0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Dose-Dependent Decrease of Activation in Bilateral Amygdala and Insula by Lorazepam During Emotion Processing FREE

Martin P. Paulus, MD; Justin S. Feinstein, BS; Gabriel Castillo, BS; Alan N. Simmons, PhD; Murray B. Stein, MD, MPH
[+] Author Affiliations

Author Affiliations: Laboratory of Biological Dynamics and Theoretical Medicine (Dr Paulus and Messrs Feinstein and Castillo) and Department of Psychiatry (Drs Paulus, Simmons, and Stein), University of California, San Diego; and Veterans Affairs San Diego Healthcare System (Drs Paulus and Stein).


Arch Gen Psychiatry. 2005;62(3):282-288. doi:10.1001/archpsyc.62.3.282.
Text Size: A A A
Published online

Background  Functional neuroimaging may elucidate the pathophysiologic features of anxiety disorders and the site of action of anxiolytic drugs. A large body of evidence suggests that the amygdala and associated limbic structures play a critical role in the expression of anxiety and may be treatment targets for anxiolytic drugs.

Objective  To determine whether lorazepam dose-dependently attenuates blood oxygenation level–dependent functional magnetic resonance imaging (BOLD fMRI) activation in the amygdala and associated limbic structures during an emotion face assessment task.

Participants and Design  Fifteen healthy volunteers participated in a double-blind, placebo-controlled, randomized dose-response study. Subjects underwent imaging 3 times (at least a week apart) and were given either a single-dose placebo or 0.25 mg or 1.0 mg of lorazepam 1 hour prior to an MRI session. During fMRI, subjects completed an emotion face assessment task, which has been shown to elicit amygdala activation.

Main Outcome Measures  The BOLD-fMRI activation in amygdala, insula, and medial prefrontal cortex during the emotion face assessment task.

Results  Lorazepam significantly attenuated the BOLD-fMRI signal in a dose-dependent manner in bilateral amygdala and insula but not in the medial prefrontal cortex. Lorazepam did not affect the BOLD-fMRI signal in the primary visual cortex.

Conclusions  The current finding provides the first neuroimaging evidence of a dose-dependent change induced by an established therapeutic agent in brain regions known to be critical for the mediation of anxiety. This investigation may help to support the use of BOLD-fMRI with pharmacological probes to investigate the neural circuits underlying anxiety and the use of fMRI as a tool in the development of new anxiolytic agents.

Figures in this Article

Anxiety disorders are among the most common psychiatric disorders but comprise a heterogeneous group of conditions. Delineating the basic neurocircuitry underlying normal and pathologic anxiety1 may help to better define anxiety disorders. The amygdala plays a critical role in normal fear conditioning and is implicated in the pathophysiologic mechanism of anxiety disorders.2,3 However, this structure is also important for other emotional information processing and behavior.4 Functional neuroimaging studies have shown amygdala activation in fear conditioning,5 reward-related processing,6 encoding of emotionally salient information,7 risk taking,8 processing positively valenced stimuli,9 and appetitive or aversive olfactory learning.10

In addition to the amygdala, a network of structures that includes the insula, anterior cingulate gyrus, and medial prefrontal cortex is important to identify the emotional significance of a stimulus, generate an affective response, and regulate the affective state.11 The insula has afferent and efferent connections to the medial and orbitofrontal cortex, anterior cingulate gyrus, and several nuclei of the amygdala.12 Although insula activation has frequently been associated with disgust,13 there is increasing evidence of a broader role for this brain structure in emotion processing.14 Insula activation is thought to be involved in differential positive vs negative emotion processing,5 in particular fearful face processing,15 pain perception,16,17 and when individuals are asked to make judgments about emotions.18

Benzodiazepine derivatives are the most commonly prescribed antianxiety agents in clinical practice. Lorazepam, a 3-hydroxy-1,4-benzodiazepine, is rapidly and readily absorbed, reaching peak concentrations in the blood proportional to the dose approximately 1 to 2 hours after oral administration.19 Previous neuroimaging investigation using 1 mg of intravenous lorazepam during a memory task found significant decreases in activation within the hippocampal, fusiform, and inferior prefrontal regions but no significant alterations in activation in the striate cortex.20

The aim of this study was to use blood oxygenation level–dependent functional magnetic resonance imaging (BOLD fMRI) to test the hypothesis that lorazepam dose-dependently attenuates activation during an emotion face paradigm in the amygdala, insula, and medial prefrontal cortex. A modified emotion face assessment task was used to determine whether this attenuation would occur with negative emotion faces (angry and fear) but not with positive emotion faces (happy). Support for this hypothesis would provide a link between the clinical efficacy of lorazepam as an anxiolytic and the biological basis of γ-aminobutyric acid (GABA)-ergic modulation of the amygdala and limbic structures as key targets for anxiety circuitry.

Pharmacological fMRI is an emerging discipline with the potential to address a variety of neural systems and drug development questions.21 One important consideration with pharmacological fMRI is the differentiation between the drug’s effect on neural tissue or on hemodynamic modulation. Some investigators have argued that pharmacological stimulation results in heterogeneous fMRI effects as opposed to global, homogeneous changes in BOLD signal. This argument is consistent with an action on specific neuronal receptor–based mechanisms.22 Moreover, focusing on a priori hypothesized areas may prevent false-positive findings.23 Thus, the current study used primarily a region-of-interest approach.

SUBJECTS

The University of California, San Diego, institutional review board approved the study procedures. All participants provided written informed consent and were paid for their participation. We studied 15 healthy, nonsmoking individuals (6 women and 9 men) aged 18 to 39 years (mean ± SD, 27.6 ± 1.4 years) with 12 to 18 years of education (mean ± SD, 15.6 ± 0.3 years). Participants did not have medical or psychiatric disorders as determined by medical history and diagnoses according to the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Revised Fourth Edition. Each subject was required to consume less than 150 mg/d of caffeine and less than 14 caffeinated beverages per week. Subjects had no history of drug or alcohol abuse and did not report a prior use of benzodiazepines. All participants passed a urine drug screen. Subjects were instructed to maintain their regular bedtimes and wake times for 1 week before and throughout the study period. Individuals presented to the MRI facility between 8 AM and 4 PM with at least 1 week between studies.

STUDY DESIGN

The study was performed in a double-blind manner. Participants underwent each of 3 conditions in randomized order between 1 and 3 weeks apart. Lorazepam was chosen as the anxiolytic because of its well-documented behavioral effects and because it has a short metabolic half-life, which peaks at about 60 to 120 minutes after ingestion,24 and no active metabolite, which eliminates the possible confounding effects of drug accumulation.25 We selected doses that minimally disrupt performance of behavioral tasks and memory (≤1.0 mg) but are used to treat anxiety. Subjects arrived at the MRI facility 60 to 90 minutes prior to the MRI study. At arrival, subjects’ vital signs were assessed and subjects orally received either placebo or 0.25 mg or 1.0 mg of lorazepam suspension mixed in diet decaffeinated cola.

ASSESSMENTS AND fMRI PARADIGM

Subjects completed the Spielberger State-Trait Anxiety Inventory26 (STAI) and the visual analog scales for anxiety, tension, alertness, and trembling before and after the MRI study. During fMRI, each subject was tested using a slightly modified version of the emotion face assessment task.27 During each 5-second trial, a subject was presented with a target face (on the top of the computer screen) and 2 probe faces (on the bottom of the screen) and was instructed to match the probe with the same emotional expression to the target by pressing the left or right key on a button box (Figure 1). A block consisted of 6 consecutive trials in which the target face was either angry, fearful, or happy.28 During the sensorimotor control task, subjects were presented with 5-second trials of ovals or circles in an analogous configuration and were instructed to match the shape of the probe to the target. Each block of faces and of the sensorimotor control task was presented 3 times in a pseudorandomized order. A fixation cross was interspersed between each block. For each trial, response accuracy and reaction time data were obtained.

Figure 1. Emotion face assessment task.27 The target and 2 probe faces or ovals and circles were presented for 5 seconds. Blocks of each target emotion consisted of six 5-second angry, fearful, or happy face trials; blocks of ovals or circles consisted of two 5-second trials. Blocks of fixation crosses with varying time length were interspersed between the face and oval/circle blocks.

Graphic Jump Location
IMAGE ACQUISITION

During the task, one BOLD-fMRI run was collected for each subject using a 1.5-T scanner (Siemens, Erlangen, Germany) (T2-weighted echoplanar imaging, time to repeat = 2000 milliseconds, echo time = 40 milliseconds, 64 × 64 matrix, twenty 4-mm axial slices, 256 repetitions). During the same experimental session, a T1-weighted image (magnetization-prepared rapid acquisition gradient echo, time to repeat = 11.4 milliseconds, echo time = 4.4 milliseconds, flip angle = 10°, field of view = 256 × 256, 1-mm3 voxels) was obtained for anatomical reference. For preprocessing, voxel time series were interpolated to correct for nonsimultaneous slice acquisition within each volume and were corrected for 3-dimensional motion.

IMAGE PROCESSING

All structural and functional image processing were done with the Analysis of Functional Neuroimages software package.29 Echoplanar images were coregistered to the 128th image using a 3-dimensional coregistration algorithm. The time series of motion parameters was used to obtain a mean for these 6 parameters for each subject. Three motion parameters (d-roll, d-pitch, and d-yaw, indicating change in roll, pitch, and yaw directions) were used as nuisance regressors to account for motion artifacts. The 4 orthogonal regressors of interest were (1) happy, (2) angry, (3) fearful, and (4) circle/oval sensorimotor condition. These regressors were convolved with a modified gamma variate function to account for the delay and the dispersion brain response of the BOLD-fMRI signal due to hemodynamics.30 Additional regressors were used to model residual motion in the roll, pitch, and yaw directions as well as baseline and linear trends. The Analysis of Functional Neuroimages program 3dDeconvolve29 was used to calculate the estimated voxelwise response amplitude. A gaussian filter with 6 mm full width at half maximum was applied to the voxelwise percent signal change data to account for individual variations of the anatomical landmarks.

Data for each subject were normalized to Talairach coordinates. A priori regions of interest (defined by the Talairach Daemon atlas31) in the bilateral amygdala, medial prefrontal cortex, primary visual cortex, and insula were used as masks. Based on these areas of interest, it was determined via simulations that a voxelwise a priori probability of .05 would result in a corrected clusterwise activation probability of .05 if a minimum volume of 128 μL and 2 connected voxels (in the amygdala) or 512 μL and 8 connected voxels (in all other regions of interest) was considered. The areas of interest were superimposed on each individual’s voxelwise percent signal change brain image. Only activations within the areas of interest that also satisfied the volume and voxel connection criteria were extracted and used for further analysis. No clusters of voxels survived the cluster threshold parameters in the medial prefrontal cortex. Thus, planned comparisons using contrasts for repeated-measures designs wereperformed for only bilateral amygdala and insula when significant omnibus F values were found. The voxelwise percent signal change data were entered into a mixed-model analysis of variance with task contrast (face type vs circle/oval comparison condition) and dose (placebo or 0.25 or 1.0 mg of lorazepam) as fixed factors and subjects as a random factor. In addition, a whole-brain analysis was carried out to determine whether lorazepam affected nonhypothesized areas. Activations clusters were extracted and corrected for multiple comparisons using an a priori P < .05 threshold and a volume mask of greater than 1000 μL.

STATISTICAL ANALYSIS

All behavioral analyses were carried out with SPSS version 10.0.32 A repeated-measures multivariate analysis of variance, with dose (placebo or 0.25 or 1.0 mg of lorazepam) as the within-subjects factor, was used to analyze the behavioral measures and neural activation patterns. Behavioral measures are reported as an interaction between dose and task type. Self-rating measures are reported as interactions between the drug and ratings before and after the MRI study. Correlational analyses were conducted for placebo administration by examining the relationship between self-rating scales or performance measures and activation in the bilateral insula and amygdala during viewing of angry, fearful, and happy faces.

BEHAVIORAL RESULTS

Subjects matched the probe face to the target face with nearly perfect accuracy (mean ± SD, 97.0% ± 0.7%), which was not affected by either the 0.25-mg or 1.0-mg dose of lorazepam (F2,28 = 0.40, P = .60, η2 = 0.03). As shown in Figure 2, although latency was affected by face type (ie, longer for matching angry or fearful faces when compared with happy faces and circles or squares [F3,12 = 48.8, P<.001, η2 = 0.92]), neither dose of lorazepam affected response latency (F2,28 = 1.47, P = .25, η2 = 0.09).

Figure 2. Behavioral effects of placebo and 0.25 mg and 1.0 mg of oral lorazepam. Lorazepam had no effect on response latency (A), the fraction of correct responses, or accuracy (B). Error bars indicate SE.

Graphic Jump Location

As shown in Figure 3, lorazepam did not affect the level of anxiety, either measured by visual analog scales (F2,22 = 1.71, P = .19, η2 = 0.14) or by the STAI (F2,28 = 0.31, P = .73, η2 = 0.02). Moreover, visual analog ratings of tension (F2,22 = 0.57, P = .57, η2 = 0.05) or trembling (F2,22 = 1.82, P = .18, η2 = 0.14) did not significantly change across drug administration. However, individuals reported increased sleepiness after 1.0 mg of lorazepam, as evidenced by a dose by pre-post interaction (F2,22 = 7.2, P = .004, η2 = 0.40) (Figure 2).

Figure 3. A, A high dose of lorazepam increased sleepiness (0 = not at all; 10 = extremely) at the 1.0-mg dose. B, Neither a low nor a high dose of lorazepam had a significant effect on state anxiety.

Graphic Jump Location
FUNCTIONAL NEUROIMAGING RESULTS

Irrespective of face type, subjects showed bilateral activation of the amygdala and anterior insula during the emotion face assessment task relative to the sensorimotor control task (see Figure 4 and the Table for statistics). Lorazepam attenuated the activation in a dose-dependent fashion in the amygdala and insula (Table, Figure 5A). Specifically, activation in bilateral amygdala after administration of 1.0 mg of lorazepam was significantly lower than after 0.25 mg (t14 = 4.83, P<.001) and significantly lower than after placebo administration (t14 = 2.85, P = .01). There was no significant difference between placebo and 0.25 mg of lorazepam (t14 = 0.62, P = .54). Similarly, activation in the bilateral insula after 1.0 mg of lorazepam was significantly lower than after 0.25 mg (t14 = 3.41, P = .004) and significantly lower than after placebo administration (t14 = 3.63, P = .003). There was no significant difference between placebo and 0.25 mg of lorazepam (t14 = 0.70, P = .50). There was no significant effect of lorazepam on activation in the bilateral visual cortex for placebo or the 2 doses of lorazepam (Table, Figure 5B). A whole-brain analysis revealed significant effects of lorazepam in the right inferior temporal gyrus (coordinates: 43,−63,0), left insula (−27,7,−6), amygdala (−9,−11,−10), and fusiform gyrus (−29,−93,−13). In all areas, there was a significant attenuation of the signal in the 1.0-mg lorazepam condition relative to both placebo and 0.25 mg of lorazepam.

Figure 4. A, The blood oxygenation level–dependent functional magnetic resonance imaging effects (mean and SE) of placebo and 0.25 mg and 1.0 mg of oral lorazepam. B, Lorazepam dose-dependently attenuated the signal difference between the face-matching task and the sensorimotor control task in bilateral amygdala and insula. Numbers indicate Talairach z coordinates.

Graphic Jump Location

Figure 5. A, Percentage of signal activation during the face matching vs the sensorimotor comparison task at z = −12 during administration of placebo and 1.0 mg of oral lorazepam. Cross-hairs indicate the approximate center of mass of the amygdala as defined by the Talairach Daemon atlas.31 The bar indicates percent signal change from 0.2% to 1.0%. B, Blood oxygenation level–dependent functional magnetic resonance imaging percent signal difference of placebo and 0.25 mg and 1.0 mg of oral lorazepam in the visual cortex.

Graphic Jump Location
Table Graphic Jump LocationTable. Statistical Analyses of Regions of Interest
CORRELATIONS BETWEEN BEHAVIORAL AND FUNCTIONAL NEUROIMAGING RESULTS

There were no significant correlations between visual analog scales before administration or after imaging with the degree of activation in the bilateral insula or amygdala during task performance. Moreover, behavioral measures such as latency of response or accuracy of response during the emotion face assessment task did not correlate with the degree of activation in the bilateral insula or amygdala.

The results of this investigation show for the first time that a known anxiolytic, the benzodiazepine lorazepam, dose-dependently attenuates task-induced activation in bilateral amygdala and insula but has no effect on the visual cortex. These effects were observed at doses of lorazepam that did not significantly affect behavior on this task and did not change levels of anxiety in these healthy (nonanxious) volunteers. In animals, a large body of evidence suggests that benzodiazepine agonists attenuate brain activity in the amygdala consistent with their anxiolytic effects.33 In humans, however, evidence of benzodiazepine effects on reducing amygdala activity had been missing.

A major focus in the field of anxiety research is the delineation of the basic neurocircuitry underlying normal and pathologic anxiety.1 Amygdala activation occurs during fear conditioning, and altered amygdala activation has been implicated in the pathophysiologic mechanism of anxiety disorders.2,3 For example, individuals with social anxiety disorder34 or posttraumatic stress disorder35 show amygdala hyperresponsivity to fearful or angry faces. Moreover, patients with panic disorder have decreased benzodiazepine receptor binding in the left hippocampus and precuneus36 as well as in the right orbitofrontal cortex and right insula.37 The insular cortex appears to be important for subjective feeling states and interoceptive awareness.38,39 To our knowledge, this is the first study to show that an anxiolytic drug can dose-dependently reduce activation in the amygdala and insula, areas that are important for emotional processing in general and anxiety in particular. Thus, pharmacological fMRI with specific behavioral probes may prove especially useful for delineating how these brain structures are altered in anxiety disorders.

Lorazepam also attenuated activation in the fusiform gyrus. Although primarily recognized as a face-processing area,40 this structure’s activation patterns are related to the degree of conscious perception,41 anticipation,42 and identification of emotionally important visual clues.43 Moreover, activation in the fusiform gyrus is altered in individuals with anxiety disorders,44 and increased activation in the fusiform gyrus to fearful faces has been observed after cholinergic enhancement.45 The amygdala can modulate early visual processing of emotional faces in the extrastriate cortex.15 Thus, lorazepam-induced attenuation of fusiform activity may be indirectly elicited by its down-regulation of the amygdala.

The behavioral effects of benzodiazepines in healthy, nonanxious volunteers have been mixed; for example, diazepam had no effect on fear-potentiated startle response,46 whereas it impaired the recognition of anger and fear but not other emotional expressions.47 Single administration vs repeated administration of lorazepam can induce loss of appetite, dizziness, and physical and mentaltiredness.48,49 Benzodiazepines dose-dependently disrupt learning and performance on acute vigilance tasks50 and on a variety of memory tasks, presumably by reducing the normally facilitative effect of emotion on memory.51,52 Thus, behavioral effects may not provide robust indicators of potential anxiolytic efficacy in healthy nonanxious subjects, whereas changes in neural activation patterns induced by these substances may be informative. A low level of state anxiety may account for the lack of correlation between attenuation of the amygdala by lorazepam and changes in anxiety levels in our study. Future studies may include individuals with high trait anxiety (and ultimately anxiety disorders) to elucidate the relationship between anxiolytic effect and amygdala attenuation.

New drugs with novel anxiolytic mechanisms have been developed, including GABA A subreceptors,53 metabotropic glutamate receptor agents,54 and neuropeptide modulators.55 The current results provide a strong rationale for using BOLD fMRI imaging and amygdala- and/or insula-sensitive behavioral paradigms to determine whether these substances exert effects similar to those seen with standard anxiolytics. Furthermore, evaluation of the effects of other known classes of anxiolytics, such as long-term administration of selective serotonin reuptake inhibitors, should be undertaken to further validate this paradigm. The effect sizes (η2) observed in this study provide proof in principle that small-scale (ie, sample sizes in the range of 15 to 30 subjects) BOLD fMRI studies can provide reasonably robust data to determine the site of action of putative anxiolytics. In summary, the current finding provides the first evidence of a dose-dependent change induced by an established therapeutic agent in brain regions known to be critical for the mediation of anxiety.

Correspondence: Martin P. Paulus, MD, Department of Psychiatry, University of California, San Diego, 8950 La Jolla Village Dr, Suite C213, La Jolla, CA 92037-0985 (mpaulus@ucsd.edu).

Submitted for Publication: March 29, 2004; final revision received July 27, 2004; accepted August 20, 2004.

Funding/Support: This work was supported by grants DA13186 and MH65413 from the National Institutes of Health, Bethesda, Md.

Acknowledgment: We acknowledge the invaluable help of Kelly Winternheimer, BS, and Thuy Le, BS.

Kent  JMRauch  SL Neurocircuitry of anxiety disorders. Curr Psychiatry Rep 2003;5266- 273
PubMed Link to Article
Rauch  SLShin  LMWright  CI Neuroimaging studies of amygdala function in anxiety disorders. Ann N Y Acad Sci 2003;985389- 410
PubMed Link to Article
Charney  DS Neuroanatomical circuits modulating fear and anxiety behaviors. Acta Psychiatr Scand Suppl 2003;38- 50
PubMed
LeDoux  JE Brain mechanisms of emotion and emotional learning. Curr Opin Neurobiol 1992;2191- 197
PubMed Link to Article
Buchel  CMorris  JDolan  RJFriston  KJ Brain systems mediating aversive conditioning: an event-related fMRI study. Neuron 1998;20947- 957
PubMed Link to Article
Breiter  HCRosen  BR Functional magnetic resonance imaging of brain reward circuitry in the human. Ann N Y Acad Sci 1999;877523- 547
PubMed Link to Article
Canli  TZhao  ZBrewer  JGabrieli  JDCahill  L Event-related activation in the human amygdala associates with later memory for individual emotional experience. J Neurosci 2000;20RC99
PubMed
Ernst  MBolla  KMouratidis  MContoreggi  CMatochik  JAKurian  VCadet  JLKimes  ASLondon  ED Decision-making in a risk-taking task: a PET study. Neuropsychopharmacology 2002;26682- 691
PubMed Link to Article
Garavan  HPendergrass  JCRoss  TJStein  EARisinger  RC Amygdala response to both positively and negatively valenced stimuli. Neuroreport 2001;122779- 2783
PubMed Link to Article
Gottfried  JAO'Doherty  JDolan  RJ Appetitive and aversive olfactory learning in humans studied using event-related functional magnetic resonance imaging. J Neurosci 2002;2210829- 10837
PubMed
Phillips  MLDrevets  WCRauch  SLLane  R Neurobiology of emotion perception, I: the neural basis of normal emotion perception. Biol Psychiatry 2003;54504- 514
PubMed Link to Article
Augustine  JR Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Brain Res Rev 1996;22229- 244
PubMed Link to Article
Phillips  MLYoung  AWScott  SKCalder  AJAndrew  CGiampietro  VWilliams  SCBullmore  ETBrammer  MGray  JA Neural responses to facial and vocal expressions of fear and disgust. Proc R Soc Lond B Biol Sci 1998;2651809- 1817
PubMed Link to Article
Phan  KLWager  TTaylor  SFLiberzon  I Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 2002;16331- 348
PubMed Link to Article
Morris  JSFriston  KJBèuchel  CFrith  CDYoung  AWCalder  AJDolan  RJ A neuromodulatory role for the human amygdala in processing emotional facial expressions. Brain 1998;12147- 57
PubMed Link to Article
Gelnar  PAKrauss  BRSheehe  PRSzeverenyi  NMApkarian  AV A comparative fMRI study of cortical representations for thermal painful, vibrotactile, and motor performance tasks. Neuroimage 1999;10460- 482
PubMed Link to Article
Peyron  RLaurent  BGarcia-Larrea  L Functional imaging of brain responses to pain: a review and meta-analysis (2000). Neurophysiol Clin 2000;30263- 288
PubMed Link to Article
Gorno-Tempini  MLPradelli  SSerafini  MPagnoni  GBaraldi  PPorro  CNicoletti  RUmita  CNichelli  P Explicit and incidental facial expression processing: an fMRI study. Neuroimage 2001;14465- 473
PubMed Link to Article
Kyriakopoulos  AAGreenblatt  DJShader  RI Clinical pharmacokinetics of lorazepam: a review. J Clin Psychiatry 1978;3916- 23
PubMed
Sperling  RGreve  DDale  AKilliany  RHolmes  JRosas  HDCocchiarella  AFirth  PRosen  BLake  SLange  NRoutledge  CAlbert  M Functional MRI detection of pharmacologically induced memory impairment. Proc Natl Acad Sci U S A 2002;99455- 460
PubMed Link to Article
Salmeron  BJStein  EA Pharmacological applications of magnetic resonance imaging. Psychopharmacol Bull 2002;36102- 129
PubMed
Stein  EA fMRI: a new tool for the in vivo localization of drug actions in the brain. J Anal Toxicol 2001;25419- 424
PubMed Link to Article
Stein  EAPankiewicz  JHarsch  HHCho  JKFuller  SAHoffmann  RGHawkins  MRao  SMBandettini  PABloom  AS Nicotine-induced limbic cortical activation in the human brain: a functional MRI study. Am J Psychiatry 1998;1551009- 1015
PubMed
Busto  UEKaplan  HLWright  CEGomez-Mancilla  BZawertailo  LGreenblatt  DJSellers  EM A comparative pharmacokinetic and dynamic evaluation of alprazolam sustained-release, bromazepam, and lorazepam. J Clin Psychopharmacol 2000;20628- 635
PubMed Link to Article
Rush  CRHiggins  STBickel  WKHughes  JR Acute effects of triazolam and lorazepam on human learning, performance and subject ratings. J Pharmacol Exp Ther 1993;2641218- 1226
PubMed
Spielberger  CD Manual for the State-Trait Anxiety Inventory (Form Y).  Palo Alto, Calif Consulting Psychologists Press1983;
Hariri  ARMattay  VSTessitore  AKolachana  BFera  FGoldman  DEgan  MFWeinberger  DR Serotonin transporter genetic variation and the response of the human amygdala. Science 2002;297400- 403
PubMed Link to Article
Ekman  PLevenson  RWFriesen  WV Autonomic nervous system activity distinguishes among emotions. Science 1983;2211208- 1210
PubMed Link to Article
Cox  RW AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res 1996;29162- 173
PubMed Link to Article
Boynton  GMEngel  SAGlover  GHHeeger  DJ Linear systems analysis of functional magnetic resonance imaging in human V1. J Neurosci 1996;164207- 4221
PubMed
Lancaster  JLWoldorff  MGParsons  LMLiotti  MFreitas  CSRainey  LKochunov  PVNickerson  DMikiten  SAFox  PT Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp 2000;10120- 131
PubMed Link to Article
Norusis  MJ SPSS Base System User's Guide.  Chicago, Ill SPSS Inc1990;
Menard  JTreit  D Effects of centrally administered anxiolytic compounds in animal models of anxiety. Neurosci Biobehav Rev 1999;23591- 613
PubMed Link to Article
Stein  MBGoldin  PRSareen  JZorrilla  LTBrown  GG Increased amygdala activation to angry and contemptuous faces in generalized social phobia. Arch Gen Psychiatry 2002;591027- 1034
PubMed Link to Article
Rauch  SLWhalen  PJShin  LMMcInerney  SCMacklin  MLLasko  NBOrr  SPPitman  RK Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Biol Psychiatry 2000;47769- 776
PubMed Link to Article
Bremner  JDInnis  RBWhite  TFujita  MSilbersweig  DGoddard  AWStaib  LStern  ECappiello  AWoods  SBaldwin  RCharney  DS SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder. Biol Psychiatry 2000;4796- 106
PubMed Link to Article
Malizia  ALCunningham  VJBell  CJLiddle  PFJones  TNutt  DJ Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. Arch Gen Psychiatry 1998;55715- 720
PubMed Link to Article
Craig  AD How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 2002;3655- 666
PubMed
Critchley  HDWiens  SRotshtein  POhman  ADolan  RJ Neural systems supporting interoceptive awareness. Nat Neurosci 2004;7189- 195
PubMed Link to Article
Kanwisher  NMcDermott  JChun  MM The fusiform face area: a module in human extrastriate cortex specialized for face perception. J Neurosci 1997;174302- 4311
PubMed
Andrews  TJSchluppeck  DHomfray  DMatthews  PBlakemore  C Activity in the fusiform gyrus predicts conscious perception of Rubin's vase-face illusion. Neuroimage 2002;17890- 901
PubMed Link to Article
Chua  PKrams  MToni  IPassingham  RDolan  R A functional anatomy of anticipatory anxiety. Neuroimage 1999;9563- 571
PubMed Link to Article
Geday  JGjedde  ABoldsen  ASKupers  R Emotional valence modulates activity in the posterior fusiform gyrus and inferior medial prefrontal cortex in social perception. Neuroimage 2003;18675- 684
PubMed Link to Article
Bremner  JDVythilingam  MVermetten  ESouthwick  SMMcGlashan  TStaib  LHSoufer  RCharney  DS Neural correlates of declarative memory for emotionally valenced words in women with posttraumatic stress disorder related to early childhood sexual abuse. Biol Psychiatry 2003;53879- 889
PubMed Link to Article
Bentley  PVuilleumier  PThiel  CMDriver  JDolan  RJ Cholinergic enhancement modulates neural correlates of selective attention and emotional processing. Neuroimage 2003;2058- 70
PubMed Link to Article
Baas  JMGrillon  CBocker  KBBrack  AAMorgan  CA  IIIKenemans  JLVerbaten  MN Benzodiazepines have no effect on fear-potentiated startle in humans. Psychopharmacology (Berl) 2002;161233- 247
PubMed Link to Article
Zangara  ABlair  RJCurran  HV A comparison of the effects of a beta-adrenergic blocker and a benzodiazepine upon the recognition of human facial expressions. Psychopharmacology (Berl) 2002;16336- 41
PubMed Link to Article
File  SEBond  AJ Impaired performance and sedation after a single dose of lorazepam. Psychopharmacology (Berl) 1979;66309- 313
PubMed Link to Article
File  SEBond  AJLister  RG Interaction between effects of caffeine and lorazepam in performance tests and self-ratings. J Clin Psychopharmacol 1982;2102- 106
PubMed Link to Article
Greenblatt  DJScavone  JMHarmatz  JSEngelhardt  NShader  RI Cognitive effects of beta-adrenergic antagonists after single doses: pharmacokinetics and pharmacodynamics of propranolol, atenolol, lorazepam, and placebo. Clin Pharmacol Ther 1993;53577- 584
PubMed Link to Article
Buchanan  TWKarafin  MSAdolphs  R Selective effects of triazolam on memory for emotional, relative to neutral, stimuli: differential effects on gist versus detail. Behav Neurosci 2003;117517- 525
PubMed Link to Article
Blair  RJCurran  HV Selective impairment in the recognition of anger induced by diazepam. Psychopharmacology (Berl) 1999;147335- 338
PubMed Link to Article
Whiting  PJ The GABAA receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Devel 2003;6648- 657
PubMed
Schoepp  DDWright  RALevine  LRGaydos  BPotter  WZ LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress. Stress 2003;6189- 197
PubMed Link to Article
Kent  JMMathew  SJGorman  JM Molecular targets in the treatment of anxiety. Biol Psychiatry 2002;521008- 1030
PubMed Link to Article

Figures

Figure 1. Emotion face assessment task.27 The target and 2 probe faces or ovals and circles were presented for 5 seconds. Blocks of each target emotion consisted of six 5-second angry, fearful, or happy face trials; blocks of ovals or circles consisted of two 5-second trials. Blocks of fixation crosses with varying time length were interspersed between the face and oval/circle blocks.

Graphic Jump Location

Figure 2. Behavioral effects of placebo and 0.25 mg and 1.0 mg of oral lorazepam. Lorazepam had no effect on response latency (A), the fraction of correct responses, or accuracy (B). Error bars indicate SE.

Graphic Jump Location

Figure 3. A, A high dose of lorazepam increased sleepiness (0 = not at all; 10 = extremely) at the 1.0-mg dose. B, Neither a low nor a high dose of lorazepam had a significant effect on state anxiety.

Graphic Jump Location

Figure 4. A, The blood oxygenation level–dependent functional magnetic resonance imaging effects (mean and SE) of placebo and 0.25 mg and 1.0 mg of oral lorazepam. B, Lorazepam dose-dependently attenuated the signal difference between the face-matching task and the sensorimotor control task in bilateral amygdala and insula. Numbers indicate Talairach z coordinates.

Graphic Jump Location

Figure 5. A, Percentage of signal activation during the face matching vs the sensorimotor comparison task at z = −12 during administration of placebo and 1.0 mg of oral lorazepam. Cross-hairs indicate the approximate center of mass of the amygdala as defined by the Talairach Daemon atlas.31 The bar indicates percent signal change from 0.2% to 1.0%. B, Blood oxygenation level–dependent functional magnetic resonance imaging percent signal difference of placebo and 0.25 mg and 1.0 mg of oral lorazepam in the visual cortex.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Statistical Analyses of Regions of Interest

References

Kent  JMRauch  SL Neurocircuitry of anxiety disorders. Curr Psychiatry Rep 2003;5266- 273
PubMed Link to Article
Rauch  SLShin  LMWright  CI Neuroimaging studies of amygdala function in anxiety disorders. Ann N Y Acad Sci 2003;985389- 410
PubMed Link to Article
Charney  DS Neuroanatomical circuits modulating fear and anxiety behaviors. Acta Psychiatr Scand Suppl 2003;38- 50
PubMed
LeDoux  JE Brain mechanisms of emotion and emotional learning. Curr Opin Neurobiol 1992;2191- 197
PubMed Link to Article
Buchel  CMorris  JDolan  RJFriston  KJ Brain systems mediating aversive conditioning: an event-related fMRI study. Neuron 1998;20947- 957
PubMed Link to Article
Breiter  HCRosen  BR Functional magnetic resonance imaging of brain reward circuitry in the human. Ann N Y Acad Sci 1999;877523- 547
PubMed Link to Article
Canli  TZhao  ZBrewer  JGabrieli  JDCahill  L Event-related activation in the human amygdala associates with later memory for individual emotional experience. J Neurosci 2000;20RC99
PubMed
Ernst  MBolla  KMouratidis  MContoreggi  CMatochik  JAKurian  VCadet  JLKimes  ASLondon  ED Decision-making in a risk-taking task: a PET study. Neuropsychopharmacology 2002;26682- 691
PubMed Link to Article
Garavan  HPendergrass  JCRoss  TJStein  EARisinger  RC Amygdala response to both positively and negatively valenced stimuli. Neuroreport 2001;122779- 2783
PubMed Link to Article
Gottfried  JAO'Doherty  JDolan  RJ Appetitive and aversive olfactory learning in humans studied using event-related functional magnetic resonance imaging. J Neurosci 2002;2210829- 10837
PubMed
Phillips  MLDrevets  WCRauch  SLLane  R Neurobiology of emotion perception, I: the neural basis of normal emotion perception. Biol Psychiatry 2003;54504- 514
PubMed Link to Article
Augustine  JR Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Brain Res Rev 1996;22229- 244
PubMed Link to Article
Phillips  MLYoung  AWScott  SKCalder  AJAndrew  CGiampietro  VWilliams  SCBullmore  ETBrammer  MGray  JA Neural responses to facial and vocal expressions of fear and disgust. Proc R Soc Lond B Biol Sci 1998;2651809- 1817
PubMed Link to Article
Phan  KLWager  TTaylor  SFLiberzon  I Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 2002;16331- 348
PubMed Link to Article
Morris  JSFriston  KJBèuchel  CFrith  CDYoung  AWCalder  AJDolan  RJ A neuromodulatory role for the human amygdala in processing emotional facial expressions. Brain 1998;12147- 57
PubMed Link to Article
Gelnar  PAKrauss  BRSheehe  PRSzeverenyi  NMApkarian  AV A comparative fMRI study of cortical representations for thermal painful, vibrotactile, and motor performance tasks. Neuroimage 1999;10460- 482
PubMed Link to Article
Peyron  RLaurent  BGarcia-Larrea  L Functional imaging of brain responses to pain: a review and meta-analysis (2000). Neurophysiol Clin 2000;30263- 288
PubMed Link to Article
Gorno-Tempini  MLPradelli  SSerafini  MPagnoni  GBaraldi  PPorro  CNicoletti  RUmita  CNichelli  P Explicit and incidental facial expression processing: an fMRI study. Neuroimage 2001;14465- 473
PubMed Link to Article
Kyriakopoulos  AAGreenblatt  DJShader  RI Clinical pharmacokinetics of lorazepam: a review. J Clin Psychiatry 1978;3916- 23
PubMed
Sperling  RGreve  DDale  AKilliany  RHolmes  JRosas  HDCocchiarella  AFirth  PRosen  BLake  SLange  NRoutledge  CAlbert  M Functional MRI detection of pharmacologically induced memory impairment. Proc Natl Acad Sci U S A 2002;99455- 460
PubMed Link to Article
Salmeron  BJStein  EA Pharmacological applications of magnetic resonance imaging. Psychopharmacol Bull 2002;36102- 129
PubMed
Stein  EA fMRI: a new tool for the in vivo localization of drug actions in the brain. J Anal Toxicol 2001;25419- 424
PubMed Link to Article
Stein  EAPankiewicz  JHarsch  HHCho  JKFuller  SAHoffmann  RGHawkins  MRao  SMBandettini  PABloom  AS Nicotine-induced limbic cortical activation in the human brain: a functional MRI study. Am J Psychiatry 1998;1551009- 1015
PubMed
Busto  UEKaplan  HLWright  CEGomez-Mancilla  BZawertailo  LGreenblatt  DJSellers  EM A comparative pharmacokinetic and dynamic evaluation of alprazolam sustained-release, bromazepam, and lorazepam. J Clin Psychopharmacol 2000;20628- 635
PubMed Link to Article
Rush  CRHiggins  STBickel  WKHughes  JR Acute effects of triazolam and lorazepam on human learning, performance and subject ratings. J Pharmacol Exp Ther 1993;2641218- 1226
PubMed
Spielberger  CD Manual for the State-Trait Anxiety Inventory (Form Y).  Palo Alto, Calif Consulting Psychologists Press1983;
Hariri  ARMattay  VSTessitore  AKolachana  BFera  FGoldman  DEgan  MFWeinberger  DR Serotonin transporter genetic variation and the response of the human amygdala. Science 2002;297400- 403
PubMed Link to Article
Ekman  PLevenson  RWFriesen  WV Autonomic nervous system activity distinguishes among emotions. Science 1983;2211208- 1210
PubMed Link to Article
Cox  RW AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res 1996;29162- 173
PubMed Link to Article
Boynton  GMEngel  SAGlover  GHHeeger  DJ Linear systems analysis of functional magnetic resonance imaging in human V1. J Neurosci 1996;164207- 4221
PubMed
Lancaster  JLWoldorff  MGParsons  LMLiotti  MFreitas  CSRainey  LKochunov  PVNickerson  DMikiten  SAFox  PT Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp 2000;10120- 131
PubMed Link to Article
Norusis  MJ SPSS Base System User's Guide.  Chicago, Ill SPSS Inc1990;
Menard  JTreit  D Effects of centrally administered anxiolytic compounds in animal models of anxiety. Neurosci Biobehav Rev 1999;23591- 613
PubMed Link to Article
Stein  MBGoldin  PRSareen  JZorrilla  LTBrown  GG Increased amygdala activation to angry and contemptuous faces in generalized social phobia. Arch Gen Psychiatry 2002;591027- 1034
PubMed Link to Article
Rauch  SLWhalen  PJShin  LMMcInerney  SCMacklin  MLLasko  NBOrr  SPPitman  RK Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Biol Psychiatry 2000;47769- 776
PubMed Link to Article
Bremner  JDInnis  RBWhite  TFujita  MSilbersweig  DGoddard  AWStaib  LStern  ECappiello  AWoods  SBaldwin  RCharney  DS SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder. Biol Psychiatry 2000;4796- 106
PubMed Link to Article
Malizia  ALCunningham  VJBell  CJLiddle  PFJones  TNutt  DJ Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. Arch Gen Psychiatry 1998;55715- 720
PubMed Link to Article
Craig  AD How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 2002;3655- 666
PubMed
Critchley  HDWiens  SRotshtein  POhman  ADolan  RJ Neural systems supporting interoceptive awareness. Nat Neurosci 2004;7189- 195
PubMed Link to Article
Kanwisher  NMcDermott  JChun  MM The fusiform face area: a module in human extrastriate cortex specialized for face perception. J Neurosci 1997;174302- 4311
PubMed
Andrews  TJSchluppeck  DHomfray  DMatthews  PBlakemore  C Activity in the fusiform gyrus predicts conscious perception of Rubin's vase-face illusion. Neuroimage 2002;17890- 901
PubMed Link to Article
Chua  PKrams  MToni  IPassingham  RDolan  R A functional anatomy of anticipatory anxiety. Neuroimage 1999;9563- 571
PubMed Link to Article
Geday  JGjedde  ABoldsen  ASKupers  R Emotional valence modulates activity in the posterior fusiform gyrus and inferior medial prefrontal cortex in social perception. Neuroimage 2003;18675- 684
PubMed Link to Article
Bremner  JDVythilingam  MVermetten  ESouthwick  SMMcGlashan  TStaib  LHSoufer  RCharney  DS Neural correlates of declarative memory for emotionally valenced words in women with posttraumatic stress disorder related to early childhood sexual abuse. Biol Psychiatry 2003;53879- 889
PubMed Link to Article
Bentley  PVuilleumier  PThiel  CMDriver  JDolan  RJ Cholinergic enhancement modulates neural correlates of selective attention and emotional processing. Neuroimage 2003;2058- 70
PubMed Link to Article
Baas  JMGrillon  CBocker  KBBrack  AAMorgan  CA  IIIKenemans  JLVerbaten  MN Benzodiazepines have no effect on fear-potentiated startle in humans. Psychopharmacology (Berl) 2002;161233- 247
PubMed Link to Article
Zangara  ABlair  RJCurran  HV A comparison of the effects of a beta-adrenergic blocker and a benzodiazepine upon the recognition of human facial expressions. Psychopharmacology (Berl) 2002;16336- 41
PubMed Link to Article
File  SEBond  AJ Impaired performance and sedation after a single dose of lorazepam. Psychopharmacology (Berl) 1979;66309- 313
PubMed Link to Article
File  SEBond  AJLister  RG Interaction between effects of caffeine and lorazepam in performance tests and self-ratings. J Clin Psychopharmacol 1982;2102- 106
PubMed Link to Article
Greenblatt  DJScavone  JMHarmatz  JSEngelhardt  NShader  RI Cognitive effects of beta-adrenergic antagonists after single doses: pharmacokinetics and pharmacodynamics of propranolol, atenolol, lorazepam, and placebo. Clin Pharmacol Ther 1993;53577- 584
PubMed Link to Article
Buchanan  TWKarafin  MSAdolphs  R Selective effects of triazolam on memory for emotional, relative to neutral, stimuli: differential effects on gist versus detail. Behav Neurosci 2003;117517- 525
PubMed Link to Article
Blair  RJCurran  HV Selective impairment in the recognition of anger induced by diazepam. Psychopharmacology (Berl) 1999;147335- 338
PubMed Link to Article
Whiting  PJ The GABAA receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Devel 2003;6648- 657
PubMed
Schoepp  DDWright  RALevine  LRGaydos  BPotter  WZ LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress. Stress 2003;6189- 197
PubMed Link to Article
Kent  JMMathew  SJGorman  JM Molecular targets in the treatment of anxiety. Biol Psychiatry 2002;521008- 1030
PubMed Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 139

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

Care at the Close of Life EDUCATION GUIDES
Agitation and Delirium at the End of Life