NIDA's Cannabis Policy Research Council Workgroup....

Adolescence is a time of dramatic changes in brain structure and function, and the adolescent brain is highly susceptible to being altered by experiences like substance use. However, there is much we have yet to learn about how these experiences influence brain development, how they promote or interfere with later health outcomes, or even what healthy brain development looks like. A large longitudinal study beginning in early adolescence could help us understand the normal variability in adolescent brain and cognitive development and tease apart the many factors that influence it. Recent advances in neuroimaging, informatics, and genetics technologies have made it feasible to conduct a study of sufficient size and scope to answer many outstanding questions. At the same time, several Institutes across the NIH recognized the value of collaborating in such a project because of its ability to address the role of biological, environmental, and behavioral factors like gender, pubertal hormones, sports participation, and social/economic disparities on brain development as well as their association with the emergence and progression of substance use and mental illness including suicide risk. Thus, the Adolescent Brain Cognitive Development study was created to answer the most pressing public health questions of our day. Keywords: Adolescent, Brain development, Neuroimaging, Longitudinal, Substance use, Mental health

The Adolescent Brain Cognitive Development (ABCD) Study is an ongoing, nationwide study of the effects of environmental influences on behavioral and brain development in adolescents. The ABCD Study is a collaborative effort, including a Coordinating Center, 21 data acquisition sites across the United States, and a Data Analysis and Informatics Center (DAIC). The main objective of the study is to recruit and assess over eleven thousand 9-10-year-olds and follow them over the course of 10 years to characterize normative brain and cognitive development, the many factors that influence brain development, and the effects of those factors on mental health and other outcomes. The study employs state-of-the-art multimodal brain imaging, cognitive and clinical assessments, bioassays, and careful assessment of substance use, environment, psychopathological symptoms, and social functioning. The data will provide a resource of unprecedented scale and depth for studying typical and atypical development. Here, we describe the baseline neuroimaging processing and subject-level analysis methods used by the ABCD DAIC in the centralized processing and extraction of neuroanatomical and functional imaging phenotypes. Neuroimaging processing and analyses include modality-specific corrections for distortions and motion, brain segmentation and cortical surface reconstruction derived from structural magnetic resonance imaging (sMRI), analysis of brain microstructure using diffusion MRI (dMRI), task-related analysis of functional MRI (fMRI), and functional connectivity analysis of resting-state fMRI.HighlightsAn overview of the MRI processing pipeline for the ABCD StudyA discussion on the challenges of large, multisite population studiesA methodological reference for users of publicly shared data from the ABCD Study

The Adolescent Brain Cognitive Development (ABCD) Study is an ongoing, nationwide study of the effects of environmental influences on behavioral and brain development in adolescents. The main objective of the study is to recruit and assess over eleven thousand 9–10-year-olds and follow them over the course of 10 years to characterize normative brain and cognitive development, the many factors that influence brain development, and the effects of those factors on mental health and other outcomes. The study employs state-of-the-art multimodal brain imaging, cognitive and clinical assessments, bioassays, and careful assessment of substance use, environment, psychopathological symptoms, and social functioning. The data is a resource of unprecedented scale and depth for studying typical and atypical development. The aim of this manuscript is to describe the baseline neuroimaging processing and subject-level analysis methods used by ABCD. Processing and analyses include modality-specific corrections for distortions and motion, brain segmentation and cortical surface reconstruction derived from structural magnetic resonance imaging (sMRI), analysis of brain microstructure using diffusion MRI (dMRI), task-related analysis of functional MRI (fMRI), and functional connectivity analysis of resting-state fMRI. This manuscript serves as a methodological reference for users of publicly shared neuroimaging data from the ABCD Study.

Tolerance development after successful long-term treatment of bipolar disorder is under recognized, as are ways to prevent or show its occurrence or reverse it once it has occurred. We review the clinical literature which suggests that tolerance can develop to most treatment approaches in bipolar illness and present an animal model of tolerance development to anticonvulsant effects of carbamazepine or lamotrigine on amgydala-kindled seizures. In this model tolerance does not have a pharmacokinetic basis, but is contingent upon the drug being present in the brain at the time of amygdala stimulation. The occurrence of seizures in the absence of drug is sufficient to reverse tolerance and re-establish anticonvulsant efficacy. Based on the model, we hypothesize that some episode-induced compensatory adaptive changes in gene expression fail to occur in tolerant subjects and that episodes off medication re-induce these changes and renew drug effectiveness. Approaches that slow or reverse tolerance development in the animal model are reviewed so that they can be tested for their applicability in the clinic. Criteria for assessing tolerance development are offered in the hope that this will facilitate a more systemic literature about its prevalence, prevention, and reversal. Careful longitudinal monitoring of episode occurrence is essential to understanding tolerance development in the affective disorder and its treatment.

Substance abuse among older adults has received little attention in the past, presumably because this population has traditionally accounted for only a small percentage of the drug abuse problem in the United States. The aging of the baby boomer generation (born 1946-1964), however, will soon swell the ranks of older adults and dramatically alter the demography of American society. Several observations suggest that this expansion will likely be accompanied by a precipitous increase in the abuse of drugs, including prescription medications and illicit substances, among older adults. While it is now evident that the brain changes continuously across life, how drugs of abuse interact with these age-related changes remains unclear. The dynamic nature of brain function, however, suggests that substance abuse during older age may augment the risks and require unique considerations for diagnosis and treatment. In addition to describing current and projected prevalence estimates of substance abuse among older adults, the present review discusses how aging affects brain systems involved in drug abuse, and explores the potential impact of drug abuse on the aging brain. Future directions for substance abuse research among older adults will also be considered.

In the authors' experience interactions between clinical and laboratory research have been greatly mutually facilitatory in the understanding and development of new treatments for the major mental illnesses. Examples in the literature are also highlighted to show how cross-disciplinary studies are important in understanding the subtle interactions of genetic and environmental mechanisms in psychiatric illness. Yet, the results of some current science policies encouraging project focus and superspecialization can lead to the separation of clinical and basic investigators, which threatens the integration of psychological complexity into the neurobiology of psychiatry at both a molecular and behavioral level. This paper endorses renewed effort toward the multidisciplinary team approach under the leadership of a physician–scientist in order to better integrate many fields of study critical to ameliorating the effects of psychiatric illness.

1. A variety of enzymes, peptides, neurotrophic factors and their receptors show complex cascades of alterations with amygdala-kindled seizure progression; some represent compensatory adaptations that could become new targets of therapeutics. 2. Non-convulsant brain stimulation with repetitive transcranial magnetic stimulation (rTMS) may be able to engage some of the neuro-adaptive effects of ECT without the necessity of inducing a seizure. 3. Data from preclinical and clinical studies raise the possibility that non-convulsant stimulation achieved by high or low frequency rTMS may be able to alter neurotransmitters, neuropeptides, and neurotrophic factors, leading to frequency- and region-dependent changes in neural excitability. 4. Individual depressed patients show differential responses to two weeks high vs. low frequency rTMS, as revealed by the inverse correlation of degree of improvement in depression achieved by these two frequencies. 5. Preliminary data from rTMS and positron emission tomography (PET) studies reveal moderately sustained differential effects of rTMS frequency on regional cerebral neural activity in depressed patients. 6. These data suggest the possibility that an individual's level of baseline rCBF or rCMRglu on PET would help predict which rTMS frequency might be the most appropriate treatment for their depression.

A number of untreated or inadequately treated psychiatric illnesses often demonstrate syndrome progression manifested by either increasing frequency, severity, or spontaneity of episodes. Behavioral sensitization to psychomotor stimulants (and its cross sensitization to stress) and electrophysiological kindling provide two very different models for conceptualizing physiological and behavioral abnormalities that progress in severity in response to the same inducing stimulation over time. These models are highly indirect, and the behaviors induced and specific pharmacologic interventions do not directly parallel those in many of these psychiatric syndromes. Nonetheless, these preclinical models help us conceptualize potential mechanisms involved in syndrome progression based on experience-dependent modifications of the genome at the level of transcriptional regulation. In both preclinical models, agents that are effective in the earlier developmental phase of sensitization or kindling are not necessarily effective in amelioration of the full-blown syndromes, and vice versa. Thus these models also suggest a variety of intervention principles that can be directly tested in the clinic, such as differential efficacy of treatment as a function of stage of evolution of the given syndrome. Although serotonergic mechanisms do not appear central to the basic phenomena of sensitization and kindling, they appear capable of modulating their development and severity. As such, it becomes of considerable importance to assess whether serotonergic mechanisms that have been implicated in acute treatment of mood and anxiety syndromes are also involved in the longitudinal course and prevention of syndrome progression or occurrence. Identification of the more precise molecular mechanisms involved might provide a target for new therapeutic approaches to these recurrent and potentially disabling major psychiatric illnesses.

Kindling is discussed in relation to affective illness as a nonhomologous model, which shares the feature of increasing illness severity and evolution over time following repeated exposures to certain forms of stimulation. This progressive aspect of kindling has proven useful in the study of approaches to pharmacotherapeutics, mechanisms and characteristics of drug tolerance, and, most recently, illness suppression through physiological rather than pharmacological strategies. Each of these themes is described and the mechanisms that have been uncovered using the kindling model are discussed in relation to how similar principles might apply in affective illness or epilepsy. It is hoped that some of the lessons from the kindling model will provide useful and novel insights into aspects of treatment and mechanisms of psychiatric and neurologic illnesses.

Whereas the basic wiring diagram of the mammalian central nervous system (CNS) is genetically preprogramed, its fine tuning throughout different phases of infancy, childhood, and adulthood are highly experience dependent. The potential neurobiological mechanisms and behavioral effects of such experience-dependent neuroplasticity as a function of stage of development are outlined. A basic thesis of this paper is that mechanisms involved in neuronal learning and memory, such as long-term potentiation (LTP) and long-term depression (LTD), are used and reused not only in the sculpting of the CNS in the initial establishment of connections, but also again in the molding of personality and behavior based on experience. It is postulated that for higher order processes such as emotional memory, such neuroplasticity is occurring at increasingly larger numbers of synapses and cell assemblies with increasing mechanistic complexity and self-organization. Just as overexcitation or deprivation can profoundly affect the development of the visual system, it is postulated that similar phenomena exist in the neural substrates of emotional and cognitive development. In addition, a secondary and potentially more widespread series of ramifications are likely to occur in the higher order and integrative systems, such as secondary and tertiary cortical association areas and prefrontal cortex that become the ultimate integrators of emotion and experience, leading to subsequent actions and plans for the future. This process is, by definition, plastic, and such remodeling is likely to take place not only at the level of the single synapse, but also at higher levels of network integration of which we currently have only the barest glimpse. Nonetheless, beginning to discuss the neurobiology of such self-organizing plastic systems may begin to change our conceptual approaches to psychopathology and open new avenues of therapeutics for the major psychiatric illnesses that are critically dependent on such higher order learning and memory mechanisms.

In this article, we discuss molecular mechanisms involved in the evolution of amygdala kindling and the episodic loss of response to pharmacological treatments during tolerance development. These phenomena allow us to consider how similar principles (in different neurochemical systems) could account for illness progression, cyclicity, and drug tolerance in affective disorders. We describe the phenomenon of amygdala-kindled seizures episodically breaking through effective daily pharmacotherapy with carbamazepine and valproate, suggesting that these observations could reflect the balance of pathological vs compensatory illness-induced changes in gene expression. Under certain circumstances, amygdala-kindled animals that were initially drug responsive can develop highly individualized patterns of seizure breakthroughs progressing toward a complete loss of drug efficacy. This initial drug efficacy may reflect the combination of drug-related exogenous neurochemical mechanisms and illness-induced endogenous compensatory mechanisms. However, we postulate that when seizures are inhibited, the endogenous illness-induced adaptations dissipate (the "time-off seizure" effect), leading to the re-emergence of seizures, a re-induction of a new, but diminished, set of endogenous compensatory mechanisms, and a temporary period of renewed drug efficacy. As this pattern repeats, an intermittent or cyclic response to the anticonvulsant treatment emerges, leading toward complete drug tolerance. We also postulate that the cyclic pattern accelerates over time because of both the failure of robust illness-induced endogenous adaptations to emerge and the progression in pathophysiological mechanisms (mediated by long-lasting changes in gene expression and their downstream consequences) as a result of repeated occurrences of seizures. In this seizure model, this pattern can be inhibited and drug responsivity can be temporarily reinstated by several manipulations, including lowering illness drive (decreasing the stimulation current), increasing drug dosage, switching to a new drug that does not show crosstolerance to the original medication, or temporarily discontinuing treatment, allowing the illness to re-emerge in an unmedicated animal. Each of these variables is discussed in relation to the potential relevance to the emergence, progression, and suppression of individual patterns of episodic cyclicity in the recurrent affective disorders. A variety of clinical studies are outlined that specifically test the hypotheses derived from this formulation. Data from animal studies suggest that illness cyclicity can develop from the relative ratio between primary pathological processes and secondary endogenous adaptations (assisted by exogenous medications). If this proposition is verified, it further suggests that illness cyclicity is inherent to the neurobiological processes of episode emergence and amelioration, and one does not need to postulate a separate defect in the biological clock. The formulation predicts that early and aggressive long-term interventions may be optimal in order to prevent illness emergence and progression and its associated accumulating neurobiological vulnerability factors.

The recurrent affective disorders are discussed from the perspective of accumulating inherited and experiential effects on gene expression. Stress and episodes of affective illness are viewed as leaving biochemical and microstructural residues in the central nervous system (CNS) in relation to their patterning, severity, and recurrence. Comorbid factors such as substance abuse and developmental disturbances may also interact with these illness-related variables. In addition to the primary pathological processes, secondary adaptive changes can also be induced, which, in concert with pharmacological interventions, may be sufficient to counter episode occurrences and illness progression. We postulate that the balance of primary pathological and secondary adaptive changes at multiple levels of CNS regulation accounts for recurrence and cyclicity in the affective disorders. The importance of early, effective, long-term interventions in the recurrent affective disorders and the therapeutic potential of several new treatment modalities including repeated transcranial magnetic stimulation (rTMS) are discussed.

Electrophysiological kindling and behavioral sensitization to psychomotor stimulants and stress provide paradigms for understanding how repeated acute events can leave neurobiological residues in gene expression, accounting for the observed long-lasting alterations in behavioral responsivity. Kindling helps conceptualize how repeated electrical stimulation of the brain can progressively evoke increased behavioral and convulsive responsivity, leading to spontaneous seizures in the absence of exogenous stimulation following sufficient stimulations. As kindling unfolds, a complex spatiotemporal cascade of events occurs and includes the induction of immediate early genes (e.g.,c-fos) and late effector genes (including peptides and growth factors) possibly associated with the observed changes in brain microstructure (e.g., synapse formation, axonal and dendritic sprouting, apoptosis). Behavioral sensitization to psychomotor stimulants and stress has also been shown to induce related but different cascades of effects on immediate early and late effector gene expression. These may be associated with the observed long-lasting alterations in behavioral responsivity based on prior experience. If these types of alterations are put into a developmental context, this would provide a paradigm for understanding how early life events could exert profound and behaviorally relevant biochemical and microstructural effects on the central nervous system of the developing organism. The conceptual overview offered by the sensitization and kindling models suggests that environmentally triggered neurobiological processes do not form a single or static residue but, instead, engage processes related to developmental neurobiology and learning and memory and whose substrate is constantly evolving over an organism's lifetime.

Examination of the neurobiology of psychiatric illness in general, and of affective disorders in particular, reveals a variety of associated biochemical abnormalities. These have generally been assumed to be part of the pathological process or secondary to it, and thus deserving of therapeutic efforts aimed at reversal. However, recent clinical and preclinical data suggest that some alterations occurring in the affective disorders may be compensatory and adaptive; that is, part of an endogenous therapeutic mechanism rather than part of the evolving disease process. For example, the symptom of sleep loss in depression seems to fall under this rubric inasmuch as sleep deprivation induced mood improvement in depressed patients. Preclinical data are presented that another primary pathological process—the occurrence of kindled seizures—can evoke endogenous compensatory processes that are either anticonvulsant in their own right, or enable the anticonvulsant effects of a drug such as carbamazepine. It may be that some biochemical abnormalities occurring in affective illness are similarly adaptive. As one example, increased thyrotropin-releasing hormone (TRH) has been reported in the cerebrospinal fluid (CSF) of depressed patients. This elevation of TRH and the resulting neuroendocrine profile may be part of an endogenous counter-regulatory process aimed at mood improvement. Again, preclinical seizure models are supportive in that TRH not only is induced following repeated seizures, but also exerts anticonvulsant effects on these same seizures. In an analogous fashion, TRH elevations in depressed patients may also exert ameliorating effects on depressive symptomatology. This formulation presents directly testable hypotheses that could importantly impact on our understanding of the pathophysiology of affective disorders, and suggests novel therapeutic strategies through the enhancement of endogenous compensatory mechanisms.

The relationship of the timing of drug administration to anticonvulsant efficacy against amygdala kindled seizures was studied. During kindling development, rats received carbamazepine (CBZ, 15mg/kg) before (CBZ-before) or after each amygdala stimulation (CBZ-after). After kindling to full seizures, when all animals were given CBZ before the stimulation, only the CBZ-after group showed a good anticonvulsant response. The rats that had received CBZ before (during development of kindled seizures) remained unresponsive to CBZ treatment (contingent inefficacy). When drug-naive or CBZ-after animals repeatedly received CBZ before electrical stimulation, they developed tolerance to its anticonvulsant effects (contingent tolerance). The tolerance could be reversed by a period of treatment with CBZ-after or by kindling the animal drug-free, but not by CBZ administration alone or by time off from both drug and seizures. These findings suggest that inefficacy and tolerance to CBZ may be affected by the temporal contingencies of drug administration and that responsiveness can be reinstated by altering these contingencies.

The failure to achieve and maintain remission is a critical problem for a high percentage of patients with epilepsy and the primary affective disorders. Early illness onset and delayed initiation of treatment may contribute to primary treatment resistance or that associated with loss of efficacy (tolerance phenomenon). Neurobiological data and principles drawn from the amygdala kindling model of seizure progression are reviewed for their heuristic value in conceptualizing molecular mechanisms of illness progression and its prevention with pharmacological agents in the epilepsies and, indirectly, the recurrent affective disorders. Caveats in the use of this model and convergences and divergences in its predictive validity for seizures and affective disorders are noted.

SENSITIZATION IN THE AFFECTIVE DISORDERS Stressor and Episode Sensitization in the Unmedicated State At the beginning of the twentieth century, Kraepelin (1921) laid out the fundamentals of the sensitization hypothesis of affective disorders: the attacks begin not infrequently after the illness or death of near relatives … we must regard all alleged injuries as possibly sparks for the discharge of individual attacks, but the real cause of the malady must be sought in permanent internal changes , which at least very often, perhaps always, are innate … in spite of the removal of the discharging cause, the attack follows its independent development. But, finally, the appearance of wholly similar attacks on wholly dissimilar occasions or quite without external occasion shows that even there where there has been external influence, it must not be regarded as a necessary presupposition for the appearance of the attack. (pp. 180–181) In this terse and insightful paragraph, he outlines four different components of the sensitization hypothesis: (1) initial episodes of affective illness are often precipitated by psychosocial stressors; (2) as recurrences emerge, later episodes do not require the same psychosocial precipitation, but may occur more spontaneously; (3) episodes tend to occur with a characteristic similarity; and (4) innate neurobiological mechanisms mediate these vulnerabilities and recurrences, and presumably these could occur both on an inherited and an experiential basis. Other aspects of this sensitization hypothesis are outlined in additional passages from his work.

Posttraumatic stress disorder is the pathological replay of emotional memory formed in response to painful, life-threatening, or horrifying events. In contrast, depression is often precipitated by more social context-related stressors. New data suggest that different types of life experiences can differentially impact biochemistry, physiology, anatomy, and behavior at the level of changes in gene expression. Repeated separation of neonatal rat pups from their mother results in many long-lasting alterations in biology and behavior paralleling that in depression, including hypercortisolism. The role of the amygdala in modulating emotional memory is highlighted, as well as some of its unique properties such as metaplasticity (i.e., the differential direction of long-term adaptation, either potentiation or depression) in response to the same input as a function of the prior history of stimulation. The implications of these emerging data on the physiological and molecular mechanisms underlying emotional memory emphasize the particular importance of prevention and early intervention.

Publisher Summary This chapter reviews basic research on the phenomena and mechanisms of changes in sensitivity to cocaine. Tolerance has long been felt to play a major role in drug abuse. It has been stated that sensitization is a consistent finding in animal studies of cocaine. The most comprehensive analysis of tolerance to cocaine is undertaken by Branch and his colleagues, investigating cocaine's effects on schedule-controlled behavior. The reinforcing effects of drugs are those effects that increase the probability of repeated drug self-administration. Reinforcing effects are essential for repeated drug administration that is necessary for tolerance to develop. If procedural and pharmacological factors are identical (species, age, drug, dose, experimental history, and injection regimen), and the only difference between groups is the novelty of the environment in which the drug is given, then any behavioral differences are likely to be attributed to associative learning. Conditioning and sensitization can be very persistent; it might be useful to explore the substrates of other well-investigated forms of long-term neuroplasticity. A great deal of research has been done to establish the mechanisms of memory in humans and nonhuman primates.

Contingent tolerance to the anticonvulsant effects of carbamazepine on amygdala kindled seizures develops when the drug is repeatedly given prior to but not after the electrical stimulation. Such tolerance can be reversed by kindling the rats for several days without drug or even by continuing to give the drug but after each seizure has occurred. Contingent tolerance can be slowed by reducing the electrical stimulus intensity and by chronic continuous (as opposed to repeated paired) drug administration. Contingent cross-tolerance has been demonstrated from carbamazepine to PK11195 (a drug active at peripheral-type benzodiazepine receptors) and valproate, but not to clonazepam and diazepam (two drugs active at central-type benzodiazepine receptors) or phenytoin. Endogenous physiological changes occur in conjunction with contingent tolerance, exemplified by the decrease in seizure threshold that returns to normal upon reversal of tolerance. We suggest that contingent tolerance is associated with a loss of seizure-induced adaptations, since many biochemical changes that occur following seizures (or in non-tolerant animals given drug after seizures) are not observed in tolerant animals. These include a loss of seizure-induced up-regulation of GABAA receptors and a loss of increases in mRNA expression for corticotropin-releasing-factor (CRF), thyrotropin-releasing-hormone (TRH), neuropeptide Y (NPY), glucocorticoid receptors and brain-derived neurotrophic factor (BDNF). Thus, several putative seizure-induced anticonvulsant adaptations, such as increases in GABAA receptors and TRH and NPY mRNA fail to occur in tolerant animals. These findings are consistent with the novel observations that, paradoxically, seizures themselves appear to facilitate the anticonvulsant effects of carbamazepine or diazepam on amygdala kindled seizures. That is, animals given a 'vacation' from seizures show a decreased response to these agents, a phenomenon we have called the 'time-off seizure' effect. Thus, seizures are postulated to induce adaptive changes that influence seizure thresholds and potentiate the anticonvulsant effects of exogenously administered drugs such as carbamazepine and diazepam. Taken together, these data suggest that seizures are associated with endogenous adaptations lasting days to weeks and that a selective failure of some of these to occur during contingent drug administration may underlie the development of contingent tolerance. These observations suggest tht endogenous illness-related mechanisms may participate both in the therapeutic responses of some agents and that their failure to occur could relate to loss of drug efficacy via tolerance; these processes may reveal new potential targets for therapeutic intervention.

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising therapeutic intervention in the treatment of affective disorders. The differences in the type of electrical stimulation required for therapeutic efficacy by rTMS and electroconvulsive therapy (ECT) are discussed. In contrast to ECT, rTMS would not appear to require the generation of a major motor seizure to achieve therapeutic efficacy. Accordingly, it carries the potentially important clinical advantages of not requiring anesthesia and of avoiding side effects such as transient memory loss. Preclinical studies on long-term potentiation (LTP) and long-term depression (LTD) in hippocampal and amygdala slices, as well as clinical data from neuroimaging studies, have provided encouraging clues for potential frequency-dependent effects of rTMS. Preliminary evidence from position emission tomography (PET) scans suggests that higher frequency (20 Hz) stimulation may increase brain glucose metabolism in a transsynaptic fashion, whereas lower frequency (1 Hz) stimulation may decrease it. Therefore, the ability of rTMS to control the frequency as well as the location of stimulation, in addition to its other advantages, has opened up new possibilities for clinical explorations and treatments of neuropsychiatric conditions.

Nervous pointer dogs have been extensively characterized as an animal model for some human pathological anxiety states. During our work with these animals suspicion developed that some of these dogs had a hearing deficit. We decided to systematically evaluate this observation and to study the relation between hearing status and fear-related behaviors in the nervous pointer dogs. Our results revealed that a majority of the nervous dogs in our colony (75%) suffer from bilateral deafness as demonstrated by complete absence of brain stem auditory evoked response. Furthermore, behavioral ratings revealed that hearing and deaf dogs do not differ in their pathological response to the characteristic fear-provoking stimuli (e.g., human interaction) and that both hearing and deaf nervous dogs markedly differ from normal dogs in that respect. The relation between these abnormalities and their implications for research involving breeding of animals for selected traits are further discussed in this report.

Repeated, intermittent administration of psychomotor stimulants has been shown to produce increasing effects (behavioral sensitization) in many species of animals. In a novel two-day sensitization paradigm, rats that received a single high dose of cocaine (40 mg/kg) compared with saline on day 1 showed an increased locomotor response to a challenge dose (10 mg/kg) on day 2. This effect is conditioned or context-dependent; i.e., it is only observed if the rats received cocaine in an environment similar to the test environment. If the cocaine-induced hyperactivity on day 1 is prevented with pharmacological agents such as haloperidol and diazepam, sensitization on day 2 does not occur. Furthermore, although moderate (0.2 mg/kg) and high doses (0.5 mg/kg) of haloperidol (day 1) prevented the development of sensitization to cocaine, they were ineffective when given prior to the day 2 challenge dose in preventing the expression of sensitization. Thus, this type of cocaine sensitization appears to involve conditioning, show stimulus generalization, and offer a possible model for clinical neuroleptic nonresponsiveness once stimulant-induced pathological behavior has been induced.

Intracerebroventricular (i.c.v.) administration of ovine corticotropin-releasing factor (CRF) in doses varying from 10 to 100 micrograms has been reported to produce the late onset of seizures that resemble those observed during electrical kindling of the amygdala. We assessed the effects of repeated CRF administration on seizure development and on subsequent electrical kindling of the amygdala. Rats were administered vehicle or CRF (100 micrograms in 10 microliter of sterile water, i.c.v.) once daily for 5 consecutive days and were rated for seizures and aggressive behavior. On days 1 or 2, all animals receiving CRF developed major motor seizures of late onset (1-5 h post-injection), accompanied by spiking in the amygdala. By day 5, however, no rats had seizures, suggesting the development of tolerance. Defensive biting attacks were also observed following latencies of several hours and tolerance appeared to develop to these as well. After the CRF regimen, treated rats developed amygdala-kindled seizures following electrical stimulation approximately twice as fast as vehicle-injected controls (P less than 0.03). In a second experiment, rats were electrically kindled or sham-kindled prior to receiving i.c.v. CRF (100 micrograms). Kindled animals were significantly less sensitive to the seizure-inducing effects of CRF (P less than 0.03), but were more intensely aggressive than sham-kindled animals or naive rats receiving CRF for the first time.

Normative data are reported for the visual acuity, luminance-difference threshold and size-difference threshold of pigeons (Columba livia). The mean visual acuity was 12.66 c/deg or 2.53 min (N = 54), the mean log luminance-difference threshold was 0.11 (N = 105) and the mean size-difference threshold was 0.94 mm (N = 20).

Various endocrinological and biochemical conceptualizations of affective illness relate to different aspects of its phenomenology and course. Most endocrinological and animal modeling investigatory approaches focus on acute state changes of depressive behavior or its opposing phase of mania. In this chapter, we focus on the longitudinal course of affective illness, which is often characterized by a tendency for recurrence of episodes and a speeding up over time. This aspect of affective illness will be considered from the perspective of two different phenomena that can be studied in the laboratory — behavioral sensitization to psychomo- tor stimulants and limbic kindling.

Nine pigeons were trained to perform a simultaneous discrimination task with stimuli that were lateral mirror images, vertical mirror images and nonmirror images. All subjects acquired the discriminations rapidly and at approximately equal rates. Following training, bilateral stereotaxic lesions were made in either the visual wulst or ectostriatum, which are telencephalic components of the thalamofugal and tectofugal visual pathways, respectively. After surgery both groups were retrained to their preoperative performance levels or for a maximum of 140 sessions. The performance of the four subjects that received visual wulst lesions was only mildly and transiently impaired and was equally disrupted on each pattern discrimination. The performance of the five subjects that received ectostriatal lesions, however, was markedly and persistently impaired on all pattern discriminations. The impairment was most severe and sustained on the lateral mirror-image discrimination problem in all subjects. Only three of the five subjects with ectostriatal lesions reached their preoperative performance levels on the lateral mirror-image problem, whereas all subjects returned to their preoperative performance levels on the other problems. Possible reasons for this selective deficit in lateral mirror-image pattern discrimination are discussed in relation to interhemispheric pathways and the relative importance of the thalamofugal and tectofugal visual pathways in birds and in mammals.

Seven pigeons were trained to perform in a psychophysical procedure to determine the smallest difference in luminous intensity (intensity difference threshold) that they could discriminate. When their performance stabilized, lesions were made in the ectostriatum in 4 birds and in the neostriatum in the remaining 3 birds. After surgery, the pigeons with ectostriatum lesions showed markedly elevated thresholds. The neostriatum control cases showed only trivial threshold changes as a consequence of the surgery. A psychophysical scaling analysis showed that the ectostriatum-lesioned pigeons had lost from 50% to 83% of their preoperative capacity to discriminate differences in the intensity of visual stimuli. A multiple-regression analysis based on quantitative reconstructions of the lesions revealed that only damage to the core region of the ectostriatum contributed to the postoperative threshold changes.

Fifteen pigeons were tested in a psychophysical procedure that determined the limits of their ability to detect differences in the sizes of stimuli. The results indicated that intact pigeons can reliably discriminate an annulus 3.0 mm in diameter from one that is 3.9 mm in diameter. In the first experiment, pigeons with lesions of the ectostriatum that spared the medial 15% were unimpaired in their size-discrimination ability. Those cases in which the lesions involved both the medial and lateral regions of the ectostriatum were greatly impaired. In a second experiment, these findings were replicated. In some cases, the electrode trajectory was varied to rule out possible effects from non-ectostriatal structures. In addition, the second study indicated that destruction of the medial ectostriatum with the lateral regions intact had no measurable effect on size-difference thresholds. The medial region of ectostriatum is part of the termination field of a second tectofugal pathway to the telencephalon. This pathway passes from the optic tectum to nucleus dorsolateralis posterior thalami and then to the neostriatum intermedium, including the medial ectostriatum. An examination of the data of the present experiment and those of other behavioral studies of the ectostriatum suggest that the medial ectostriatum may be involved in the processing of visual information with low spatial-frequency components and the lateral ectostriatum may be processing information about the high-frequency composition of stimuli.

In many ways this chapter would be better titled “uses and abuses of animal models of affective disorders.” The previous two chapters have outlined some of the systematic criteria for the development and use of animal models for various psychiatric disorders, including: similarity of behaviors, inducing agents or principles, biochemical and physiological correlates, and pharmacological responsivity. These criteria have been widely accepted, as have, for example, the criteria for confirming that a given chemical is a neurotransmitter in the central nervous system. Without fulfilling each of several criteria, a putative neurotransmitter candidate cannot be considered “proven.” The paradigms discussed in this chapter cannot be considered formal animal models for affective disorder, as they do not meet many of the basic requirements of an animal model. In particular, there is little evidence of (1) parallel inducing procedures, (2) behavioral homology to the disorder studied, or (3) selective response to those pharmacological interventions that are successful in affective illness. Nonetheless, these models are potentially useful for other purposes. Specifically, they help focus on possible parallel processes in the clinical situation that can be conceptualized in new ways, perhaps leading to a new series of clinical-research formulations, testable hypotheses, and even pharmacotherapies.

Psychomotor stimulant-induced behavioral sensitization and electrophysiological kindling are not animal models of stress with obvious face validity; however, we discuss them here as they may guide us to new principles concerning changes in long-term responsivity in behavior that may be relevant to some stress situations. Moreover, there is an extensive literature indicating that there are important interactions between psychomotor stimulant-induced behavioral sensitization and stress-induced behavioral alterations. Stimulants such as amphetamine and cocaine are thought to exert many of their actions by potentiating noradrenergic and dopaminergic neurotransmission. Stresses, in many instances, are also capable of acting on these catecholamine and related neurochemical substrates. Thus, it is not surprising that under some conditions, stresses may facilitate subsequent reactivity to psychomotor stimulants and, vice-versa, that psychomotor stimulant pretreatment may enhance stress responsivity. Seymour Antelman and colleagues have reviewed elsewhere (1,2) evidence for cross-sensitization between stress and stimulants. It is not the point of this paper to argue that this is a universal principle; we and others have observed in some instances that stresses may decrease subsequent stimulant-induced behavior. What we are suggesting is that, in many instances, stimulant-induced effects on short- and long-term alterations in behavior may be mediated by the same neurochemical systems that are relevant to the consideration of stress-induced changes in behavior.