Search

Anxiety disorders are among the most prevalent psychiatric disorders, causing significant suffering and disability. Relative to other psychiatric disorders, anxiety disorders tend to emerge early in life, supporting the importance of developmental mechanisms in their emergence and maintenance. Behavioral inhibition (BI) is a temperament that emerges early in life and, when stable and extreme, is linked to an increased risk for the later development of anxiety disorders and other stress-related psychopathology. Understanding the neural systems and molecular mechanisms underlying this dispositional risk could provide insight into treatment targets for anxiety disorders. Nonhuman primates (NHPs) have an anxiety-related temperament, called anxious temperament (AT), that is remarkably similar to BI in humans, facilitating the design of highly translational models for studying the early risk for stress-related psychopathology. Because of the recent evolutionary divergence between humans and NHPs, many of the anxiety-related brain regions that contribute to psychopathology are highly similar in terms of their structure and function, particularly with respect to the prefrontal cortex. The orbitofrontal cortex plays a critical role in the flexible encoding and regulation of threat responses, in part through connections with subcortical structures like the amygdala. Here, we explore individual differences in the transcriptional profile of cells within the region, using laser capture microdissection and single nuclear sequencing, providing insight into the molecules underlying individual differences in AT-related function of the pOFC, with a particular focus on previously implicated cellular systems, including neurotrophins and glucocorticoid signaling., Competing Interests: Competing interests statement:N.H.K. serves as a consultant to the Board of Scientific Advisors, Pritzker Neuropsychiatric Disorders Consortium; Skyland Trail National Advisory Board; CME Outfitters, LLC; Corcept Therapeutics Incorporated; and the Institute for Early Adversity Research External Scientific Advisory Board at the University of Texas-Austin. He is the current Editor-in-Chief of the American Journal of Psychiatry. No other authors have potential conflicts to declare.

The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood 1,2 . Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that human PSDs mature about two to three times slower than those of other species and contain higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of RhoGEF signalling in human neurons delays morphological maturation of dendritic spines and functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell-type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The granular dorsolateral prefrontal cortex (dlPFC) is an evolutionary specialization of primates that is centrally involved in cognition. We assessed more than 600,000 single-nucleus transcriptomes from adult human, chimpanzee, macaque, and marmoset dlPFC. Although most cell subtypes defined transcriptomically are conserved, we detected several that exist only in a subset of species as well as substantial species-specific molecular differences across homologous neuronal, glial, and non-neural subtypes. The latter are exemplified by human-specific switching between expression of the neuropeptide somatostatin and tyrosine hydroxylase, the rate-limiting enzyme in dopamine production in certain interneurons. The above molecular differences are also illustrated by expression of the neuropsychiatric risk gene FOXP2 , which is human-specific in microglia and primate-specific in layer 4 granular neurons. We generated a comprehensive survey of the dlPFC cellular repertoire and its shared and divergent features in anthropoid primates.

Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: NHK has received honoraria from CME Outfitters, Elsevier, and the Pritzker Consortium; has served on scientific advisory boards for Actify Neurotherapies and Neuronetics; currently serves as an advisor to the Pritzker Neuroscience Consortium and consultant to Corcept Therapeutics; has served as co-editor of Psychoneuroendocrinology and currently serves as Editor-in-Chief of The American Journal of Psychiatry; and has patents on promoter sequences for corticotropin-releasing factor CRF2α and a method of identifying agents that alter the activity of the promoter sequences (70,71,323; 75,31,356), promoter sequences for urocortin II and the use thereof (70,87,385), and promoter sequences for corticotropin-releasing factor binding protein and the use thereof (71,22,650). All other authors report no biomedical financial interests or potential conflicts of interest.

Background: Children exhibiting extreme anxious temperament (AT) are at an increased risk for developing anxiety and depression. Our previous mechanistic and neuroimaging work in young rhesus monkeys linked the central nucleus of the amygdala to AT and its underlying neural circuit., Methods: Here, we used laser capture microscopy and RNA sequencing in 47 young rhesus monkeys to investigate AT's molecular underpinnings by focusing on neurons from the lateral division of the central nucleus of the amygdala (CeL). RNA sequencing identified numerous AT-related CeL transcripts, and we used immunofluorescence (n = 3) and tract-tracing (n = 2) methods in a different sample of monkeys to examine the expression, distribution, and projection pattern of neurons expressing one of these transcripts., Results: We found 555 AT-related transcripts, 14 of which were confirmed with high statistical confidence (false discovery rate < .10), including protein kinase C delta (PKCδ), a CeL microcircuit cell marker implicated in rodent threat processing. We characterized PKCδ neurons in the rhesus CeL, compared its distribution with that of the mouse, and demonstrated that a subset of these neurons project to the laterodorsal bed nucleus of the stria terminalis., Conclusions: These findings demonstrate that CeL PKCδ is associated with primate anxiety, provides evidence of a CeL to laterodorsal bed nucleus of the stria terminalis circuit that may be relevant to understanding human anxiety, and points to specific molecules within this circuit that could serve as potential treatment targets for anxiety disorders., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: An early-life anxious temperament (AT) is a risk factor for the development of anxiety, depression, and comorbid substance abuse. We validated a nonhuman primate model of early-life AT and identified the dorsal amygdala as a core component of AT's neural circuit. Here, we combine RNA sequencing, viral-vector gene manipulation, functional brain imaging, and behavioral phenotyping to uncover AT's molecular substrates., Methods: In response to potential threat, AT and brain metabolism were assessed in 46 young rhesus monkeys. We identified AT-related transcripts using RNA-sequencing data from dorsal amygdala tissue (including central nucleus of the amygdala [Ce] and dorsal regions of the basal nucleus). Based on the results, we overexpressed the neurotrophin-3 gene, NTF3, in the dorsal amygdala using intraoperative magnetic resonance imaging-guided surgery (n = 5 per group)., Results: This discovery-based approach identified AT-related alterations in the expression of well-established and novel genes, including an inverse association between NTRK3 expression and AT. NTRK3 is an interesting target because it is a relatively unexplored neurotrophic factor that modulates intracellular neuroplasticity pathways. Overexpression of the transcript for NTRK3's endogenous ligand, NTF3, in the dorsal amygdala resulted in reduced AT and altered function in AT's neural circuit., Conclusions: Together, these data implicate neurotrophin-3/NTRK3 signaling in the dorsal amygdala in mediating primate anxiety. More generally, this approach provides an important step toward understanding the molecular underpinnings of early-life AT and will be useful in guiding the development of treatments to prevent the development of stress-related psychopathology., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Cortico-limbic circuits provide a substrate for adaptive behavioral and emotional responses. However, dysfunction of these circuits can result in maladaptive responses that are associated with psychopathology. The prefrontal-limbic pathways are of particular interest because they facilitate interactions among emotion, cognition, and decision-making functions, all of which are affected in psychiatric disorders. Regulatory aspects of the prefrontal cortex (PFC) are especially relevant to human psychopathology, as the PFC, in addition to its functions, is more recent from an evolutionary perspective and is considerably more complex in human and nonhuman primates compared with other species. This review provides a neuroanatomical and functional perspective of selected regions of the limbic system, the medial temporal lobe structures-the hippocampus and amygdala as well as regions of the PFC. Beyond the specific brain regions, emphasis is placed on the structure and function of critical PFC-limbic circuits, linking alterations in the processing of information across these pathways to the pathophysiology and psychopathology of various psychiatric illnesses.

Alterations in central extended amygdala (EAc) function have been linked to anxiety, depression, and anxious temperament (AT), the early-life risk to develop these disorders. The EAc is composed of the central nucleus of the amygdala (Ce), the bed nucleus of the stria terminalis (BST), and the sublenticular extended amygdala (SLEA). Using a non-human primate model of AT and multimodal neuroimaging, the Ce and the BST were identified as key AT-related regions. Both areas are primarily comprised of GABAergic neurons and the lateral Ce (CeL) and lateral BST (BSTL) have among the highest expression of neuropeptides in the brain. Somatostatin (SST) is of particular interest because mouse studies demonstrate that SST neurons, along with corticotropin-releasing factor (CRF) neurons, contribute to a threat-relevant EAc microcircuit. Although the distribution of CeL and BSTL SST neurons has been explored in rodents, this system is not well described in non-human primates. In situ hybridization demonstrated an anterior-posterior gradient of SST mRNA in the CeL but not the BSTL of non-human primates. Triple-labeling immunofluorescence staining revealed that SST protein-expressing cell bodies are a small proportion of the total CeL and BSTL neurons and have considerable co-labeling with CRF. The SLEA exhibited strong SST mRNA and protein expression, suggesting a role for SST in mediating information transfer between the CeL and BSTL. These data provide the foundation for mechanistic non-human primate studies focused on understanding EAc function in neuropsychiatric disorders., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

The lateral division of the bed nucleus of the stria terminalis (BSTL) and central nucleus of the amygdala (Ce) form the two poles of the 'central extended amygdala', a theorized subcortical macrostructure important in threat-related processing. Our previous work in nonhuman primates, and humans, demonstrating strong resting fMRI connectivity between the Ce and BSTL regions, provides evidence for the integrated activity of these structures. To further understand the anatomical substrates that underlie this coordinated function, and to investigate the integrity of the central extended amygdala early in life, we examined the intrinsic connectivity between the Ce and BSTL in non-human primates using ex vivo neuronal tract tracing, and in vivo diffusion-weighted imaging and resting fMRI techniques. The tracing studies revealed that BSTL receives strong input from Ce; however, the reciprocal pathway is less robust, implying that the primate Ce is a major modulator of BSTL function. The sublenticular extended amygdala (SLEAc) is strongly and reciprocally connected to both Ce and BSTL, potentially allowing the SLEAc to modulate information flow between the two structures. Longitudinal early-life structural imaging in a separate cohort of monkeys revealed that extended amygdala white matter pathways are in place as early as 3 weeks of age. Interestingly, resting functional connectivity between Ce and BSTL regions increases in coherence from 3 to 7 weeks of age. Taken together, these findings demonstrate a time period during which information flow between Ce and BSTL undergoes postnatal developmental changes likely via direct Ce → BSTL and/or Ce ↔ SLEAc ↔ BSTL projections., Competing Interests: Dr. Kalin has received honoraria from CME Outfitters, Elsevier, and the Pritzker Neuropsychiatric Disorders Research Consortium. He is on the Advisory Boards for Corcept Therapeutics and Skyland Trail - George West Mental Health Foundation. Dr. Kalin is a Stockholder in Corcept Therapeutics, and owns several patents including: promoter sequences for corticotropin-releasing factor alpha (U.S. Patent #7071323, issued on 07-04-06); a method of identifying agents that alter the activity of the promoter sequences (U.S. Patent #7531356 issued on 05-12-09); promoter sequences for urocortin II and the use thereof (U.S. Patent #7087385 issued on 08-08-06); and promoter sequences for corticotropin-releasing factor binding protein and use thereof (U.S. Patent #7122650, issued on 10-17-06). All other authors declare no conflicts of interest.

Background: Nonhuman primate models are critical for understanding mechanisms underlying human psychopathology. We established a nonhuman primate model of anxious temperament (AT) for studying the early-life risk to develop anxiety and depression. Studies have identified the central nucleus of the amygdala (Ce) as an essential component of AT's neural substrates. Corticotropin-releasing factor (CRF) is expressed in the Ce, has a role in stress, and is linked to psychopathology. Here, in young rhesus monkeys, we combined viral vector technology with assessments of anxiety and multimodal neuroimaging to understand the consequences of chronically increased CRF in the Ce region., Methods: Using real-time intraoperative magnetic resonance imaging-guided convection-enhanced delivery, five monkeys received bilateral dorsal amygdala Ce-region infusions of adeno-associated virus serotype 2 containing the CRF construct. Their cagemates served as unoperated control subjects. AT, regional brain metabolism, resting functional magnetic resonance imaging, and diffusion tensor imaging were assessed before and 2 months after viral infusions., Results: Dorsal amygdala CRF overexpression significantly increased AT and metabolism within the dorsal amygdala. Additionally, we observed changes in metabolism in other AT-related regions, as well as in measures of functional and structural connectivity., Conclusions: This study provides a translational roadmap that is important for understanding human psychopathology by combining molecular manipulations used in rodents with behavioral phenotyping and multimodal neuroimaging measures used in humans. The results indicate that chronic CRF overexpression in primates not only increases AT but also affects metabolism and connectivity within components of AT's neural circuitry., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Tremulous jaw movements (TJMs) have become a commonly used rat model of Parkinsonian tremor. TJMs can be induced by a number of neurochemical conditions that parallel those seen in human Parkinsonism, including DA depletion, DA antagonism, and cholinomimetic administration, and can be reduced by various antiparkinsonian agents. TJMs typically occur in bursts with the peak frequency in the range of 3-7.5 Hz, which is similar to the Parkinsonian tremor frequency range. While the vast majority of this work has been done using rats, current efforts have focused on extending the TJM model to mice. The aim of the present studies was to establish a mouse model of Parkinsonian resting tremor using the anticholinesterase galantamine, and to investigate the effects of adenosine A2A antagonism on galantamine-induced TJMs. Galantamine significantly induced TJMs in a dose-dependent manner (0.5, 1.0, 1.5, 2.0, 2.5 mg/kg IP). The TJMs tended to occur in bursts in the 3-7.5 Hz frequency range, with a peak frequency of approximately 6 Hz. Systemic administration of the adenosine A2A antagonist MSX-3 (2.5, 5.0, 10.0 mg/kg) significantly attenuated galantamine-induced TJMs. Co-administration of MSX-3 also altered the local frequency of galantamine-induced TJMs, decreasing the peak frequency from approximately 6 Hz to 5 Hz, though the vast majority of TJMs remained in the frequency range characteristic of Parkinsonian resting tremor. These results indicate that adenosine A2A antagonism is capable of reducing anticholinesterase-induced TJMs in mice. Extending the TJM model to mice gives researchers an additional avenue for investigating drug-induced Parkinsonism and tremorogenesis, and could be a useful addition to the study of motor abnormalities observed in mouse genetic models of Parkinsonism., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Deep brain stimulation (DBS) of the subthalamic nucleus is increasingly being employed as a treatment for parkinsonian symptoms, including tremor. The present studies used tremulous jaw movements, a pharmacological model of tremor in rodents, to investigate the tremorolytic effects of subthalamic DBS in rats. Subthalamic DBS reduced the tremulous jaw movements induced by the dopamine D2 family antagonist pimozide and the D1 family antagonist ecopipam, as well as the cholinomimetics pilocarpine and galantamine. The ability of DBS to suppress tremulous jaw movements was dependent on the neuroanatomical locus being stimulated (subthalamic nucleus vs. a striatal control site), as well as the frequency and intensity of stimulation used. Importantly, administration of the adenosine A2A receptor antagonist MSX-3 reduced the frequency and intensity parameters needed to attenuate tremulous jaw movements. These results have implications for the clinical use of DBS, and future studies should determine whether adenosine A2A antagonism could be used to enhance the tremorolytic efficacy of subthalamic DBS at low frequencies and intensities in human patients., (© 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Adenosine A(2A) and dopamine D2 receptors interact to regulate diverse aspects of ventral and dorsal striatal functions related to motivational and motor processes, and it has been suggested that adenosine A(2A) antagonists could be useful for the treatment of depression, parkinsonism and other disorders. The present experiments were performed to characterize the effects of MSX-4, which is an amino acid ester prodrug of the potent and selective adenosine A(2A) receptor antagonist MSX-2, by assessing its ability to reverse pharmacologically induced motivational and motor impairments. In the first group of studies, MSX-4 reversed the effects of the D2 antagonist eticlopride on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. MSX-4 was less potent after intraperitoneal administration than the comparison compound, MSX-3, though both were equally efficacious. With this task, MSX-4 was orally active in the same dose range as MSX-3. MSX-4 also reversed the locomotor suppression induced by eticlopride in the open field, but did not induce anxiogenic effects as measured by the relative amount of interior activity. Behaviorally active doses of MSX-4 also attenuated the increase in c-Fos and pDARPP-32(Thr34) expression in nucleus accumbens core that was induced by injections of eticlopride. In addition, MSX-4 suppressed the oral tremor induced by the anticholinesterase galantamine, which is consistent with an antiparkinsonian profile. These actions of MSX-4 indicate that this compound could have potential utility as a treatment for parkinsonism, as well as some of the motivational symptoms of depression and other disorders., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Tremulous jaw movements in rats can be induced by several conditions associated with parkinsonism and tremorogenesis, including dopamine depletion, dopamine antagonism, and cholinomimetic drugs. Previous research indicates that neostriatal mechanisms are involved in the generation of tremulous jaw movements, but the striatal output pathways involved in these movements remain uncertain. One important pathway for striatal output is the GABAergic striatopallidal system. The present studies were undertaken to determine if extracellular levels of GABA in globus pallidus are associated with the induction of tremulous jaw movements by either a dopamine D2 antagonist (haloperidol) or a cholinomimetic (the muscarinic agonist pilocarpine). The first experiment studied the effects of both acute and repeated (i.e. 8 days) administration of the D2 antagonist haloperidol. In the second experiment, the effect of acute administration of the muscarinic agonist pilocarpine on GABA levels in the globus pallidus was examined. In both experiments, behavioral observations of tremulous jaw movements were conducted in parallel with the collection of microdialysis samples. Acute and repeated haloperidol treatment induced tremulous jaw movements, and significantly elevated extracellular GABA in globus pallidus. Pooling across all treatment groups, there was a significant positive correlation between pallidal GABA levels and the number of tremulous jaw movements induced during the first three samples collected after injection. However, injection of 4.0mg/kg pilocarpine had no effect on pallidal GABA release, despite the robust induction of tremulous jaw movements. These results indicate that the tremulous jaw movements induced by dopamine D2 antagonism and those induced through muscarinic receptor stimulation may be generated via distinct mechanisms., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Diagnosing adult ADHD is frequently problematic because behavioral information from the patient's childhood, and multiple informants who can delineate the patient's current behavior, are often unavailable. This preliminary study was designed to explore whether objective neuropsychological testing may be a useful adjunct in the diagnosis of adult ADHD. Nineteen adults diagnosed with ADHD according to DSM-IV criteria, along with 10 controls, were assessed using a neuropsychological battery which comprised tests assessing linguistic, visual-spatial perceptual, academic, attentional and inhibitory control, mnestic and executive functions. Following preliminary analyses, designed to determine which variables best discriminated the groups, receiver operating characteristic (ROC) curves were constructed to determine the sensitivity and specificity of the best measures both alone and in combination. Only three measures significantly (p < 0.01) distinguished the groups; Digits Backwards from the WAIS-R and two reaction time measures from a computerized task modeled after Luria's Competing Motor Programs. ROC curve analyses indicated that in combination these measures had greater than 90% accuracy for classifying ADHD and non-ADHD patients. While further research is necessary these preliminary findings suggest that neuropsychological testing may be a useful adjunct in the differential diagnosis of adult ADHD.

Alzheimer's disease (AD) patients and normal adults were tested in two complementary recognition tasks. On each trial of the faces task, participants matched the photograph of a famous individual to one of four names. On each tial of the names task, participants matched the name of a famous individual to one of four photographs. The AD patients made enough consistent errors across the two tasks to suggest an impairment in the storage of information about the individuals. In addition, they made enough inconsistent errors to suggest a generalized retrieval deficit. The AD patients performed as well on the faces taslk as on the names task, providing no evidence of a specialized deficit in the retrieval of lexical information.

Korsakoff's amnesics and normal controls read descriptions of five famous and five unknown individuals. Each individual was linked with five exemplars of one semantic category and three of another. Subjects decided which of the two relevant categories had been linked more frequently with each individual and made recognition judgments with respect to the exemplars. An analysis of the relationship between recognition and frequency judgment performance suggested that the normals but not the amnesics had used explicit memory for the exemplars in making their frequency judgments. An analysis of frequency judgment performance suggested that the judgments of the amnesics but not the normals reflected implicit memory for the associations between the individuals and the categories that had been used to describe them.

Intravenous drug abusers (IVDAs) represent an increasing proportion of the HIV epidemic. Forty-three IVDA's (22 HIV-negative, 21 HIV-positive) were studied using the Mattis Dementia Rating Scale (DRS). All subjects had used intravenous heroin, but reported that they were drug-free at the time of testing. HIV-positive subjects were predominantly symptomatic and were dichotomized into AIDS and non-AIDS groups. All subjects with abnormal DRS scores were HIV-positive (57% of all HIV-positives). All HIV-negative subjects had normal DRS scores while 43% of the positive group obtained such scores. The DRS reliably identifies neuropsychological impairment, and may be a useful screening tool in this population.

Six Korsakoffs amnesics, three mixed amnesics, and eight normal controls were taught the meaning of "bice", the word for a particular shade of blue-green. The conceptual interpretation that the Korsakoffs developed for "bice" differed in three respects from the one that the controls developed. (1) Although both Korsakoffs and controls applied the term more liberally to pens than to other objects, two of the Korsakoffs showed an extreme form of this tendency. (2) The Korsakoffs tended to generalize more broadly along the spectral dimension in using the term. (3) Whereas there was a positive relationship, in the data for the controls, between measures of syntactic and semantic awareness concerning "bice", there was no such relationship in the Korsakoffs data. It was concluded that the Korsakoffs had difficulty mastering the new word, and difficulty specifically in integrating their representation for the word with the rest of their lexical knowledge.

A learning technique was developed for chronically amnesic subjects which linked word-list items in a novel manner utilizing ridiculously-imaged-stories (RIS). By the 8th week of once-weekly 45 minute training sessions with RIS the five amnesic subjects were able to freely recall an average of 14 items from a 20-item list after a 1-week interval, but showed minimal recall after the same interval of another 20-word list that had been concurrently learned in a cued, modified free-recall condition. The effective RIS technique producing this robust recall combines stimuli embedded in a novel-arousing context with high-imagery, storyline, cuing, and spaced repetition. The net effect of this technique is interpreted as providing artificial "chunks" that can be encoded and transferred relatively normally into long-term memory.

A previously reported technique for promoting robust free recall in amnesic subjects (Ridiculously Imaged Stories) was further studied in two amnesic patients to determine if there is a limit to the amount of information that can be acquired, and if the novelty of the storyline is essential for its efficacy. Two different lists of words were taught to each subject embedded in either a ridiculous or a logical story. The subjects learned combined totals of 160 (S1) and 120 (S2) words with perfect free recall at intervals up to 7 weeks between last list exposure and recall. No differences were observed in rates of learning between the two types of stories. These results challenge the view that amnesic subjects are unable to freely recall large amounts of new information within a newly acquired context. A theoretical integration of the data is explored.

Tests that tapped memory for spatial location, temporal order, frequency of occurrence, and category membership were administered to a group of alcoholic Korsakoff patients, a group of mixed amnesic patients with primarily temporal lobe pathology, and a group of normal subjects. The four tests were administered with incidental as well as intentional learning conditions. All groups performed better in the intentional than the incidental condition of the category recognition test. None of the groups performed better in the intentional than the incidental conditions on any of the other tests. The data were interpreted as implying that amnesic patients do not benefit from intentional learning conditions in tests of memory for contextual stimuli.

A test designed to assess the adequacy of knowledge about specific words, presumed to be well established in long-term storage, was administered to 5 alcoholic Korsakoff patients, 3 post-trauma amnesics, and 5 normal controls. The 400 question true/false test tapped knowledge of basic and obscure attributes and functions of 25 noun-concepts. The data indicate that traumatic amnesics made more total errors than Korsakoff amnesics, who in turn made more errors than normals. However, Korsakoffs made a greater proportion of errors on basic-knowledge items than the other groups. It is concluded that semantic organization is impaired in both amnesic groups, although differently. The post-trauma error pattern suggests a uni-factor deficit while the Korsakoff pattern suggests a multifactor deficit.