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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.

The HEALthy Brain and Child Development (HBCD) study will establish a large cohort of pregnant women from regions of the country significantly affected by the opioid crisis and follow them and their children for at least 10 years. Findings from this cohort will help researchers understand normative childhood brain development as well as the long-term impact of prenatal and postnatal opioid and other drug and environmental exposures. The study will collect data on pregnancy and fetal development; infant and early childhood structural and functional brain imaging; anthropometrics; medical history; family history; biospecimens; and social, emotional, and cognitive development. Knowledge gained from this research will be critical to help predict and prevent some of the known effects of prenatal and postnatal exposure to certain drugs or environmental exposures, including risk for future substance use, mental disorders, and other behavioral and developmental problems. In this special issue, a subset of investigators that received funding for planning grants for the HBCD study provide careful guidelines and frameworks for study design, recruitment and retention of vulnerable populations, culturally sensitive practices, and biospecimen and neurodevelopmental assessment recommendations gathered in feasibility studies that will help inform the full HBCD study planned to begin recruitment in 2022.

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

Importance Incidental findings (IFs) are unexpected abnormalities discovered during imaging and can range from normal anatomic variants to findings requiring urgent medical intervention. In the case of brain magnetic resonance imaging (MRI), reliable data about the prevalence and significance of IFs in the general population are limited, making it difficult to anticipate, communicate, and manage these findings. Objectives To determine the overall prevalence of IFs in brain MRI in the nonclinical pediatric population as well as the rates of specific findings and findings for which clinical referral is recommended. Design, setting, and participants This cohort study was based on the April 2019 release of baseline data from 11 810 children aged 9 to 10 years who were enrolled and completed baseline neuroimaging in the Adolescent Brain Cognitive Development (ABCD) study, the largest US population-based longitudinal observational study of brain development and child health, between September 1, 2016, and November 15, 2018. Participants were enrolled at 21 sites across the US designed to mirror the demographic characteristics of the US population. Baseline structural MRIs were centrally reviewed for IFs by board-certified neuroradiologists and findings were described and categorized (category 1, no abnormal findings; 2, no referral recommended; 3; consider referral; and 4, consider immediate referral). Children were enrolled through a broad school-based recruitment process in which all children of eligible age at selected schools were invited to participate. Exclusion criteria were severe sensory, intellectual, medical, or neurologic disorders that would preclude or interfere with study participation. During the enrollment process, demographic data were monitored to ensure that the study met targets for sex, socioeconomic, ethnic, and racial diversity. Data were analyzed from March 15, 2018, to November 20, 2020. Main outcomes and measures Percentage of children with IFs in each category and prevalence of specific IFs. Results A total of 11 679 children (52.1% boys, mean [SD] age, 9.9 [0.62] years) had interpretable baseline structural MRI results. Of these, 2464 participants (21.1%) had IFs, including 2013 children (17.2%) assigned to category 2, 431 (3.7%) assigned to category 3, and 20 (0.2%) assigned to category 4. Overall rates of IFs did not differ significantly between singleton and twin gestations or between monozygotic and dizygotic twins, but heritability analysis showed heritability for the presence or absence of IFs (h2 = 0.260; 95% CI, 0.135-0.387). Conclusions and relevance Incidental findings in brain MRI and findings with potential clinical significance are both common in the general pediatric population. By assessing IFs and concurrent developmental and health measures and following these findings over the longitudinal study course, the ABCD study has the potential to determine the significance of many common IFs.

Cannabis is a natural product that, when used chronically, has been associated with the development of cannabis use disorder. This disorder, as described in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) of the American Psychiatric Association (2013. Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Association, Washington, DC), is clinically characterized by the inability to stop using cannabis despite psychosocial/medical problems, the presence of craving, the need to use larger amounts to obtain the same effect (tolerance), and/or the onset of symptoms when its use is stopped (withdrawal). The current increase in the frequency of cannabis use, the availability and use of cannabis products with high concentration of the psychoactive ingredient tetrahydrocannabinol (THC), and the presence in the markets of highly potent synthetic cannabinoids may result in an increased risk of CUD. Recent studies have provided a wealth of information about the endocannabinoid system, the effects of cannabinoids, and the brain mechanisms of CUD. These new discoveries are allowing the identification of novel pharmacological targets and medications that may affect the endocannabinoid system and may be useful for the treatment of CUD and other medical conditions. The purpose of this book is to provide an overview of the epidemiology, neurobiological basis, developmental aspects, and clinical characteristics of CUD, including its pharmacological and non-pharmacological therapeutic approaches.

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.

Social attitudes and cultural norms around the issue of substance abuse are shifting rapidly around the world, leading to complex and unpredictable consequences. On the positive side, efforts to more intensely disseminate the scientific evidence for the many connections between chronic substance use and the emergence of measurable and discrete brain dysfunctions, has ushered in an evolving climate of acceptance and a new era of improved access to more effective interventions, at least in the United States. On the negative side, there has been a steady erosion in the public perception of the harms associated with the use of popular drugs, especially cannabis. This worrisome trend has sprouted at the convergence of several forces that have combined, more or less fortuitously, to effectively change long-standing policies away from prohibition and toward decriminalization or legalization. These forces include the outsized popularity of the cannabis plant among recreational users, the unflagging campaign by corporate lobbyists and patient advocates to mainstream its medicinal use, and the honest realization in some quarters of the deleterious impact of the drug war and its draconian cannabis laws, in particular, on society's most vulnerable populations. Updating drug policies is a desirable goal, and significant changes may indeed be warranted. However, there is a real concern when policy changes are hurriedly implemented without the required input from the medical, scientific, or policy research communities. Regardless of how well intentioned, such initiatives are bound to magnify the potential for unintended adverse consequences in the form of far ranging health and social costs. To minimize this risk, science must be front and center in this important policy debate. Here, we review the state of the science on cannabis and cannabinoid health effects, both adverse and therapeutic. We focus on the prevalence of use in different populations, the mechanisms by which cannabis exerts its effects (i.e., via the endocannabinoid system), and the double-edged potential of this system to inspire new medications, on one hand, and to cause short and long term harmful effects on the other. By providing knowledge of cannabis' broad ranging effects, we hope to enable better decision making regarding cannabis legislation and policy implementation.

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.

Gender is increasingly being studied for risk and protective factors underlying substance abuse and addiction.The aim of this study was to assess gender differences in rates of substance abuse and dependence among drug users.A national population sample was examined, focusing on 2 age groups (youths, aged 12-17 years, and young adults, aged 18-25 years) and several commonly abused substances (alcohol, marijuana, and nonmedical prescription medication use). Combined annual data from the National Survey on Drug Use and Health (NSDUH), aggregated from 2002-2005, were used for gender comparisons of rates of substance use, as well as abuse and dependence, among users.Overall rates of substance use were significantly higher for males than for females (P0.01 for all substances except sedatives and tranquilizers); however, patterns of use, abuse, or dependence among users differed by age group and drug. Interestingly, patterns for youths differed from the overall population and from young adults. Girls exceeded boys in their use of alcohol (P0.01) and their nonmedical use of psychotherapeutics (ie, prescription-type pain relievers, stimulants, tranquilizers, sedatives) (P0.01); among users, girls were significantly more likely to be dependent on the latter (P0.01). Boys reported significantly greater use and abuse of and dependence on marijuana (P0.01). In the young adults, the proportion of female users reporting dependence on cocaine or psychotherapeutics was significantly higher than for male users (P0.01), who nonetheless reported significantly greater use of these drugs (P0.01). Among users, males generally exceeded females in meeting abuse criteria (P0.01 for marijuana among 12- to 17-year-olds and for alcohol, marijuana, and psychotherapeutics among 18- to 25-year-olds), with some exceptions mainly in the youngest cohort.In this national population sample of youths and young adults, these findings suggest that gender, age, and substance of abuse may all play a role in the observed patterns of drug use, abuse, and dependence. Understanding the reasons for these differences and continuing to evaluate these patterns over time could help in the development of targeted and more effective prevention and treatment interventions.

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.

Ro15-4513 (ethyl-8-azido-5,6-dihydro-5methyl-6-oxo-4H-imidazo-[1,5-a]-1,4-benzodiazepine-3-carboxylate), a benzodiazepine partial inverse agonist of the GABA(A) receptor, is known to protect against alcohol toxicities. The present study was designed to determine the role of Ro15-4513 in preventing anticonvulsant, toxic, and lethal effects of carbamazepine (CBZ) in amygdala-kindled rats. Acute treatment with CBZ (25 mg/kg, i.p.) produced anticonvulsant effects in fully kindled rats characterized by a significant decrease in afterdischarge and seizure duration and stage. Repeated administration of this high dose of CBZ induced sedation and high (56%) lethality. The anticonvulsant and sedative effects of CBZ were strikingly suppressed by pretreatment with Ro15-4513 (2.5 and 5 mg/kg, i.p.), and there was no mortality in animals co-administrated with Ro15-4513 during the entire experimental period. These results indicate that Ro15-4513 protects against CBZ-induced sedation and lethality, while suppressing the anticonvulsant effects of CBZ, suggesting a role for the GABA(A) receptor in CBZ efficacy and side effects. The potential clinical implications for CBZ-induced toxicity and overdose remain to be explored.

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.

As marijuana use becomes legal in some states, the dominant public opinion is that marijuana is a harmless source of mood alteration. Although the harms associated with marijuana use have not been well studied, enough information is available to cause concern.

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.

Kindling is a model of the neural plasticity that occurs following stimulation to the brain, which can result in epileptogenesis. The amygdala (Am), one of the most sensitive structures from which to induce electrical kindling, is comprised of distinct nuclei that possess differences in threshold for seizure initiation, unique cellular and molecular morphology, and specific neuroanatomical connections within the amygdala and, to other cortical and subcortical brain structures. The aim of this study was to map the spread of epileptiform activity throughout the ipsilateral and contralateral hemispheres during the transition stage between oral automatisms and generalized clonic seizures, by measuring changes in mRNA expression for c- fos, NGFI-A , and BDNF. The stimulating electrode was implanted in either the basolateral (BL) or the lateral (CeL) or medial (CeM) subdivisions of the central nucleus of the amygdala. The rats were kindled once daily using afterdischarge-threshold electrical stimulation until the first forelimb clonic seizure was induced. They were sacrificed 30 min later, and their brains were prepared for in situ hybridization to measure mRNA expression of c -fos, NGFI-A and BDNF . The results demonstrate that: (1) the threshold to elicit an afterdischarge from the BL was lower than that of either the medial (CeM) or lateral (CeL) subdivisions of the Ce, which did not differ from each other; (2) the patterns of mRNA expression for c -fos, NGFI-A and BDNF were highly similar to each other when the stimulation site was the BL or the CeL, and included mainly limbic cortical and subcortical areas ipsilateral to the electrode; (3) c- fos was the only probe to be expressed in the contralateral hemisphere following the first motor seizure, and the pattern of its expression reflected a subset of structures recruited in the ipsilateral hemisphere including the claustrum, insular and perirhinal cortices; (4) unexpectedly, stimulation of the CeM elicited seizures and afterdischarges of shorter duration than those evoked by stimulation of the BL or CeL, and failed to increase mRNA expression for any of the probes in the hippocampus or in the contralateral hemisphere. A neuroanatomical model of Am-induced seizure propagation is proposed suggesting that the Claust–Ins–PRh play a pivotal role during the transition between oral automatisms and generalized clonic convulsions.

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.

This study examines forms of activity-dependent synaptic plasticity in the basolateral amygdalain vitroand demonstrates that a brief high frequency stimulus (HFS) train can induce a switch in the direction of the enduring change in synaptic strength induced by subsequent low-frequency stimulation (LFS). LFS (1 Hz, 15 min) of the external capsule (EC) induced a persistent 1.7-fold enhancement in the amplitude of synaptic potentials recorded intracellularly in basolateral amygdala neurons. The enhancement occurred gradually during the stimulation and was maintained for >30 min after termination of the stimulus train. LFS-induced enduring synaptic facilitation was not affected by the NMDA receptor antagonistd(−)-2-amino-5-phosphonopentanoate (APV; 100 μm). Brief high-frequency EC stimulation (HFS; 100 Hz, 1 sec) induced APV-sensitive short-term potentiation (2.5-fold) that generally decayed within 10 min. When LFS was applied after recovery from the short-term potentiating effect of HFS (HFS/LFS), there was an initial transient (m) prevented the HFS-dependent switch from synaptic facilitation to depression. Thus, LFS in thein vitroamygdala slice can induce either enduring synaptic potentiation or depression, depending on whether a priming HFS train has been applied. This experience-dependent switch, a novel form of metaplasticity, is not dependent on NMDA receptors but may require group II metabotropic glutamate receptors. In the amygdala, experiential modification of activity-dependent long-term synaptic plasticity adds flexibility to the ways in which synaptic strength can be modified and could play a role in diverse amygdala-dependent processes, including the formation, storage, and extinction of emotional memory and the regulation of epileptogenesis.

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.

We isolated a rat orphan nuclear hormone receptor from a brain cortex cDNA library. The sequence of the cDNA insert was 2154 bp with an open reading frame of 1794 bp encoding a putative protein of 598 amino acids and predicted molecular mass of 65 kDa. The deduced amino acid sequence showed a strong homology to the mouse nurr1 and human NOT1 orphan nuclear hormone receptors of the NGFI-B/nur77/NAK1 gene subfamily. We refer to this rat clone as r-nurr1. Northern blot analysis showed that r-nurr1 mRNA was highly expressed in the brain and moderately in the lung as a 4.0 kb transcript. A smaller transcript of 2.5 kb was also detected in the testes. The level of r-nurr1 transcript in the heart, skeletal muscle, liver, kidney and spleen was marginal. In situ hybridization showed that r-nurr1 mRNA was constitutively expressed in various regions of the CNS, particularly in the deeper layers (IV to VI) of the perirhinal cortex and area 2 of parietal cortex. We further evaluated the modulation of r-nurr1 expression in CNS by an electroconvulsive seizure (ECS) and by an amgydala-kindled seizure. A single ECS administered via earclip electrodes induced a rapid and transient increase of r-nurr1 mRNA in the granule cells of the dentate gyrus, being significant at 15 min after the seizure, maximal approximately 1 h and back to baseline at 4 h. The amygdala kindled seizure revealed a less robust and restricted nurr-1 induction in the CNS, as only two of the four kindled animals showed a unilateral induction of nurr1 mRNA in the dentate gyrus. These results suggest that r-nurr1 is an immediate-early gene that is differentially induced by ECS vs. kindled seizures. In addition, as r-nurr1 is prominently expressed in the specific brain sites associated with memory acquisition and consolidation, it may play a role in memory processing.

Kindling involves repeated administration of brief high-frequency electrophysiological stimulation of the brain at initially subthreshold intensities that eventually evoke full-blown seizures. It has thus been used not only as a model of epileptogenesis, but of long-term neuronal memory. Quenching is a phenomenon that utilizes low-frequency stimulation for much longer periods of time (eg, 1 Hz for 15 minutes), and appears to exert preventive effects on the development of kindling and inhibit the manifestation of full-blown kindled seizures by markedly increasing the amygdala afterdischarge and seizure threshold. (See also “Kindling and Quenching: Conceptual Implications for rTMS,” by Weiss and Post, page 32). The parameters of kindling and quenching with intracerebral stimulation of the amygdala in vivo are highly similar to those achieved in vitro in hippocampai slice preparations for inducing long-term potentiation (LTP) and longterm depression (LTD), respectively. These neuroplastic changes are relatively long lasting and appear reversible at the level of synaptic function with either LTD or LTP capable of countering the effects of the other.

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.

Cholecystokinin (CCK) can be a potent anticonvulsant neuropeptide in certain seizure models. Therefore, we examined whether seizures produced by electrical kindling of the amygdala or electroconvulsive seizures (ECS) would affect the expression of CCK mRNA in rat brain. Following a single kindled seizure, CCK mRNA expression was decreased about 20-58% in the amygdala. In contrast, after multiple consecutive kindled seizures, CCK mRNA expression was increased in the amygdala, cerebral cortex, CA1 pyramidal cell layer of the hippocampus and dentate hilus. A single ECS produced no effect on CCK mRNA expression, but multiple ECS increased expression in the interneurons of the hippocampus 24 h after the last seizure. Since seizures produced by ECS can be anticonvulsant to further ECS or kindled seizures, the CCK increases in the hippocampus may represent a compensatory anticonvulsant adaptation observed in both models. Overall, the kindling-induced alterations in CCK expression appear to be more complex involving multiple brain regions and distinct temporal properties.

We have isolated a new rat sequence containing motifs of a nuclear hormone receptor from a brain cDNA library. The deduced amino acid sequence encoded by the cDNA clone showed a strong homology to the human NUCI and the mouse peroxisome proliferator activated receptor delta (PPAR delta). We therefore refer to this new clone as rat PPAR delta (rPPAR delta). The new feature of rPPAR delta is a 14 CGG triplet repeat on the 5' untranslated region, not previously reported in either NUCI or mPPAR delta. We found that rPPAR delta was expressed as a 3.5-kb transcript which showed a wide distribution in adult rat tissues. Abundant expression was detected in brain, heart, skeletal muscle, kidney and lung. Weaker expression was noted in the liver, spleen and testis. To determine the specific brain localization of rPPAR delta we performed in situ hybridization analysis. Prominent expression was observed in the thalamus, particularly in the posterior part of the ventral medial nucleus, a site responsive to pain and cold stress. These results raise the possibility that PPAR delta might play a role in modulating response to thermal and pain sensations.

Using brain microdialysis, acetylcholine (Ach) levels were assessed in the nucleus amygdaloideus lateralis of electrically kindled rats using a cholinesterase inhibitor in the perfusion fluid to prevent Ach breakdown. During kindling development, when the animals displayed afterdischarges lasting more than 30 s but no seizures, a significant increase in Ach levels (+66%) was observed after electrical stimulation. Ach levels were also elevated after a stage 5 kindled seizure (+48%), with no additional increment compared to rats experiencing only afterdischarges. Chronic diazepam administration prevented kindling development and the increment in Ach overflow; however, diazepam itself (following acute administration) tended to decrease Ach levels in the amygdala. These findings are convergent with pharmacological data suggesting that changes in the cholinergic function may be important especially during amygdaloid kindling development.

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.

While serotonin (5-HT) has been shown to be anticonvulsant in several types of experimentally induced seizures, 5-HT receptor binding has not been investigated in the kindling model of epilepsy. The present study examined the effects of amygdala kindling on two 5-HT receptor subtypes and on the 5-HT transporter in rat brain. Kindling induced a persistent bilateral increase in 5-HT1A binding in the dentate gyrus, while 5-HT1B receptors increased only in a delayed fashion. Binding to the 5-HT transporter was transiently decreased in dentate gyrus. In cerebral cortex, binding of the three ligands was unchanged. Alterations in 5-HT receptors and the 5-HT transporter may endogenously modulate kindled seizures. Additionally, autoradiography of adenosine A1 receptors revealed no change for these receptors in any brain region.

Repeated administration of a subconvulsant dose of a local anesthetic will eventually induce seizures, a phenomenon similar to electrical kindling. We have investigated the effect of repeated lidocaine and cocaine administration on the phosphoinositide (PI) hydrolysis induced by batrachotoxin (BTX), a specific Na channel activator. Rats were injected with cocaine or saline daily for 6 days and PI hydrolysis was assayed in sliced frontal cortex. Cocaine treatment had no effect on BTX-induced PI hydrolysis while in vitro cocaine blocked the BTX effect. In a second experiment, rats received daily injections of lidocaine or saline. After a rat developed at least two seizures, it was sacrificed together with a rat receiving lidocaine injections which had never seized and a rat receiving saline injections. Basal, BTX and ibotenic acid (IBO; a glutamate receptor agonist)-stimulated PI hydrolysis did not differ among the three groups in slices of either hippocampus (HC) or piriform cortex (PC) though IBO-stimulated PI hydrolysis was mucg greater in the HC than in the PC. Neither in vitro nor in vivo carbamazepine altered the effect of cocaine on BTX-induced PI hydrolysis. These results demonstrate that local anesthetic kindling does not alter PI hydrolysis coupled to Na channel or IBO activation.

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.

In situ hybridization for c-fos mRNA was performed on brain sections (a) from rats after an acute cocaine-induced seizure or from saline-injected controls and (b) from rats after their first cocaine-kindled seizure, as well as from rats that had not yet developed cocaine-kindled seizures (but were exposed to the same amount of cocaine as those that did exhibit convulsions) and from saline-injected controls. Increased expression of c-fos mRNA was observed in animals demonstrating cocaine-induced seizures acutely or following pharmacological kindling. Rats that experienced acute seizures after cocaine (65 mg/kg) showed pronounced increase in expression of c-fos mRNA in the dentate gyrus of the hippocampus and olfactory bulb. Increases were also observed in several other limbic cortical regions, as well as the striatum and ventromedial hypothalamic nucleus (VMH). In rats that were injected daily with an initially subconvulsive dose of cocaine-HCl (40 mg/kg), the cocaine-kindled seizures induced elevations in c-fos mRNA in the same brain regions as with an acute cocaine-induced seizure with the single exception of the VMH. These findings not only suggest the involvement of limbic, cortical and striatal structures in the cocaine-induced seizure, but also raise the possibility that alterations in the proto-oncogene c-fos and its subsequent impact on gene expression could play a role in the changes in neural excitability associated with cocaine-induced kindling.

We examined the effects of generalized seizures on heat shock protein (hsp) mRNA induction in the rat brain using in situ hybridization. Seizures induced by electroconvulsive shock, electrical or cocaine kindling caused a selective induction of the constitutive hsp 73 gene in the dentate gyrus. In these seizure paradigms, not thought to induce widespread tissue damage, neither the heat-inducible hsp 72 gene nor a member of the hsp 90 family (hsp 84) were induced. Hsp 73 may play a role in the adaptation and/or in the maintenance of dentate granule cell integrity following seizures.

Summary: Carbamazepine (CBZ) blocks the development of local anesthetic seizures kindled by cocaine and lidocaine. Cocaine and lidocaine release corticotropin-releasing hormone (CRH) in hypothalamic cell cultures, and this effect is also blocked by CBZ. Because CRH administered intracerebroventricularly (i.c.v.) can produce seizures, its potential role in the development of cocaine seizures and in the anticonvulsant effects of CBZ was studied. CRH (at doses of 5, 10, and 100 μg) potentiated cocaine-kindled seizure development and lethality in a dose-related fashion. CRH also reversed the effects of CBZ on cocaine kindling and lethality, but only at the highest doses, which also affected cocaine kindling. Thus, a selective role for CRH in the anticonvulsant effects of CBZ was not demonstrated. The findings suggest a potentially important role for CRH in exacerbating cocaine-seizure evolution and its associated lethality and confirm the inhibition of cocaine kindling and lethality by CBZ. RESUMEN La carbamacepina (CBZ) bloquea el desarrollo de ataques locales anestesicos condicionados (kindled) con cocaina y lidocaina. La cocaina y lidocaina generan la hormona liberadora de corticotropina (CRH) en cultivos de celulas hipotalamicas y este efecto tambien lo bloquea la CBZ. Puesto que la administracion intracerebroventricular (i.c.v.) de CRH puede producir ataques, se ha estudiado su posible participacion en el desarrollo de 10s ataques producidos por cocaina y 10s efectos anticonvulsivos de la CBZ. La CRH (a dosis de 5, 10 y 100 μg) potencia el desarrollo de ataques condicionados (kindled) y la mortalidad de una manera relacionada con la dosis. La CRH tambien invierte los efectos de la CBZ sobre el “kindling” de la cocaina y la mortalidad pero solamente en las dosis mas elevadas que tambien afectaron el “kindling” de la cocaina. Asi pues, no se ha demostrado un papel selectivo de la CRH sobre los efectos anticonvulsivos de la CBZ. Estos hallazgos sugieren la existencia de un papel potencialmente importante de la CRH en la exacerbacion de la evolucion de los ataques inducidos por cocaina y en la mortalidad asociada y confirman la inhibicion del “kindling” producido por la cocaina y la mortalidad producida por la CBZ. ZUSAMMENFASSUNG Carbamazepin (CBZ) blockiert die Entwicklung von Anfallen, die durch Kokain- und Lidocain-Kindling entstehen. Kokain und Lidocain setzen Corticotropin-Releasing Hormon (CRH) in hy pothalamischen Zellkulturen frei, und dieser Effekt wird ebenfalls durch CBZ blockiert. Da intraventrikular (i.c.v.) gegebenes CRH Anfalle produzieren kann, wurde seine mogliche Rolle bei der Entwicklung von Kokain-Anfallen und der antikonvulsiven Wirkung von CBZ untersucht. CRH (in Dosierungen von 5, 10 und 100 μg) verstarkte die Kokaingekindelte Anfallsentwicklung und Letalitat in einer dosisabhangigen Weise. CRH kehrte die CBZ-Wirkung auf Kokain-kindling und Letalitat um, jedoch nur in den hochsten Dosen, die ebenfalls das Kokain-Kindling beeinfluβten. Demnach wurde eine selektive Rolle von CRH bei der antikonvulsiven Wirkung von CBZ nicht gezeigt. Die Befunde demonstrieren eine moglicherweise wichtige Rolle von CRH in der Entwicklung von Kokain-Anfallen und der assoziierten Letalitat und bestatigen die Inhibition von Kokain-Kindling und Letalitat durch CBZ.

Rats were tested for anticonvulsant responsivity to agents active at central and peripheral-type benzodiazepine receptors before and after they were made tolerant to the anticonvulsant effects of carbamazepine on amygdala-kindled seizures. Tolerance to carbamazepine in this paradigm is a contingent process; it occurs when the drug is administered prior to, but not following the kindled seizure. In animals tolerant to carbamazepine, cross-tolerance was observed to the anticonvulsant effects of PK11195, which is active at peripheral-type benzodiazepine receptors, but not to diazepam, which affects central-type benzodiazepine receptors. In animals treated with carbamazepine after the kindled seizure (not tolerant), no alteration in the anticonvulsant effect of PK11195 was observed. These data extend previous biochemical and pharmacological findings suggesting the importance of peripheral-type benzodiazepine receptor mechanisms in the anticonvulsant effects of carbamazepine and suggest a role for this site in the process of contingent tolerance development.

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.

A unique form of pharmacodynamic tolerance develops when effective anticonvulsants are given as pre-treatment before once-daily amygdala-kindled seizures in animals.1,2 This loss of efficacy (i.e., tolerance) is contingent upon the drug’s administration before, but not immediately after, the kindling stimulation.3, 4, 5, 6 This form of tolerance can be reversed after a period of seizures off anticonvulsants, or even continuing to give anticonvulsants on a once-daily basis but after a fully developed kindled seizure has already occurred.

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.

Using an amygdala-kindled seizure paradigm, we evaluated the acute and chronic anticonvulsant effects of lamotrigine (LTG). Lamotrigine produced dose-dependent inhibitory effects on seizure stage, afterdischarge (AD), and seizure duration. Lamotrigine (15 mg/kg) also increased the afterdischarge and seizure thresholds. Following repeated LTG administration and stimulation at 48-h intervals, tolerance developed to LTG's (15 mg/kg) anticonvulsant effects, and cross-tolerance was observed to the anticonvulsant effects of carbamazepine (CBZ, 15 mg/kg). In a separate group of kindled rats, CBZ (15 mg/kg) was repeatedly administered to induce tolerance. This led to a partial cross-tolerance to LTG, manifesting as an increased rate of tolerance development to LTG, and seizures following the first injection in some animals, which were not observed in CBZ-nontolerant controls. When these rats were made fully tolerant to LTG and then exposed to higher doses of LTG (30 and 50 mg/kg), no anticonvulsant effects were observed. In contrast, higher doses of CBZ (30 mg/kg) did restore efficacy in CBZ-tolerant animals. Cross-tolerance from LTG to valproate and diazepam was not observed, although cross-tolerance from CBZ to valproate has been reported previously. These data suggest that LTG has both shared and distinct anticonvulsant mechanisms from those of CBZ on amygdala-kindled seizures. The implications of these results for clinical therapeutics remain to be evaluated.