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Key Points Question What is the completeness of reporting for the literature on acute point-of-care ultrasound, as indicated by adherence to the Standards for Reporting of Diagnostic Accuracy (STARD) 2015 guidelines? Findings This systematic review of 74 studies found that overall adherence to STARD was moderate, with a mean of 19.7 of 30 items (66%) reported. Studies citing STARD and those published in journals endorsing STARD had a higher number of reported items. Meaning These findings suggest that adherence of point-of-care ultrasound research to the STARD 2015 guidelines is moderate, which may limit the ability to detect bias in individual studies and prevent appropriate translation of research into clinical practice., This systematic review assesses adherence to the Standards for Reporting of Diagnostic Accuracy (STARD) 2015 guidelines in the acute care point-of-care ultrasound literature., Importance Incomplete reporting of diagnostic accuracy research impairs assessment of risk of bias and limits generalizability. Point-of-care ultrasound has become an important diagnostic tool for acute care physicians, but studies assessing its use are of varying methodological quality. Objective To assess adherence to the Standards for Reporting of Diagnostic Accuracy (STARD) 2015 guidelines in the literature on acute care point-of-care ultrasound. Evidence Review MEDLINE was searched to identify diagnostic accuracy studies assessing point-of-care ultrasound published in critical care, emergency medicine, or anesthesia journals from 2016 to 2019. Studies were evaluated for adherence to the STARD 2015 guidelines, with the following variables analyzed: journal, country, STARD citation, STARD-adopting journal, impact factor, patient population, use of supplemental material, and body region. Data analysis was performed in November 2019. Findings Seventy-four studies were included in this systematic review for assessment. Overall adherence to STARD was moderate, with 66% (mean [SD], 19.7 [2.9] of 30 items) of STARD items reported. Items pertaining to imaging specifications, patient population, and readers of the index test were frequently reported (>66% of studies). Items pertaining to blinding of readers to clinical data and to the index or reference standard, analysis of heterogeneity, indeterminate and missing data, and time intervals between index and reference test were either moderately (33%-66%) or infrequently ( .99), patient population (mean [SD], pediatric, 20.0 [3.1] items; adult, 20.2 [2.7] items; mixed, 17.9 [1.9] items; P = .09), use of supplementary materials (mean [SD], yes, 19.2 [3.0] items; no, 19.7 [2.8] items; P = .91), or journal impact factor (mean [SD], higher impact factor, 20.3 [3.1] items; lower impact factor, 19.1 [2.4] items; P = .08). Conclusions and Relevance Overall, the literature on acute care point-of-care ultrasound showed moderate adherence to the STARD 2015 guidelines, with more complete reporting found in studies citing STARD and those published in STARD-adopting journals. This study has established a current baseline for reporting; however, future studies are required to understand barriers to complete reporting and to develop strategies to mitigate them.

Amygdalostriatal and intra-amygdaloid fiber connectivity was studied in rats via injections of one of the tracers Phaseolus vulgaris leucoagglutinin (PHA-L) or biotinylated dextran amine (BDA) into various amygdaloid nuclei. To determine the neurotransmitter identity of labeled fibers we combined tracer detection with immunofluorescence staining, using antibodies against vesicular transporters (VTs) associated with glutamatergic (VGluT1, VGluT2) or GABAergic (VGAT) neurotransmission. High-magnification confocal laser scanning images were screened for overlap: occurrence inside tracer labeled fibers or axon terminals of immunofluorescence signal associated with one of the VTs. Labeled amygdalostriatal fibers were seen when tracer had been injected into the magnocellular and parvicellular portions of the basal amygdaloid nucleus and the lateral amygdaloid nucleus (nuclei belonging to 'cortical type' amygdaloid nuclei). Intra-amygdaloidal projection fibers were mostly found after tracer injections in the central and medial amygdaloid nuclei ('striatal type' amygdaloid nuclei). Terminals of tracer-labeled amygdalostriatal fibers contained immunofluorescence signal associated mostly with VGluT1 and to a lesser degree with VGluT2 or VGAT. Intra-amygdaloid labeled fibers showed colocalization mostly of VGluT1, followed by VGAT. VGluT2 co-occurred in a minority of intra-amygdaloid tracer-containing fiber terminals. We conclude from our observations that both amygdalostriatal and intra-amygdaloid projections, arising from, respectively, 'cortical type' and 'striatal type' amygdaloid nuclei contain strong glutamatergic and modest GABAergic components. The glutamatergic fibers express either VGluT1 or VGluT2. The absence in large numbers of tracer labeled fibers of expression of one of the selected VTs leads us to suspect that amygdalostriatal projection fibers may contain hitherto neglected neurotransmitters in these connections, e.g., aspartate.

Background The phase 3 studies of telaprevir (T) in combination with peginterferon α-2a and ribavirin (PR) in treatment-naive genotype 1 chronic hepatitis C virus-infected patients (ADVANCE/ILLUMINATE) were not designed a priori to assess the effect of race and ethnicity on treatment response. However, these factors are important given the lower sustained virologic response (SVR) rates observed in black and Hispanic/Latino patients treated with PR. Goals This retrospective pooled analysis evaluated the effect of race or ethnicity on treatment-naive patient response to telaprevir-based therapy and assessed resistant variant profiles. Materials and methods This analysis comprised patients enrolled in ADVANCE (N=363) and ILLUMINATE (N=540) who received 12 weeks of telaprevir in combination with PR followed by 12 or 36 weeks of PR alone and patients in ADVANCE (N=361) who received 48 weeks of PR alone. Race and ethnicity were self-reported and not mutually exclusive. Results Higher SVR rates were observed with telaprevir-based therapy compared with PR in blacks [n=99 (62%) vs. n=28 (29%), respectively] and in Hispanics/Latinos [n=89 (72%) vs. n=38 (39%)]. The SVR was lower in telaprevir-treated blacks [n=99 (62%)] compared with nonblacks [n=791 (78%)] and in Hispanic/Latinos compared with non-Hispanics/Latinos [n=89 (72%) vs. n=801 (76%)]. Low discontinuation rates due to adverse events, including rash and anemia, were observed across subgroups. Resistance profiles were similar among the subgroups. Conclusions Treatment-naive black and Hispanic/Latino patients with genotype 1 chronic hepatitis C virus infection may benefit from telaprevir-based therapy, an important finding given the lower SVR rates observed in these patients when they are treated with PR alone.

Emerging evidence indicates that stimulus novelty is affectively potent and reliably engages the amygdala and other portions of the affective workspace in the brain. Using fMRI, we examined whether novel stimuli remain affectively salient across the lifespan, and therefore, whether novelty processing—a potentially survival-relevant function—is preserved with aging. Nineteen young and 22 older healthy adults were scanned during observing novel and familiar affective pictures while estimating their own subjectively experienced aroused levels. We investigated age-related difference of magnitude of activation, hemodynamic time course, and functional connectivity of BOLD responses in the amygdala. Although there were no age-related differences in the peak response of the amygdala to novelty, older individuals showed a narrower, sharper (i.e., “peakier”) hemodynamic time course in response to novel stimuli, as well as decreased connectivity between the left amygdala and the affective areas including orbito-frontal regions. These findings have relevance for understanding age-related differences in memory and affect regulation.

Experimental evidence and clinical observations indicate that brain inflammation is an important factor in epilepsy. In particular, induction of interleukin-converting enzyme (ICE)/caspase-1 and activation of interleukin (IL)-1β/IL-1 receptor type 1 axis both occur in human epilepsy, and contribute to experimentally induced acute seizures. In this study, the anticonvulsant activity of VX-765 (a selective ICE/caspase-1 inhibitor) was examined in a mouse model of chronic epilepsy with spontaneous recurrent epileptic activity refractory to some common anticonvulsant drugs. Moreover, the effects of this drug were studied in one acute model of seizures in mice, previously shown to involve activation of ICE/caspase-1. Quantitative analysis of electroencephalogram activity was done in mice exposed to acute seizures or those developing chronic epileptic activity after status epilepticus to assess the anticonvulsant effects of systemic administration of VX-765. Histological and immunohistochemical analysis of brain tissue was carried out at the end of pharmacological experiments in epileptic mice to evaluate neuropathology, glia activation and IL-1β expression, and the effect of treatment. Repeated systemic administration of VX-765 significantly reduced chronic epileptic activity in mice in a dose-dependent fashion (12.5-200 mg/kg). This effect was observed at doses ≥ 50 mg/kg, and was reversible with discontinuation of the drug. Maximal drug effect was associated with inhibition of IL-1β synthesis in activated astrocytes. The same dose regimen of VX-765 also reduced acute seizures in mice and delayed their onset time. These results support a new target system for anticonvulsant pharmacological intervention to control epileptic activity that does not respond to some common anticonvulsant drugs.

Financial planning decisionss are fundamentally affective in nature; they are decisions related to money, longevity and quality of life. Over the next several decades people will be increasingly responsible for managing their own assets and investments, and they will be subject to the affective influences on active, personal decision-making. Many of these crucial decisions are made and revised across the lifespan, including when to buy or sell a home, how to save for childrens’ education, how to manage healthcare costs, when to retire, how much to save for retirement and how to allocate retirement funds. As average life expectancy increases, many retirees will be faced with inadequate savings to live comfortably until the end of their lives. In the current article, we examine the problems of and potential solutions to inadequate financial planning through the lens of affective science, with an emphasis on how brain-based changes in affective processing with age might contribute to the challenge of financial planning.

Many neuroscience studies have demonstrated that the human amygdala is a central element in the neural workspace that computes affective value. Emerging evidence suggests that novelty is an affective dimension that engages the amygdala independently of other affective properties. This current study is the first in which novelty, valence, and arousal were systematically examined for their relative contributions to amygdala activation during affective processing. Healthy young adults viewed International Affective Picture System (IAPS) images that varied along the dimensions of valence (positive, negative, neutral), arousal (high, mid, low), and novelty (novel, familiar). The results demonstrate that, in comparison to negative (vs. positive) and high (vs. low) arousal stimuli, the amygdala has higher peak responses and a selectively longer time course of activation to novel (vs. familiar) stimuli. In addition, novelty differentially engaged other affective brain areas including those involved in controlling and regulating amygdala responses (e.g., orbitofrontal cortex), as well as those transmitting sensory signals that the amygdala modulates (e.g., occipitotemporal visual cortex). Taken together with other findings, these results support the idea that an essential amygdala function is signaling stimulus importance or salience. The results also suggest that novelty is a critical stimulus dimension for amygdala engagement (in addition to valence and arousal).

Alzheimer's disease (AD) is associated with neurodegeneration in vulnerable limbic and heteromodal regions of the cerebral cortex, detectable in vivo using magnetic resonance imaging. It is not clear whether abnormalities of cortical anatomy in AD can be reliably measured across different subject samples, how closely they track symptoms, and whether they are detectable prior to symptoms. An exploratory map of cortical thinning in mild AD was used to define regions of interest that were applied in a hypothesis-driven fashion to other subject samples. Results demonstrate a reliably quantifiable in vivo signature of abnormal cortical anatomy in AD, which parallels known regional vulnerability to AD neuropathology. Thinning in vulnerable cortical regions relates to symptom severity even in the earliest stages of clinical symptoms. Furthermore, subtle thinning is present in asymptomatic older controls with brain amyloid binding as detected with amyloid imaging. The reliability and clinical validity of AD-related cortical thinning suggests potential utility as an imaging biomarker. This “disease signature” approach to cortical morphometry, in which disease effects are mapped across the cortical mantle and then used to define ROIs for hypothesis-driven analyses, may provide a powerful methodological framework for studies of neuropsychiatric diseases., National Institute on Aging (K23-AG22509), National Institute on Aging (P50-AG05134), National Institute on Aging (P50-AG05681), National Institute on Aging (P01-AG03991), National Institute on Aging (R01-AG29411), National Institute on Aging (R21-AG29840), National Institute of Neurological Disorders and Stroke (U.S.) (grant R01-NS042861), National Center for Research Resources (U.S.) (P41RR14075), National Center for Research Resources (U.S.) (U24-RR021382), Alzheimer's Association, Howard Hughes Medical Institute, Mental Illness and Neuroscience Discovery (MIND) Institute

Trichotillomania (TTM) may be related to obsessive-compulsive disorder (OCD) and other neuropsychiatric conditions characterized by cortico-striatal dysfunction. Functional imaging studies of OCD using an implicit learning task have found abnormalities in striatal and hippocampal activation. The current study investigated whether similar abnormalities occur in TTM. Functional MRI and the serial reaction time (SRT) task were used to assess striatal and hippocampal activation during implicit sequence learning in TTM and healthy control (HC) subjects. The results for 20 age- and education-matched participants (10 TTM, 10 HC) are reported. In comparison with HC participants, those with TTM exhibited no significant differences in implicit learning, or in activation within the striatum, hippocampus, or other brain regions. The current findings do not provide evidence for cortico-striatal dysfunction in TTM. Future studies directly comparing OCD and TTM subjects are warranted to confirm the specificity of abnormal striatal and hippocampal findings during implicit sequence learning in OCD.

Background Corticostriatal circuitry has been implicated in the pathophysiology of obsessive–compulsive disorder (OCD). The serial reaction time (SRT) task, a paradigm that tests implicit sequence learning, has been used with imaging to probe striatal function. Initial studies have indicated that OCD patients exhibit deficient striatal activation and aberrant hippocampal recruitment compared with healthy control (HC) subjects. Here, we used the SRT and functional magnetic resonance imaging (fMRI) to replicate prior results in a larger sample and to test for relationships between regional activation and OCD symptom dimensions. Methods Using SPM99, fMRI-SRT data from 12 OCD and 12 matched HC subjects were analyzed. Symptom dimensions followed a four-factor model scored on a 0- to 10-point scale. Results For the implicit learning versus random contrast, group by condition interactions revealed aberrant recruitment within the hippocampus as well as orbitofrontal cortex (OCD > HC) but no striatal group differences. However, an inverse correlation was found between striatal activation and specific symptom factors. Conclusions These results replicate previous smaller studies showing aberrant hippocampal recruitment in OCD during SRT performance. Although findings of deficient striatal activation in OCD were not replicated, correlation results suggest that this inconsistency may be attributable to differences among OCD symptom dimensions.

Previous neuroimaging research has shown diminished anterior cingulate cortex (ACC) function in posttraumatic stress disorder (PTSD), with most of these findings occurring in pregenual/subgenual ACC. This study investigates whether dorsal ACC (dACC) function is also diminished in PTSD. The authors used functional magnetic resonance imaging to study dACC function during the performance of the counting Stroop. Thirteen men with PTSD and 13 trauma-exposed men without PTSD participated. In the interference-neutral comparison, both groups showed response time increases and dACC activations. These results suggest that dACC function in PTSD is not diminished during the performance of this nonemotional task. In fact, there were statistical trends in the opposite direction. These findings will help to better characterize functional brain abnormalities in this disorder.

Objective: To examine 3 different aspects of the emotional memory effect in aging and Alzheimer disease (AD): itemspecific recollection, gist memory, and recognition response bias. Method: Younger adults, older adults, and patients with AD performed a false recognition memory test in which participants were tested on ‘‘lure’’ items that were not seen at study, but were semantically related to the study items. Participants were tested on 5 emotional and 5 non-emotional lists. Results: In addition to finding an increase in true recognition for emotional versus non-emotional items in healthy younger and older adults but not in patients with AD, and confirming that emotional items led younger adults to shift their response bias to a more liberal one, 3 novel findings were observed. First, the emotional effect on response bias was also observed in healthy older adults. Second, the opposite emotional effect on response bias was observed in patients with AD. Third, emotional items did not lead to an improvement in item-specific recollection or gist memory. Conclusions: Although healthy older adults show the normal amygdala-modulated criterion shift for emotional items— influencing their subjective feeling that information has been previously encountered, the amygdala pathology present in early AD may disrupt this influence.

A balance of inhibitory and facilitatory mechanisms is essential for efficient and goal-directed behaviors. These mechanisms may go awry in several neuropsychiatric disorders characterized by uncontrolled, repetitive behaviors. The visuospatial priming paradigm is a well-established probe of inhibition and facilitation that has been used to demonstrate behavioral deficits in patients with Tourette syndrome and obsessive–compulsive disorder. However, the brain correlates of this visuospatial priming paradigm are not yet well established. In the present study, we used a visuospatial priming paradigm and event-related functional MRI, to probe inhibitory and facilitatory brain mechanisms in healthy adult women. When subjects performed the negative priming (i.e., inhibitory) task, several regions of the prefrontal cortex were selectively activated relative to the neutral condition. Non-overlapping regions of the prefrontal cortex were deactivated in the positive priming condition. These results support the notion that the prefrontal cortex is involved in both inhibitory and facilitatory processing and demonstrate that this visuospatial priming task shares brain correlates with other positive and negative priming tasks. In conjunction with functional MRI, this visuospatial priming task may be useful for studying the pathophysiology of neuropsychiatric disorders in which deficient inhibitory processing or excessive facilitation is a feature.

Introduction Patients with schizophrenia show deficits in facial affect and facial identity recognition and exhibit structural and neurophysiological abnormalities in brain regions known to mediate these processes. Functional neuroimaging studies of neural responses to emotional facial expressions in schizophrenia have reported both increases and decreases in medial temporal lobe (MTL) activity in schizophrenia. Some of this variability may be related to the tasks performed and the baseline conditions used. Here we tested whether MTL responses to human faces in schizophrenia are abnormal when unconstrained by a cognitive task and measured relative to a low-level baseline (fixation) condition. Methods 15 patients with schizophrenia and 16 healthy control subjects underwent functional magnetic resonance imaging (fMRI) while passively viewing human faces displaying fearful, happy, and neutral emotional expressions. Results Relative to control subjects, the patients demonstrated (1) significantly greater activation of the left hippocampus while viewing all three facial expressions and (2) increased right amygdala activation during the initial presentation of fearful and neutral facial expressions. Conclusions In schizophrenia, hippocampal and amygdala activity is elevated during the passive viewing of human faces.

Introversion/extraversion and neuroticism are 2 important and frequently studied dimensions of human personality. These dimensions describe individual differences in emotional responding across a range of situations and may contribute to a predisposition for psychiatric disorders. Recent neuroimaging research has begun to provide evidence that neuroticism and introversion/extraversion have specific functional and structural neural correlates. Previous studies in healthy adults have reported an association between neuroticism, introversion/extraversion, and the activity of the prefrontal cortex and amygdala. Studies of individuals with psychopathological states have also indicated that anatomic variations in these brain areas may relate to extraversion and neuroticism. The purpose of the present study was to examine selected structural correlates of neuroticism and extraversion in healthy subjects (n = 28) using neuroanatomic measures of the cerebral cortex and amygdala. We observed that the thickness of specific prefrontal cortex regions correlates with measures of extraversion and neuroticism. In contrast, no such correlations were observed for the volume of the amygdala. The results suggest that specific aspects of regional prefrontal anatomy are associated with specific personality traits.

Functional magnetic resonance imaging (fMRI) was used to study age-related differences in the neural circuitry involved in perception of negative facial affect. During scanning, 24 younger and 22 older adults viewed blocks of angry and neutral faces. The fMRI data analysis of the angry versus neutral faces contrast demonstrated greater activation in younger versus older individuals in the right amygdala/hippocampus region, whereas older adults demonstrated greater activation in the right anterior-ventral insula cortex. Hence, normal aging seems to affect specific nodes in the neural network involved in processing negative emotional face information. This age-related change from more subcortical to more cortical involvement could reflect functional compensation within the neural system involved in perception of facial affect, or the fact that older adults process emotional information in a different manner than do young adults.

Background In healthy individuals, the activity of the medial temporal lobe habituates rapidly with the repeated presentation of a stimulus. Using functional magnetic resonance imaging (fMRI), we tested the hypothesis that habituation of the medial temporal lobe is reduced in schizophrenia. Methods During fMRI scanning, fearful and happy faces were presented repeatedly to healthy control subjects (n =16) and patients with schizophrenia (n =18). Habituation of medial temporal lobe structures was measured by comparing the hemodynamic response occurring during the early and late portions of the presentation of each face. Results Control subjects demonstrated significant medial temporal lobe habituation to fearful but not to happy faces. In contrast, patients with schizophrenia did not demonstrate medial temporal lobe habituation in response to fearful or happy faces. In a direct, between-group comparison, right hippocampal habituation to fearful faces was significantly greater in control subjects than in the schizophrenia patients. Also, there were no significant differences between the patients and control subjects in the early medial temporal lobe response to fearful faces, suggesting that attenuated hippocampal habituation in schizophrenia is not associated with a reduction in initial activation. Conclusions These findings suggest that there is abnormal modulation of hippocampal responses to fearful faces in schizophrenia.

Inhibitory mechanisms that begin to develop in childhood are essential for efficient and goal-directed behaviors. These inhibitory mechanisms may go awry in several childhood-onset neuropsychiatric disorders, such as Tourette syndrome, obsessive-compulsive disorder and attention deficit hyperactivity disorder. Negative visuospatial priming is a well-established behavioral probe of inhibition that has been used to demonstrate deficits in children with neuropsychiatric disorders of inhibition, but the brain correlates of negative visuospatial priming have not previously been well delineated. In the present study, we use a visuospatial priming paradigm and event-related functional magnetic resonance imaging (fMRI) to probe inhibitory brain mechanisms in healthy children. When subjects performed the control (i.e. neutral) motor task, a network of cortical and subcortical sensorimotor regions was activated. In contrast, during performance of the negative priming (i.e. inhibitory) task, several regions of the prefrontal cortex were selectively engaged. These results support the notion that the prefrontal cortex is involved in inhibitory processing in healthy children and demonstrate that negative visuospatial priming shares brain correlates with other inhibitory tasks. In conjunction with fMRI, the visuospatial priming task described in the current study may be useful for studying the pathophysiology of childhood-onset neuropsychiatric disorders characterized by deficient inhibitory processing.

Background To assess the amygdala response to emotional faces in obsessive-compulsive disorder (OCD) using functional magnetic resonance imaging (fMRI). Methods Ten subjects with current OCD and 10 healthy control subjects underwent fMRI, during which they viewed pictures of fearful, happy, and neutral human faces, as well as a fixation cross. Results Across both groups, there was significant activation in left and right amygdala for the fearful versus neutral faces contrast. Data extracted from these functionally defined regions of interest indicated that OCD subjects exhibited a weaker response than control subjects bilaterally across all face conditions versus fixation. No group-by-face condition interactions were observed. Conclusions Contrary to findings in other anxiety disorders, there was no observed increase in amygdala responsivity to fearful versus neutral human faces in OCD as compared with healthy control subjects. Moreover, across all face conditions, amygdala responsivity was attenuated in OCD subjects relative to control subjects. Therefore, the present findings are consistent with abnormal amygdala function in OCD and are of a character that may distinguish OCD from other anxiety disorders.

Blood-oxygenation-level-dependent signal was measured with functional magnetic resonance imaging in 24 healthy young subjects (12 men and 12 women) during viewing of angry, fearful, and neutral male and female face pictures. Exposure to angry male as opposed to angry female faces activated the visual cortex and the anterior cingulate gyrus significantly more in men than in women. A similar sex-differential brain activation pattern was present during exposure to fearful but not neutral faces. Previous behavioral studies indicate enhanced physiological arousal in men but not in women during exposure to angry male as opposed to female faces, and brain imaging studies have shown that the occipital cortex and the anterior cingulate gyrus are influenced by activity in the autonomic nervous system as well as by visual attention. Hence, we suggest that the elevated occipital and anterior cingulate activation in men during confrontation with other angry and fearful males may reflect enhanced vigilance in a potentially dangerous situation.

Background: Despite the high prevalence of specific phobia (SP), its neural substrates remain undetermined. Although an initial series of functional neuroimaging studies have implicated paralimbic and sensory cortical regions in the pathophysiology of SP, to date contemporary morphometric neuroimaging methods have not been applied to test specific hypotheses regarding structural abnormalities. Methods: Morphometric magnetic resonance imaging (MRI) methods were used to measure regional cortical thickness in 10 subjects with SP (animal type) and 20 healthy comparison (HC) subjects. Results: Consistent with a priori hypotheses, between-group differences in cortical thickness were found within paralimbic and sensory cortical regions. Specifically, in comparison with the HC group, the SP group exhibited increased cortical thickness in bilateral insular, bilateral pregenual anterior cingulate, and bilateral posterior cingulate cortex as well as left visual cortical regions. Conclusions: Taken together, these structural findings parallel results from initial functional imaging studies that implicate paralimbic and sensory cortical regions in the mediating anatomy of SP symptoms. Further research will be necessary to replicate these findings and to determine their specificity as well as their pathophysiologic significance.

Recent studies of amygdala function have focused on examining responses to emotionally valenced versus neutral stimuli. However, electrophysiologic and neuroimaging studies also suggest that novel neutral faces activate the amygdala, though few investigations have examined the effects of novelty and its relation to changes in stimulus condition. To further investigate how the human amygdala and related structures react to novel neutral faces and to stimulus condition changes, we evaluated human brain responses to blocks containing multiple novel and single repeated face stimuli, presented in two different orders, using functional magnetic resonance imaging (fMRI). Significantly increased signal was present in the amygdala, substantia innominata (SI), and inferior temporal cortex (ITC) to the contrast of multiple novel versus single faces. However, these regions differed in their responses based on whether a stimulus condition was presented 1st or 2nd, with the amygdala and SI having significantly different response profiles than the ITC. Specifically, greater responses to stimuli presented 2nd (i.e., after a condition change) were found in the amygdala and SI, but not in the ITC. Furthermore, the response difference to the Multiple versus Single contrast was greatest in the amygdala and SI, when single faces were presented 1st, and multiple faces presented 2nd, but this pattern was the reverse in the ITC. We speculate that the signal changes to neutral faces in the amygdala and SI with respect to condition (multiple or single faces) and stimulus order may relate to the involvement of these structures in novelty detection and the orienting response.

Central nervous system habituation in humans was studied using functional magnetic resonance imaging and repeated presentations of single fearful and neutral faces. Habituation of blood-oxygenation-level-dependent (BOLD) signal during exposure to face stimuli, collapsed over fearful and neutral expressions, was evident in the right amygdala and hippocampus, as well as in the medial/inferior temporal cortex bilaterally. In the hippocampus, significantly greater habituation was evident on the right as compared to the left side, which could reflect the visual nature of the stimuli. There were no time by expression interaction effects in these regions, suggesting similar neural attenuation rates to fearful and neutral face stimuli. These results indicate that brain regions involved in novelty detection and memory processing habituate at similar rates regardless of whether the face in focus displays an aversive emotional expression or not.

The nucleus accumbens, in view of its afferent and efferent fiber connections, appears to hold a key position for “limbic” (e.g., hippocampal and amygdaloid) influences to reach somatomotor and autonomic brain structures, and it has therefore been considered as a limbic-motor interface. The nucleus accumbens can be subdivided into a shell and a core region, which both contain further inhomogeneities. The present account first summarizes the detailed topographical anatomical relationships of inputs from different dorso-ventral parts of the hippocampus and different rostrocaudal parts of the basal amygdaloid complex at the level of the accumbens. Subsequently, the electrophysiological characteristics of hippocampal and amygdaloid inputs in the accumbens are described. Interactions between hippocampal and amygdaloid inputs appear to exist primarily in the medial parts of both the shell and the core of the nucleus accumbens. In the short term, stimulating amygdaloid inputs appear to facilitate hippocampal throughput (heterosynaptic paired pulse facilitation), whereas stimulation of hippocampal inputs depresses amygdaloid throughput in a paired pulse paradigm. Tetanic stimulation of hippocampal inputs to the accumbens leads to a decremental long-term potentiation (LTP) of this fiber pathway (homosynaptic LTP) but, along a similar time range, to a depression of amygdaloid inputs (heterosynaptic long-term depression). The involvement of dopaminergic, GABAergic, and glutamatergic mechanisms in these interactions is discussed. Finally, it is suggested that the interactions between hippocampal and amygdaloid inputs at the level of the nucleus accumbens play a role in different aspects of associative learning.

The ventral striatum, which prominently includes the nucleus accumbens (Acb), is a heterogeneous area. Within the Acb of rats, a peripherally located shell and a centrally situated core can be recognized that have different connectional, neurochemical, and functional identities. Although the Acb core resembles in many respects the dorsally adjacent caudate-putamen complex in its striatal character, the Acb shell has, in addition to striatal features, a more diverse array of neurochemical characteristics, and afferent and efferent connections. Inputs and outputs of the Acb, in particular of the shell, are inhomogeneously distributed, resulting in a mosaical arrangement of concentrations of afferent fibers and terminals and clusters of output neurons. To determine the precise relationships between the distributional patterns of various afferents (e.g., from the prefrontal cortex, the basal amygdaloid complex, the hippocampal formation, and the midline/intralaminar thalamic nuclei) and efferents to the ventral pallidum and mesencephalon, neuroanatomical anterograde and retrograde tracing experiments were carried out. The results of the double anterograde, double retrograde, and anterograde/retrograde tracing experiments indicate that various parts of the shell (dorsomedial, ventromedial, ventral, and lateral) and the core (medial and lateral) have different input-output characteristics. Furthermore, within these Acb regions, various populations of neurons can be identified, arranged in a cluster-like fashion, onto which specific sets of afferents converge and that project to particular output stations, distinct from the input-output relationships of neighboring, cluster-like neuronal populations. These results support the idea that the nucleus accumbens may consist of a collection of neuronal ensembles with different input-output relationships and, presumably, different functional characteristics.

Tourette syndrome (TS) is a complex neurobehavioral disorder principally characterized by motor and vocal tics. However, features of obsessive-compulsive and attention-deficit/hyperactivity disorders are often present. The basal ganglia and associated brain structures have been implicated in the pathophysiology of TS, as well as in these related conditions. Specifically, it is believed that the neuroanatomically and functionally defined basal ganglia thalamocortical loops are involved in TS. These loops are composed of a sequence of connections originating in the cortex and passing in series through the striatum (caudate and putamen), globus pallidus, and thalamus before returning to the cortical areas of origin. This review concentrates on the neuroimaging findings in Ts, particularly as they relate to alterations in components of the basal ganglia thalamocortical circuits. These neuroimaging data suggest that the major abnormalities in TS involve striatal or cortical dysfunction, as well as dysfunction of dopaminergic systems that regulate basas ganglia neurotransmission.

This paper briefly discusses the anatomical criteria that have been used to delineate the prefrontal cortex (PFC) from the (pre)motor cortical areas in the frontal lobe. Single anatomical criteria, such as cytoarchitecture, connectivity with the mediodorsal thalamic nucleus or a dopaminergic innervation, are insufficient to unequivocally define the PFC. It is argued that, with respect to a number of structural aspects, the prefrontal and the (pre)motor cortical areas must be viewed as a continuum, whereas a (functional) differentiation is based on the type of information that is being processed in different parts of the frontal lobe. The involvement of the PFC, like the premotor cortex, in a number of basal ganglia-thalamocortical circuits may be interpreted in the same way. The paper also summarizes the organization of the inputs from midline/intralaminar thalamic nuclei, the basal amygdaloid complex and the hippocampus into the PFC-ventral striatal system. The results of tracing studies in rats indicate that these thalamic and limbic inputs both at the level of the PFC and the ventral striatum show various patterns of convergence and segregation. This leads to the conclusion that the PFC-ventral striatal system consists of a number of smaller modules.

The basal amygdaloid complex (BAC) topographically projects to the nucleus accumbens (Acb) in patchy, inhomogeneous patterns. These termination patterns may be related to the histological features of the Acb that define the shell, core, and adjacent ventral caudate-putamen (CPv), and the ventral striatal compartments providing output to different autonomic, motor, and endocrine targets. Knowledge of the relationships of BAC afferents with these compartments is essential for understanding the activities of amygdalostriatal circuits. Therefore, anterograde tracing experiments were performed, combined with calbindin- D28K (CaB) immunohistochemistry or Nissl staining. The results demonstrated that the caudal parvicellular basal amygdala (Bpc) projected primarily to cell clusters in the dorsal shell of the medial Acb, and to patches in the core/CPv. Fibers from the caudal accessory basal nucleus (AB) selectively reached CaB-immunoreactive cell clusters in the ventral shell, avoiding the core/CPv. The rostral AB projected to the same ventral shell compartments as the caudal AB; in addition, dense terminations were found in the matrix of the core/CPv, avoiding the patches. Caudal magnocellular basal amygdala (Bmg) fibers reached ventral parts of the shell, including the CaB-immunoreactive cell clusters. The caudal Bmg projected strongly to the patches of the core/CPv, evading the matrix. Finally, the rostral Bmg densely innervated the moderately CaB-immunoreactive lateral shell and the patches of the core/CPv, largely avoiding the matrix. These results indicate the specific compartmental relationships of the patchy BAC terminations and suggest that BAC subregions differentially influence particular ventral striatal outputs.

Neurofibrillary tangles and amyloid plaques express acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity in Alzheimer's disease. We had found that traditional AChE inhibitors such as BW284C51, tacrine and physostigmine were more potent inhibitors of the AChE in normal axons and cell bodies than of the AChE in plaques and tangles. We now report that the reverse pattern is seen with indolamines, carboxypeptidase inhibitor, and the nonspecific protease inhibitor bacitracin. These substances are more potent inhibitors of the cholinesterases in plaques and tangles than of those in normal axons and cell bodies. These results show that the enzymatic properties of plaque and tangle-associated cholinesterases diverge from those of normal axons and cell bodies. The selective susceptibility to bacitracin and carboxypeptidase inhibitor indicates that the catalytic sites of plaque and tangle-bound cholinesterases are more closely associated with peptidase or protease-like properties than the catalytic sites of cholinesterases in normal neurons and axons. This shift in enzymatic affinity may lead to the abnormal protein processing which is thought to play a major role in the pathogenesis of AD. The availability of pharmacological and dietary means for altering brain indolamines raises novel therapeutic possibilities for inhibiting the abnormal cholinesterase activity associated with Alzheimer's disease.

The amygdala detects aversive events and coordinates with the rostral anterior cingulate cortex to adapt behavior. We assessed error-related activation in these regions and its relation to task performance using functional MRI and a saccadic paradigm. Both amygdalae showed increased activation during error versus correct antisaccade trials that was correlated with error-related activation in the corresponding rostral anterior cingulate cortex. Together, activation in the right amygdala and right rostral anterior cingulate cortex predicted greater accuracy. In contrast, the left amygdala activation predicted a higher error rate. These findings support a role for the amygdala in response monitoring. Consistent with proposed specializations of the right and left amygdala in aversive conditioning, we hypothesize that right amygdala-rostral anterior cingulate cortex interactions mediate learning to avoid errors, whereas left error-related amygdala activation underpins detrimental negative affect.

Introduction: Recently, human studies using exposure therapy to treat anxiety have demonstrated that pretreatment with D-cycloserine (DCS) enhances fear reduction in anxiety disorders. However, the underlying brain mechanisms mediating this fear reduction have yet to be determined.Methods: The effects of orally administered DCS on amygdala activity during the processing of repeated facial expressions were examined in this double-blind study. Fourteen healthy males (30.0±8.7 years of age) randomly received DCS 500 mg or placebo prior to 3.0 Tesla functional magnetic resonance imaging acquisition. All participants viewed four separate runs, consisting of a single block of a repeated facial expression (happy or fearful) bracketed by fixation blocks.Results: Anatomic region-of-interest analyses showed that the placebo group exhibited amygdala activation and response habituation, while the DCS group displayed blunted amygdala responses to emotional faces across the experiment, whereby habituation was not detected.Conclusion: This finding may have relevance for testing treatments of anxiety and depression.

Transient bradycardic hypotensive events occur in resting rabbits. If the hypotension is due to vasodepression, these events may be a model for vasovagal syncope.To determine whether these events are responses to brief stimuli and whether the hypotensive episodes are solely due to rapid-onset bradycardia.Rabbits were instrumented with subcutaneous electrocardiogram leads, and cannulae were acutely inserted into an ear artery to obtain continuous arterial pressure measurements. Exposure to brief, low-level auditory stimuli at 5 kHz transiently increased the RR interval by approximately 70 ms and decreased mean arterial pressure by approximately 5 mmHg.These evoked bradycardic hypotensive events were almost identical to previously reported spontaneous bradycardic hypotensive events. Intra-aortic telemetric blood pressure monitoring was used to demonstrate that the evoked hypotension reflected prolonged diastole, rather than local ear arterial vasoconstriction. Furthermore, administration of the muscarinic blocker glycopyrrolate abolished not only bradycardia (RR interval 64+/-14 ms to 1+/-1 ms; P0.0001), but also hypotension (--4.1+/-0.8 mmHg to --0.4+/-0.3 mmHg; P=0.0055). Finally, cardiac pacing abolished the inducible bradycardia (RR interval 51+/-10 ms to 2+/-1 ms; P=0.0006) and its associated hypotension (--4.1+/-0.7 mmHg to --1.2+/-0.3 mmHg; P=0.003).Brief auditory stimuli evoked a transient bradycardia mediated by cardiac muscarinic receptors and consequent hypotension. This is not a model for vasovagal syncope.

Neuroimaging studies using angry or contemptuous human facial photographic stimuli have suggested amygdala hyper-responsivity in social anxiety disorder (SAD). We sought to determine if an angry "schematic face" (simple line drawing) would evoke exaggerated amygdalar responses in SAD patients compared with healthy control (HC) subjects. Angry, happy, and neutral schematic faces were overtly presented to matched cohorts of 11 SAD and 11 HC subjects for passive viewing, whereas brain functional magnetic resonance imaging signal was measured at 1.5 Tesla. Voxel-wise analyses were performed using a random effects model in SPM99. Compared with HC subjects, SAD patients exhibited exaggerated responses in the right amygdala for the Angry versus Neutral contrast. The findings of exaggerated amygdala responses to angry schematic faces in SAD converge with results from earlier neuroimaging studies and illustrate the potential utility of schematic faces for probing amygdala function in psychiatric disorders. One prospective advantage of schematic faces is that they may minimize confounds related to gender, age, or race effects. However, extending earlier findings in healthy subjects, schematic faces appear more effective for probing amygdala responses to arousal-based (Angry versus Neutral) as opposed to valence-based (Angry versus Happy) contrasts.

The current study examined the hypothesis that amygdala activation serves as a neural precondition for negative affective experience. Participants’ affective experience was measured by asking them to report on their momentary experiences several times a day over the course of a month using an electronic experience-sampling procedure. One year later, participants viewed backwardly masked depictions of fear while functional magnetic resonance imaging was used to measure their amygdala and fusiform gyrus activation. Negative affect, as measured during the experience-sampling procedure 1-year prior, was positively correlated with amygdala activation in response to these brief presentations of fear depictions. Furthermore, descriptive analyses indicated that fusiform gyrus activation and negative affective experience in the scanner were associated for participants reporting increased nervousness during the imaging procedure. The results are consistent with the interpretation that the amygdala contributes to negative affective experience by increasing perceptual sensitivity for negative stimuli.

Extraversion and neuroticism are two important and frequently studied dimensions of human personality. They describe individual differences in emotional responding that are quite stable across the adult lifespan. Neuroimaging research has begun to provide evidence that neuroticism and extraversion have specific neuroanatomical correlates within the cerebral cortex and amygdala of young adults. However, these brain areas undergo alterations in size with aging, which may influence the nature of these personality factor-brain structure associations in the elderly. One study in the elderly demonstrated associations between perisylvian cortex structure and measures of self transcendence [Kaasinen, V., Maguire, R.P., Kurki, T., Bruck, A., Rinne, J.O., 2005. Mapping brain structure and personality in late adulthood. NeuroImage 24, 315-322], but the neuroanatomical correlates of extraversion and neuroticism, or other measures of the Five Factor Model of personality have not been explored. The purpose of the present study was to investigate the structural correlates of neuroticism and extraversion in healthy elderly subjects (n=29) using neuroanatomic measures of the cerebral cortex and amygdala. We observed that the thickness of specific lateral prefrontal cortex (PFC) regions, but not amygdala volume, correlates with measures of extraversion and neuroticism. The results suggest differences in the regional neuroanatomic correlates of specific personality traits with aging. We speculate that this relates to the influences of age-related structural changes in the PFC.

Background Neuropsychiatric symptoms are very common even in mild stages of Alzheimer’s disease (AD). The amygdala exhibits very early pathology in AD, but amygdala function in mild AD has received relatively little attention. The current study investigates functional alterations in the amygdala in aging and mild AD, and their relationships with neuropsychiatric symptoms. Methods Functional magnetic resonance imaging (fMRI) was used to examine and compare amygdala responses in 12 young and elderly controls and in 12 mild AD patients during viewing of neutral and emotional human facial expressions. Results Amygdala responses in the young and elderly did not significantly differ from each other. However, the AD group had significantly greater amygdala responses to both neutral and emotional faces relative to elderly controls. This group effect was maintained when amygdala volume, sex and age were included as covariates in the analysis. Furthermore, amygdala activity correlated with the severity of irritability and agitation symptoms in AD. Conclusions The amygdala in patients with mild AD is excessively responsive to human faces relative to elderly controls. These amygdala functional alterations may represent a physiologic marker for certain neuropsychiatric manifestations of AD.

Background Extinction of conditioned fear is thought to form a new safety memory that is expressed in the context in which the extinction learning took place. Rodent studies implicate the ventromedial prefrontal cortex (vmPFC) and hippocampus in extinction recall and its modulation by context, respectively. The aim of the present study is to investigate the mediating anatomy of extinction recall in healthy humans. Methods We used event-related functional magnetic resonance imaging (fMRI) and a 2-day fear conditioning and extinction protocol with skin conductance response as the index of conditioned responses. Results During extinction recall, we found significant activations in vmPFC and hippocampus in response to the extinguished versus an unextinguished stimulus. Activation in these brain regions was positively correlated with the magnitude of extinction memory. Functional connectivity analysis revealed significant positive correlation between vmPFC and hippocampal activation during extinction recall. Conclusions These results support the involvement of the human hippocampus as well as vmPFC in the recall of extinction memory. Furthermore, this provides a paradigm for future investigations of fronto-temporal function during extinction recall in psychiatric disorders such as posttraumatic stress disorder.

Previous functional neuroimaging studies have demonstrated exaggerated amygdala responses and diminished medial prefrontal cortex responses during the symptomatic state in posttraumatic stress disorder (PTSD).To determine whether these abnormalities also occur in response to overtly presented affective stimuli unrelated to trauma; to examine the functional relationship between the amygdala and medial prefrontal cortex and their relationship to PTSD symptom severity in response to these stimuli; and to determine whether responsivity of these regions habituates normally across repeated stimulus presentations in PTSD.Case-control study.Academic medical center.Volunteer sample of 13 men with PTSD (PTSD group) and 13 trauma-exposed men without PTSD (control group).We used functional magnetic resonance imaging (fMRI) to study blood oxygenation level-dependent signal during the presentation of emotional facial expressions.The PTSD group exhibited exaggerated amygdala responses and diminished medial prefrontal cortex responses to fearful vs happy facial expressions. In addition, in the PTSD group, blood oxygenation level-dependent signal changes in the amygdala were negatively correlated with signal changes in the medial prefrontal cortex, and symptom severity was negatively related to blood oxygenation level-dependent signal changes in the medial prefrontal cortex. Finally, relative to the control group, the PTSD group tended to exhibit diminished habituation of fearful vs happy responses in the right amygdala across functional runs, although this effect did not exceed our a priori statistical threshold.These results provide evidence for exaggerated amygdala responsivity, diminished medial prefrontal cortex responsivity, and a reciprocal relationship between these 2 regions during passive viewing of overtly presented affective stimuli unrelated to trauma in PTSD.

Habituation is a highly adaptive property of the nervous system, which allows for the allocation of attention and other cognitive resources to more imperative environmental events. The amygdala is an important site of habituation in humans, but no studies to date have examined the effects of aging on amygdala habituation. Given the amygdala's role in evaluating the salience of a stimulus and initiating behavioral responses, the potential importance of amygdala habituation in aging may be far-reaching. Therefore, we assessed for differences in habituation in the amygdalae of healthy young and elderly adults during repeated presentations of neutral human faces using functional magnetic resonance imaging (fMRI). In addition, we evaluated the relationship between amygdala volume and habituation, to examine the effects of atrophy. Eighteen healthy young controls and 18 healthy elderly subjects were scanned with fMRI during viewing of repeatedly presented neutral human face stimuli. Significant fMRI signal decrement was observed across all subjects for early versus late face presentations. Analysis of group, condition, and hemisphere revealed a significant three-way interaction, with right greater than left habituation in the young, but left greater than right amygdala habituation in the elderly. Volumetric and correlational analyses demonstrated that amygdala volume is associated with habituation in the right, but not left, hemisphere. We conclude that, in healthy elderly adults, the amygdala retains its adaptive habituation response, but speculate that intrinsic changes in amygdala anatomy during aging may modulate its laterality.

The Brooksby-Donald approach uses two flow probes to measure the inflow and outflow from an organ or vascular bed; the difference in flow can be time-integrated to assess changes in venous capacitance.To measure changes in subdiaphragmatic venous capacitance and arterial conductance in acutely instrumented rabbits, and to document the acute vascular responses to intravenous injections of pharmacological agents.In artificially ventilated, fentanyl-anesthetized New Zealand female rabbits, ultrasonic flow probes were attached to the descending thoracic aorta and inferior vena cava to measure subdiaphragmatic inflow and outflow. Systemic arterial and venous pressures were measured. Conductance was calculated as aortic flow divided by the difference between systemic arterial and venous pressures. Changes in capacitance were assessed by integrating flow differences. Nitroglycerin (NG), isoproterenol hydrochloride, phenylephrine hydrochloride (PE) and vasopressin (VP) were administered intravenously in stepwise injections, and transient conductance and capacitance responses were determined.NG significantly increased conductance and capacitance, while isoproterenol hydrochloride had significant effects only on conductance. Both VP and PE significantly decreased conductance and capacitance.The modified Brooksby-Donald approach used in the present study was validated by the observed concordant increases in conductance and capacitance caused by NG, and decreases caused by VP and PE. This approach may be useful to characterize specific comparative conductance-capacitance properties of various vasoactive agents.

Activation of the amygdala to emotionally valenced stimuli, and particularly to fearful faces, has been widely demonstrated in healthy young adults. However, recent studies assessing amygdala responses to fearful emotional faces in the normal elderly have not shown similar results. The reason for this is uncertain, but it may relate to life-span developmental changes in processing emotional stimuli or structural alterations in the amygdala with aging. In order to examine whether the amygdala could be activated in the elderly, we developed a paradigm designed to engage the amygdala on several levels. Based on recent imaging work indicating that novelty and stimulus change activates the amygdala, we assessed amygdala responses in young and elderly adults to novel fearful faces (versus familiar neutral ones). We demonstrate a robust activation in both groups, indicating that the amygdala remains responsive in aging. This activation did not differ between the two groups when we examined regions of interest in the amygdala based on functional or structural criteria. However, there were significantly greater activations in the inferior temporal cortex in the young versus elderly subjects.