Anxiety Disorders: Drevets WC

Savitz J, Drevets WC. · Section on Neuroimaging in Mood and Anxiety Disorders, Mood and Anxiety Disorders Program, National Institute of Mental Health/NIH, Bethesda, MD 20892, USA. · Neurosci Biobehav Rev. · Pubmed #19428491 No free full text.

Abstract: Both major depressive disorder and bipolar disorder are the subject of a voluminous imaging and genetics literature. Here, we attempt a comprehensive review of MRI and metabolic PET studies conducted to date on these two disorders, and interpret our findings from the perspective of developmental and degenerative models of illness. Elevated activity and volume loss of the hippocampus, orbital and ventral prefrontal cortex are recurrent themes in the literature. In contrast, dorsal aspects of the PFC tend to display hypometabolism. Ventriculomegaly and white matter hyperintensities are intimately associated with depression in elderly populations and likely have a vascular origin. Important confounding influences are medication, phenotypic and genetic heterogeneity, and technological limitations. We suggest that environmental stress and genetic risk variants interact with each other in a complex manner to alter neural circuitry and precipitate illness. Imaging genetic approaches hold out promise for advancing our understanding of affective illness.

Drevets WC, Price JL, Furey ML. · Section on Neuroimaging in Mood and Anxiety Disorders, National Institute of Mental Health, National Institutes of Health (NIH/NIMH DIRP), 15K North Dr., Room 210, Bethesda, MD 20892, USA. · Brain Struct Funct. · Pubmed #18704495 links to  free full text

Abstract: The neural networks that putatively modulate aspects of normal emotional behavior have been implicated in the pathophysiology of mood disorders by converging evidence from neuroimaging, neuropathological and lesion analysis studies. These networks involve the medial prefrontal cortex (MPFC) and closely related areas in the medial and caudolateral orbital cortex (medial prefrontal network), amygdala, hippocampus, and ventromedial parts of the basal ganglia, where alterations in grey matter volume and neurophysiological activity are found in cases with recurrent depressive episodes. Such findings hold major implications for models of the neurocircuits that underlie depression. In particular evidence from lesion analysis studies suggests that the MPFC and related limbic and striato-pallido-thalamic structures organize emotional expression. The MPFC is part of a larger "default system" of cortical areas that include the dorsal PFC, mid- and posterior cingulate cortex, anterior temporal cortex, and entorhinal and parahippocampal cortex, which has been implicated in self-referential functions. Dysfunction within and between structures in this circuit may induce disturbances in emotional behavior and other cognitive aspects of depressive syndromes in humans. Further, because the MPFC and related limbic structures provide forebrain modulation over visceral control structures in the hypothalamus and brainstem, their dysfunction can account for the disturbances in autonomic regulation and neuroendocrine responses that are associated with mood disorders. This paper discusses these systems together with the neurochemical systems that impinge on them and form the basis for most pharmacological therapies.

Drevets WC, Savitz J, Trimble M. · Section on Neuroimaging in Mood and Anxiety Disorders, Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA. · CNS Spectr. · Pubmed #18704022 links to  free full text

Abstract: The anterior cingulate cortex (ACC) ventral to the genu of the corpus callosum has been implicated in the modulation of emotional behavior on the basis of neuroimaging studies in humans and lesion analyses in experimental animals. In a combined positron emission tomography/magnetic resonance imaging study of mood disorders, we demonstrated that the mean gray matter volume of this "subgenual" ACC (sgACC) cortex is abnormally reduced in subjects with major depressive disorder (MDD) and bipolar disorder, irrespective of mood state. Neuropathological assessments of sgACC tissue acquired postmortem from subjects with MDD or bipolar disorder confirmed the decrement in gray matter volume, and revealed that this abnormality was associated with a reduction in glia, with no equivalent loss of neurons. In positron emission tomography studies, the metabolic activity was elevated in this region in the depressed relative to the remitted phases of the same MDD subjects, and effective antidepressant treatment was associated with a reduction in sgACC activity. Other laboratories replicated and extended these findings, and the clinical importance of this treatment effect was underscored by a study showing that deep brain stimulation of the sgACC ameliorates depressive symptoms in treatment-resistant MDD. This article discusses the functional significance of these findings within the context of the preclinical literature that implicates the putative homologue of this region in the regulation of emotional behavior and stress response. In experimental animals, this region participates in an extended "visceromotor network" of structures that modulates autonomic/neuroendocrine responses and neurotransmitter transmission during the neural processing of reward, fear, and stress. These data thus hold important implications for the development of neural models of depression that can account for the abnormal motivational, neuroendocrine, autonomic, and emotional manifestations evident in human mood disorders.

Drevets WC, Thase ME, Moses-Kolko EL, Price J, Frank E, Kupfer DJ, Mathis C. · Mood and Anxiety Disorders Program, MINH Molecular Imaging Branch, Bethesda, MD 20892, USA. · Nucl Med Biol. · Pubmed #17921037 links to  free full text

Abstract: INTRODUCTION: Serotonin-1A receptor (5-HT1AR) function appears to be decreased in major depressive disorder (MDD) based on physiological responses to 5-HT1AR agonists in vivo and to 5-HT1AR binding in brain tissues postmortem or antemortem. We have previously assessed 5-HT1AR binding potential (BP) in depression using positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635, and we have demonstrated reduced 5-HT1AR BP in the mesiotemporal cortex (MTC) and raphe in depressives with primary recurrent familial mood disorders (n=12) versus controls (n=8) [Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Huang Y, Gautier C, Mathis C. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999;46(10):1375-87]. These findings were replicated by some, but not other, studies performed in depressed samples that were more generally selected using criteria for MDD. In the current study, we attempted to replicate our previous findings in an independent sample of subjects selected according to the criteria for primary recurrent depression applied in our prior study. METHODS: Using PET and [carbonyl-(11)C]WAY-100635, 5-HT1AR BP was assessed in 16 depressed subjects and 8 healthy controls. RESULTS: Mean 5-HT1AR BP was reduced by 26% in the MTC (P<.005) and by 43% in the raphe (P<.001) in depressives versus controls. CONCLUSIONS: These data replicate our original findings, which showed that BP was reduced by 27% in the MTC (P<.025) and by 42% in the raphe (P<.02) in depression. The magnitudes of these reductions in 5-HT1AR binding were similar to those found postmortem in 5-HT1AR mRNA concentrations in the hippocampus in MDD [López JF, Chalmers DT, Little KY, Watson SJ. Regulation of serotonin 1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for neurobiology of depression. Biol Psychiatry 1998;43:547-73] and in 5-HT1AR-binding capacity in the raphe in depressed suicide victims [Arango V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung S, Chen JJ, Mann JJ. Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology 2001;25(6):892-903]. There exists disagreement within the literature, however, regarding the presence and direction of 5-HT1AR-binding abnormalities in depression, which may be explained in some cases by differences in anatomical location (e.g., [Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression--postmortem evidence for decreased serotonin activity. J Neurosci 1998;18(18):7394-401]) and in other cases by pathophysiological heterogeneity within MDD (e.g., some depressives hypersecrete cortisol, which would be expected to down-regulate 5-HT1AR expression [López JF, Chalmers DT, Little KY, Watson SJ. Regulation of serotonin 1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for neurobiology of depression. Biol Psychiatry 1998;43:547-73]). Antidepressant drug treatment does not alter these abnormalities in 5-HT1AR binding [Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J, Gunn RN, Grasby PM, Cowen PJ. Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 2000;57(2):174-80; Moses-Kolko EL, Price JC, Thase ME, Meltzer CC, Kupfer DJ, Mathis CA, Bogers WD, Berman SR, Houck PR, Schneider TN, Drevets WC. Measurement of 5-HT1A receptor binding in depressed adults before and after antidepressant drug treatment using positron emission tomography and [11C]WAY-100635. Synapse 2007;61(7):523-30] but may compensate for blunted 5-HT1AR function by increasing post-synaptic 5-HT1AR transmission [Chaput Y, de Montigny C, Blier P. Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments. An in vivo electrophysiologic study in the rat. Neuropsychopharmacology 1991;5(4):219-29].

Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK. · Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, Maryland, USA. · Biol Psychiatry. · Pubmed #16406007 No free full text.

Abstract: Research aimed at elucidating the underlying neurobiology and genetics of bipolar disorder, and factors associated with treatment response, have been limited by a heterogeneous clinical phenotype and lack of knowledge about its underlying diathesis. We used a survey of clinical, epidemiological, neurobiological, and genetic studies to select and evaluate candidate endophenotypes for bipolar disorder. Numerous findings regarding brain function, brain structure, and response to pharmacological challenge in bipolar patients and their relatives deserve further investigation. Candidate brain function endophenotypes include attention deficits, deficits in verbal learning and memory, cognitive deficits after tryptophan depletion, circadian rhythm instability, and dysmodulation of motivation and reward. We selected reduced anterior cingulate volume and early-onset white matter abnormalities as candidate brain structure endophenotypes. Symptom provocation endophenotypes might be based on bipolar patients' sensitivity to sleep deprivation, psychostimulants, and cholinergic drugs. Phenotypic heterogeneity is a major impediment to the elucidation of the neurobiology and genetics of bipolar disorder. We present a strategy constructed to improve the phenotypic definition of bipolar disorder by elucidating candidate endophenotypes. Studies to evaluate candidate endophenotypes with respect to specificity, heritability, temporal stability, and prevalence in unaffected relatives are encouraged.

Hasler G, Drevets WC, Manji HK, Charney DS. · Mood and Anxiety Disorders Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, USA. · Neuropsychopharmacology. · Pubmed #15213704 links to  free full text

Abstract: The limited success of genetic studies of major depression has raised questions concerning the definition of genetically relevant phenotypes. This paper presents strategies to improve the phenotypic definition of major depression by proposing endophenotypes at two levels: First, dissecting the depressive phenotype into key components results in narrow definitions of putative psychopathological endophenotypes: mood bias toward negative emotions, impaired reward function, impaired learning and memory, neurovegetative signs, impaired diurnal variation, impaired executive cognitive function, psychomotor change, and increased stress sensitivity. A review of the recent literature on neurobiological and genetic findings associated with these components is given. Second, the most consistent heritable biological markers of major depression are proposed as biological endophenotypes for genetic studies: REM sleep abnormalities, functional and structural brain abnormalities, dysfunctions in serotonergic, catecholaminergic, hypothalamic-pituitary-adrenocortical axis, and CRH systems, and intracellular signal transduction endophenotypes. The associations among the psychopathological and biological endophenotypes are discussed with respect to specificity, temporal stability, heritability, familiality, and clinical and biological plausibility. Finally, the case is made for the development of a new classification system in order to reduce the heterogeneity of depression representing a major impediment to elucidating the genetic and neurobiological basis of this common, severe, and often life-threatening illness.

Drevets WC. · Mood and Anxiety Disorders Program, Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-2670, USA. · Ann N Y Acad Sci. · Pubmed #12724175 No free full text.

Abstract: Neuroimaging technology has been applied to investigate the pathophysiology of mood disorders in studies aimed at characterizing the anatomical correlates of depressive symptoms, the neurophysiological effects of antidepressant treatments, and the trait-like abnormalities that persist despite symptom remission. These studies have identified cerebral blood flow and metabolic differences between depressives and controls in the amygdala and anatomically related areas of the prefrontal cortex, striatum, and thalamus. Taken together with converging evidence from neuroendocrine, lesion analysis, and postmortem studies of clinically depressed subjects, these data suggest that emotional/stress-response systems that include the amygdala are pathologically activated in major depression and that this activity is associated with dysfunction of the prefrontal cortex and monoamine neurotransmitter systems that normally modulate such responses.

Drevets WC. · Mood and Anxiety Disorders Program, National Institutes of Mental Health, 1 Center Drive, Room B3-07 MSC 0135, Bethesda, MD 20892-0135, USA. · Curr Opin Neurobiol. · Pubmed #11301246 No free full text.

Abstract: Neuroimaging technology has provided unprecedented opportunities for elucidating the anatomical correlates of major depression. The knowledge gained from imaging research and from the postmortem studies that have been guided by imaging data is catalyzing a paradigm shift in which primary mood disorders are conceptualized as illnesses that involve abnormalities of brain structure, as well as of brain function. These data suggest specific hypotheses regarding the neural mechanisms underlying pathological emotional processing in mood disorders. They particularly support a role for dysfunction within the prefrontal cortical and striatal systems that normally modulate limbic and brainstem structures involved in mediating emotional behavior in the pathogenesis of depressive symptoms.

Holmes MK, Erickson K, Luckenbaugh DA, Drevets WC, Bain EE, Cannon DM, Snow J, Sahakian BJ, Manji HK, Zarate CA. · Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. · Bipolar Disord. · Pubmed #19032712 No free full text.

Abstract: OBJECTIVE: Neuropsychological studies of bipolar disorder reveal deficits in a variety of domains, including affective processing, memory, and sustained attention. These findings are difficult to interpret due to the potential confounding effects of mood-stabilizing medications. The present study aims to compare the cognitive performance of medicated and unmedicated subjects with bipolar depression to healthy control subjects. METHOD: Unmedicated subjects with bipolar depression (UBD, n = 32), subjects with bipolar depression on therapeutic doses of lithium or valproic acid (MBD, n = 33), and healthy control subjects (HC, n = 52) performed neuropsychological tasks measuring affective processing, visual memory, and sustained attention. Performance measures were covaried with age and mood ratings, where applicable. RESULTS: With regard to affective processing, the MBD group exhibited greater response latency than the UBD and HC groups. For the same task, the MBD group made more omission errors during the happy condition than in the sad condition. On a task of sustained attention, the MBD group made more errors than the HC group. There were no significant group differences on measures of visual memory. CONCLUSIONS: Deficits in affective processing were found in the medicated group, while unmedicated subjects appear to be unaffected. In particular, the MBD group made more errors during happy conditions, indicating a potential attentional bias in subjects with bipolar depression on mood-stabilizing medications. The present study also implicates impairment in sustained attention for medicated subjects with bipolar disorder, particularly those with the type II variety.

Neumeister A, Wood S, Bonne O, Nugent AC, Luckenbaugh DA, Young T, Bain EE, Charney DS, Drevets WC. · Section on Experimental Therapeutics and Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, Maryland, USA. · Biol Psychiatry. · Pubmed #15820716 No free full text.

Abstract: BACKGROUND: Hippocampal volumes obtained from a group of medication-free, remitted subjects with recurrent major depressive disorder (MDD) were compared against corresponding measures from healthy controls. METHODS: Thirty-one subjects with recurrent MDD in full remission, and 57 healthy controls underwent high resolution magnetic resonance imaging (MRI) on a GE 3T scanner. Eight patients with MDD were medication-naive, and twenty-three MDD patients were off antidepressant medications for a mean of 30 months at the time of the MRI study. RESULTS: Patients showed smaller total and posterior hippocampal volume relative to controls. Anterior hippocampal volume did not differ between patients and controls. CONCLUSIONS: Recurrent depression is associated with smaller hippocampal volume which is most prominent in the posterior hippocampus. Smaller hippocampal volume appears to be a trait characteristic for MDD.

Neumeister A, Nugent AC, Waldeck T, Geraci M, Schwarz M, Bonne O, Bain EE, Luckenbaugh DA, Herscovitch P, Charney DS, Drevets WC. · Section on Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, MD 20892-2670, USA. · Arch Gen Psychiatry. · Pubmed #15289275 links to  free full text

Abstract: CONTEXT: An instructive paradigm for investigating the relationship between brain serotonin function and major depressive disorder (MDD) is the response to tryptophan depletion (TD) induced by oral loading with all essential amino acids except the serotonin precursor tryptophan. OBJECTIVE: To determine whether serotonin dysfunction represents a trait abnormality in MDD in the context of specific neural circuitry abnormalities involved in the pathogenesis of MDD. DESIGN: Randomized double-blind crossover study. SETTING: Outpatient clinic. PARTICIPANTS: Twenty-seven medication-free patients with remitted MDD (18 women and 9 men; mean +/- SD age, 39.8 +/- 12.7 years) and 19 controls (10 women and 9 men; mean +/- SD age, 34.4 +/- 11.5 years). INTERVENTIONS: We induced TD by administering capsules containing an amino acid mixture without tryptophan. Sham depletion used identical capsules containing hydrous lactose. Fluorodeoxyglucose F 18 positron emission tomography studies were performed 6 hours after TD. Magnetic resonance images were obtained for all participants. MAIN OUTCOME MEASURES: Quantitative positron emission tomography of regional cerebral glucose utilization to study the neural effects of sham depletion and TD. Behavioral assessments used a modified (24-item) version of the Hamilton Depression Rating Scale. RESULTS: Tryptophan depletion induced a transient return of depressive symptoms in patients with remitted MDD but not in controls (P<.001). Compared with sham depletion, TD was associated with an increase in regional cerebral glucose utilization in the orbitofrontal cortex, medial thalamus, anterior and posterior cingulate cortices, and ventral striatum in patients with remitted MDD but not in controls. CONCLUSION: The pattern of TD-induced regional cerebral glucose utilization changes in patients with remitted MDD suggests that TD unmasks a disease-specific, serotonin system-related trait dysfunction and identifies a circuit that probably plays a key role in the pathogenesis of MDD.

Neumeister A, Bain E, Nugent AC, Carson RE, Bonne O, Luckenbaugh DA, Eckelman W, Herscovitch P, Charney DS, Drevets WC. · National Institutes of Health, National Institute of Mental Health, Mood and Anxiety Disorders Program, Bethesda, Maryland 20892-2670, USA. · J Neurosci. · Pubmed #14736842 links to  free full text

Abstract: Recent animal models suggest that disturbances in serotonin type-1A receptor (5-HT(1A)R) function may contribute to chronic anxiety, although it is not clear at all whether such models constitute relevant models for panic disorder (PD) in humans. The selective 5-HT(1A)R radioligand [18F]trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (FCWAY) permits in vivo assessment of central 5-HT(1A)R binding using positron emission tomography (PET). We studied 16 unmedicated symptomatic outpatients with PD and 15 matched healthy controls. Seven patients had an additional diagnosis of a current major depressive episode, however PD was the primary diagnosis. A 120 min PET study of 5-HT(1A)R binding was acquired using a GE Advance scanner in three-dimensional mode. Using quantitative PET image analysis, regional values were obtained for [18F]-FCWAY volume of distribution (DV), corrected for plasma protein binding, and K1, the delivery rate of [18F]-FCWAY from plasma to tissue. MRI scanning was performed using a GE Signa Scanner (3.0 Tesla) to provide an anatomical framework for image analysis and partial volume correction of PET data. PD patients showed lower DV in the anterior cingulate (t = 4.3; p < 0.001), posterior cingulate (t = 4.1; p < 0.001), and raphe (t = 3.1; p = 0.004). Comparing patients with PD, patients with PD and comorbid depression, and healthy controls revealed that DVs did not differ between PD patients and PD patients with comorbid depression, whereas both patient groups differed significantly from controls. These results provide for the first time in vivo evidence for the involvement of 5-HT(1A)Rs in the pathophysiology of PD.

Savitz J, Lucki I, Drevets WC. · Section on Neuroimaging in Mood and Anxiety Disorders, Mood and Anxiety Disorders Program, NIH/NIMH, Bethesda, MD 20892, United States. · Prog Neurobiol. · Pubmed #19428959 No free full text.

Abstract: Dysfunction of the serotonin 1A receptor (5-HT(1A)) may play a role in the genesis of major depressive disorder (MDD). Here we review the pharmacological, post-mortem, positron emission tomography (PET), and genetic evidence in support of this statement. We also touch briefly on two MDD-associated phenotypes, cognitive impairment and somatic pain. The results of pharmacological challenge studies with 5-HT(1A) receptor agonists are indicative of blunted endocrine responses in depressed patients. Lithium, valproate, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and other treatment, such as electroconvulsive shock therapy (ECT), all increase post-synaptic 5-HT(1A) receptor signaling through either direct or indirect effects. Reduced somatodendritic and postsynaptic 5-HT(1A) receptor numbers or affinity have been reported in some post-mortem studies of suicide victims, a result consistent with well-replicated PET analyses demonstrating reduced 5-HT(1A) receptor binding potential in diverse regions such as the dorsal raphe, medial prefrontal cortex (mPFC), amygdala and hippocampus. 5-HT(1A) receptor knockout (KO) mice display increased anxiety-related behavior, which, unlike in their wild-type counterparts, cannot be rescued with antidepressant drug (AD) treatment. In humans, the G allele of a single nucleotide polymorphism (SNP) in the 5-HT(1A) receptor gene (HTR1A; rs6295), which abrogates a transcription factor binding site for deformed epidermal autoregulatory factor-1 (Deaf-1) and Hes5, has been reported to be over-represented in MDD cases. Conversely, the C allele has been associated with better response to AD drugs. We raise the possibility that 5-HT(1A) receptor dysfunction represents one potential mechanism underpinning MDD and other stress-related disorders.

Hasler G, Nugent AC, Carlson PJ, Carson RE, Geraci M, Drevets WC. · Department of Psychiatry, University Hospital, Culmannstrasse 8, 8091 Zurich, Switzerland. · Arch Gen Psychiatry. · Pubmed #18838633 No free full text.

Abstract: CONTEXT: The benzodiazepine (BZD) receptor system has been implicated in the pathophysiologic mechanism of panic disorder (PD) by indirect evidence from pharmacological challenge studies and by direct evidence from single-photon emission computed tomography and positron emission tomography neuroimaging studies. However, the results of previous neuroimaging studies are in disagreement, possibly because of experimental design limitations related to sample size, matching between patients and controls, and confounding medication effects. OBJECTIVE: To compare BZD receptor binding between subjects with PD and healthy control subjects. DESIGN: Cross-sectional study for association. SETTING: Psychiatric outpatient clinic of the National Institute of Mental Health. PARTICIPANTS: Fifteen subjects with PD who were naïve to BZD drug exposure and were not receiving other drug treatment, and 18 healthy controls. INTERVENTION: Images of BZD receptor binding were acquired using positron emission tomography and flumazenil tagged with carbon 11. MAIN OUTCOME MEASURES: The BZD receptor binding potential was assessed by a simplified reference tissue-tracer kinetic model. RESULTS: The BZD receptor binding potential was decreased in multiple areas of the frontal, temporal, and parietal cortices and was increased in the hippocampus/parahippocampal region in subjects with PD vs controls. The most significant decrease was located in the dorsal anterolateral prefrontal cortex (DALPFC); the most significant increase, in the hippocampus/parahippocampal gyrus. These abnormalities were not accounted for by comorbid depression. In subjects with PD, the severity of panic and anxiety symptoms correlated positively with BZD receptor binding in the DALPFC but negatively with binding in the hippocampus/parahippocampal gyrus. CONCLUSIONS: These data provide evidence of abnormal BZD-gamma-aminobutyric acid type A receptor binding in PD, suggesting that basal and/or compensatory changes in inhibitory neurotransmission play roles in the pathophysiologic mechanism of PD. They also provide evidence of an impairment of frontal-limbic interaction in the modulation of anxiety responses, consistent with previous functional and structural neuroimaging studies in PD.

Nugent AC, Neumeister A, Goldman D, Herscovitch P, Charney DS, Drevets WC. · Section on Neuroimaging in Mood and Anxiety Disorders, National Institute of Mental Health, NIH, Bethesda, MD 20892-0940, USA. · Neuroimage. · Pubmed #18718871 No free full text.

Abstract: Acute tryptophan depletion (ATD) putatively results in a transient reduction in central serotonin transmission, and induces depressed mood in some un-medicated subjects with remitted major depressive disorder (MDD). The 5-HT transporter promoter region length polymorphism (5-HTTLPR) has been shown to influence behavioral and metabolic responses to ATD, as well as the risk for developing MDD within the context of stress. The current study investigates the relationships between 5-HTTLPR genotype, neurophysiologic response to ATD, and diagnostic phenotype (healthy control subjects versus MDD subjects differentiated by their depressive response to ATD) using (18)FDG-PET. Un-medicated subjects with remitted MDD and healthy controls were genotyped for the long (l) and short (s) alleles of the 5-HTTLPR polymorphism and categorized into one of three genotypes. On two separate occasions, subjects received either a placebo or an amino acid mixture designed to deplete plasma tryptophan, followed by (18)FDG-PET scanning. Depressive symptoms were rated to determine the diagnostic phenotype. Descriptive and predictive discriminant analyses were performed using brain regional metabolic data to classify according to phenotype and genotype. Overall, 79% of the cases were classified correctly by genotype, and 85% were classified correctly by phenotype. In a leave-one-out cross-validation, 72% of the subjects were classified correctly as carrying an s-allele, and 79% of the subjects were classified correctly by primary diagnosis. The robust nature of the classification results indicates that much of the variance in metabolic response to ATD is accounted for by genotypic and phenotypic category.

Hasler G, van der Veen JW, Geraci M, Shen J, Pine D, Drevets WC. · Department of Psychiatry, University Hospital, Zurich, Switzerland. · Biol Psychiatry. · Pubmed #18692172 No free full text.

Abstract: BACKGROUND: Panic disorder (PD) is hypothesized to be associated with altered function of the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). Previous proton magnetic resonance spectroscopy (MRS) studies found lower GABA concentrations in the occipital cortex of subjects with PD relative to healthy control subjects. The current study is the first MRS study to compare GABA concentrations between unmedicated PD subjects and control subjects in the prefrontal cortex (PFC). METHODS: Unmedicated subjects with PD (n = 17) and age- and sex-matched healthy control subjects (n = 17) were scanned on a 3 Tesla scanner using a transmit-receive head coil that provided a sufficiently homogenous radiofrequency field to obtain spectroscopic measurements in the dorsomedial/dorsal anterolateral and ventromedial areas of the PFC. RESULTS: The prefrontal cortical GABA concentrations did not differ significantly between PD subjects and control subjects. There also was no statistically significant difference in glutamate/glutamine (Glx), choline, or N-acetyl aspartate concentrations. CONCLUSIONS: The previously reported finding of reduced GABA concentrations in the occipital cortex of PD subjects does not appear to extend to the PFC.

Bonne O, Vythilingam M, Inagaki M, Wood S, Neumeister A, Nugent AC, Snow J, Luckenbaugh DA, Bain EE, Drevets WC, Charney DS. · Department of Psychiatry, Hadassah Hebrew University Medical Center, Jerusalem, Israel. · J Clin Psychiatry. · Pubmed #18572983 links to  free full text

Abstract: OBJECTIVE: Hippocampal volume is reduced in posttraumatic stress disorder (PTSD). In the present study, we sought to determine whether volume loss is homogenously distributed or confined to a certain part of the structure. METHOD: Twenty-two adult outpatients with PTSD (11 after prolonged prepubertal trauma and 11 after single adult trauma) and 22 matched healthy subjects were scanned at the National Institute of Mental Health using high-resolution 3T magnetic resonance imaging between September 2003 and August 2004. PTSD diagnosis was conferred using the Structured Clinical Interview for DSM-IV. Volumes of whole, anterior, and posterior hippocampus and subiculum were compared between groups. RESULTS: Total hippocampal volume was lower in patients with PTSD (p = .02), with a significant diagnosis by hippocampal-subregion interaction (p = .02). Post hoc analysis revealed significantly smaller posterior hippocampi in PTSD (p = .006), with no difference in the volumes of anterior hippocampus or subiculum. No volume differences were found between PTSD participants with prolonged childhood abuse compared to single adult trauma exposure. CONCLUSIONS: The posterior hippocampus has been associated with storage, processing, and retrieval of spatiotemporal memories, central to the protective function of fear conditioning. Volume deficit in the posterior hippocampus may indicate malfunction in this faculty, leading to the exaggerated conditioned fear response observed in PTSD.

Blair K, Shaywitz J, Smith BW, Rhodes R, Geraci M, Jones M, McCaffrey D, Vythilingam M, Finger E, Mondillo K, Jacobs M, Charney DS, Blair RJ, Drevets WC, Pine DS. · Mood and Anxiety Program, NIMH, NIH, 15K North Dr., MSC 2670, Bethesda, MD 20892, USA. · Am J Psychiatry. · Pubmed #18483136 No free full text.

Abstract: OBJECTIVE: Generalized social phobia involves fear/avoidance, specifically of social situations, whereas generalized anxiety disorder involves intrusive worry about diverse circumstances. It remains unclear the degree to which these two, often comorbid, conditions represent distinct disorders or alternative presentations of a single, core underlying pathology. Functional magnetic resonance imaging assessed the neural response to facial expressions in generalized social phobia and generalized anxiety disorder. METHOD: Individuals matched on age, IQ, and gender with generalized social phobia without generalized anxiety disorder (N=17), generalized anxiety disorder (N=17), or no psychopathology (N=17) viewed neutral, fearful, and angry expressions while ostensibly making a simple gender judgment. RESULTS: The patients with generalized social phobia without generalized anxiety disorder showed increased activation to fearful relative to neutral expressions in several regions, including the amygdala, compared to healthy individuals. This increased amygdala response related to self-reported anxiety in patients with generalized social phobia without generalized anxiety disorder. In contrast, patients with generalized anxiety disorder showed significantly less activation to fearful relative to neutral faces compared to the healthy individuals. They did show significantly increased response to angry expressions relative to healthy individuals in a lateral region of the middle frontal gyrus. This increased lateral frontal response related to self-reported anxiety in patients with generalized anxiety disorder. CONCLUSIONS: These results suggest that neural circuitry dysfunctions differ in generalized social phobia and generalized anxiety disorder.

Osuch EA, Willis MW, Bluhm R, Anonymous00064, Ursano RJ, Drevets WC. · Department of Psychiatry, University of Western Ontario, London, Ontario, Canada. · Biol Psychiatry. · Pubmed #18423575 No free full text.

Abstract: BACKGROUND: Neuroimaging studies report that individuals with posttraumatic stress disorder show abnormal responses in the amygdala and medial prefrontal cortex (mPFC)/anterior cingulate cortex (ACC) during exposure to traumatic reminders. However, neural responses arising in the early aftermath of a traumatic event have not been studied. METHODS: Twenty-two motor vehicle collision survivors and 12 nontraumatized control subjects participated. Regional cerebral blood flow (rCBF) was measured using [(15)O]-H(2)O positron emission tomography (PET) at rest and as subjects listened to scripts of traumatic and neutral events. Self-report measures rated emotional responses to the scripts; standardized assessments (Impact of Events--Revised) evaluated acute stress symptoms at scanning and at 3-month follow-up. Most subjects improved symptomatically. RESULTS: At rest, trauma subjects showed hyperperfusion in right mPFC/ACC and hypoperfusion in right amygdala compared with control subjects. In trauma subjects, listening to trauma scripts versus neutral scripts resulted in decreased flow in the right amygdala and left amygdala/perirhinal cortex, and symptom scores correlated negatively with right hippocampal flow changes. Symptom improvement at 3 months correlated negatively with rCBF changes in right perirhinal cortex and hippocampus during the trauma versus neutral script contrast. Subjective disturbance during the trauma versus neutral contrast correlated positively with rCBF changes in right amygdala and left mPFC. Functional connectivity analyses of rCBF changes during trauma versus neutral scripts demonstrated left amygdala coupling with right ACC and bilateral anterior insula, as well as coupling between the amygdala and contralateral hippocampus. CONCLUSIONS: In recently traumatized subjects functional interactions between the amygdala, perirhinal cortex and ACC/mPFC that occur during exposure to traumatic reminders may underlie adaptive/recuperative processes.

Drevets WC. · Section on Neuroimaging in Mood and Anxiety Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-2670, USA. · Ann N Y Acad Sci. · Pubmed #17872395 No free full text.

Abstract: The orbitofrontal cortex (OFC) has been implicated in the pathophysiology of major depression by evidence obtained using neuroimaging, neuropathologic, and lesion analysis techniques. The abnormalities revealed by these techniques show a regional specificity, and suggest that some OFC regions which appear cytoarchitectonically distinct also are functionally distinct with respect to mood regulation. For example, the severity of depression correlates inversely with physiological activity in parts of the posterior lateral and medial OFC, consistent with evidence that dysfunction of the OFC associated with cerebrovascular lesions increases the vulnerability for developing the major depressive syndrome. The posterior lateral and medial OFC function may also be impaired in individuals who develop primary mood disorders, as these patients show grey-matter volumetric reductions, histopathologic abnormalities, and altered hemodynamic responses to emotionally valenced stimuli, probabilistic reversal learning, and reward processing. In contrast, physiological activity in the anteromedial OFC situated in the ventromedial frontal polar cortex increases during the depressed versus the remitted phases of major depressive disorder to an extent that is positively correlated with the severity of depression. Effective antidepressant treatment is associated with a reduction in activity in this region. Taken together these data are compatible with evidence from studies in experimental animals indicating that some orbitofrontal and medial prefrontal cortex regions function to inhibit, while others function to enhance, emotional expression. Alterations in the functional balance between these regions and the circuits they form with anatomically related areas of the temporal lobe, striatum, thalamus, and brain stem thus may underlie the pathophysiology of mood disorders, such as major depression.

Cannon DM, Ichise M, Rollis D, Klaver JM, Gandhi SK, Charney DS, Manji HK, Drevets WC. · Molecular Imaging Branch, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA. · Biol Psychiatry. · Pubmed #17678634 No free full text.

Abstract: BACKGROUND: Altered serotonergic function is thought to play a role in the pathophysiology of major depressive episodes based upon evidence from neuroimaging, pharmacological, postmortem and genetic studies. It remains unclear, however, whether depressed samples that differ with respect to having shown a unipolar versus a bipolar illness course also would show distinct patterns of abnormalities within the serotonergic system. The current study compared serotonin transporter (5-HTT) binding between unipolar-depressives (MDD), bipolar-depressives (BD) and healthy-controls (HC) to assess whether the abnormalities in 5-HTT binding recently found in depressed subjects with BD extend to depressed subjects with MDD. METHODS: The 5-HTT binding-potential (BP) measured using positron emission tomography (PET) and [(11)C]DASB was compared between unmedicated, depressed subjects with MDD (n = 18) or BD (n = 18) and HC (n = 34). RESULTS: Relative to the healthy group both MDD and BD groups showed significantly increased 5-HTT BP in the thalamus (24%, 14%, respectively), insula (15%) and striatum (12%). The unipolar-depressives had elevated 5-HTT BP relative to both BD and HC groups in the vicinity of the periaqueductal gray (PAG, 20%, 22%, respectively). The bipolar-depressives had reduced 5-HTT BP relative to both HC and MDD groups in the vicinity of the pontine raphe nuclei. Depression-severity correlated negatively with 5-HTT BP in the thalamus in MDD-subjects. CONCLUSIONS: The depressed phases of MDD and BD both were associated with elevated 5-HTT binding in the insula, thalamus and striatum, but showed distinct abnormalities in the brainstem. The latter findings conceivably could underlie differences in the patterns of illness symptoms and pharmacological sensitivity observed between MDD and BD.

Hasler G, Fromm S, Alvarez RP, Luckenbaugh DA, Drevets WC, Grillon C. · Psychiatric University Hospital, 8091 Zurich, Switzerland. · J Neurosci. · Pubmed #17554005 links to  free full text

Abstract: The goal of this study was to compare cerebral blood flow (CBF) changes associated with phasic cued fear versus those associated with sustained contextual anxiety. Positron emission tomography images of CBF were acquired using [O-15]H2O in 17 healthy human subjects as they anticipated unpleasant electric shocks that were administered predictably (signaled by a visual cue) or unpredictably (threatened by the context). Presentation of the cue in either threat condition was associated with increased CBF in the left amygdala. A cue that specifically predicted the shock was associated with CBF increases in the ventral prefrontal cortex (PFC), hypothalamus, anterior cingulate cortex, left insula, and bilateral putamen. The sustained threat context increased CBF in the right hippocampus, mid-cingulate gyrus, subgenual PFC, midbrain periaqueductal gray, thalamus, bilateral ventral striatum, and parieto-occipital cortex. This study showed distinct neuronal networks involved in cued fear and contextual anxiety underlying the importance of this distinction for studies on the pathophysiology of anxiety disorders.

Furey ML, Pietrini P, Haxby JV, Drevets WC. · Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. · Neuropsychopharmacology. · Pubmed #17534379 links to  free full text

Abstract: The cholinergic neurotransmitter system is critically linked to cognitive functions including attention. The current studies were designed to evaluate the effect of a cholinergic agonist and an antagonist on performance during a selective visual attention task where the inherent salience of attended/unattended stimuli was modulated. Two randomized, placebo-controlled, crossover studies were performed, one (n=9) with the anticholinesterase physostigmine (1.0 mg/h), and the other (n=30) with the anticholinergic scopolamine (0.4 mc/kg). During the task, two double-exposure pictures of faces and houses were presented side by side. Subjects were cued to attend to either the face or the house component of the stimuli, and were instructed to perform a matching task with the two exemplars from the attended category. The cue changed every 4-7 trials to instruct subjects to shift attention from one stimulus component to the other. During placebo in both studies, reaction time (RT) associated with the first trial following a cued shift in attention was longer than RT associated with later trials (p<0.05); RT also was significantly longer when attending to houses than to faces (p<0.05). Physostigmine decreased RT relative to placebo preferentially during trials greater than one (p<0.05), with no change during trial one; and decreased RT preferentially during the attention to houses condition (p<0.05) vs attention to faces. Scopolamine increased RT relative to placebo selectively during trials greater than one (p<0.05), and preferentially increased RT during the attention to faces condition (p<0.05). The results suggest that enhancement or impairment of cholinergic activity preferentially influences the maintenance of selective attention (ie trials greater than 1). Moreover, effects of cholinergic manipulation depend on the selective attention condition (ie faces vs houses), which may suggest that cholinergic activity interacts with stimulus salience. The findings are discussed within the context of the role of acetylcholine both in stimulus processing and stimulus salience, and in establishing attention biases through top-down and bottom-up mechanisms of attention.

Blair KS, Smith BW, Mitchell DG, Morton J, Vythilingam M, Pessoa L, Fridberg D, Zametkin A, Sturman D, Nelson EE, Drevets WC, Pine DS, Martin A, Blair RJ. · Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-2670, USA. <> · Neuroimage. · Pubmed #17239620 links to  free full text

Abstract: In this study, we examined the impact of goal-directed processing on the response to emotional pictures and the impact of emotional pictures on goal-directed processing. Subjects (N=22) viewed neutral or emotional pictures in the presence or absence of a demanding cognitive task. Goal-directed processing disrupted the BOLD response to emotional pictures. In particular, the BOLD response within bilateral amygdala and inferior frontal gyrus decreased during concurrent task performance. Moreover, the presence of both positive and negative distractors disrupted task performance, with reaction times increasing for emotional relative to neutral distractors. Moreover, in line with the suggestion of the importance of lateral frontal regions in emotional regulation [Ochsner, K. N., Ray, R. D., Cooper, J. C., Robertson, E. R., Chopra, S., Gabrieli, J. D., et al. (2004). For better or for worse: neural systems supporting the cognitive down-and up-regulation of negative emotion. NeuroImage, 23(2), 483-499], connectivity analysis revealed positive connectivity between lateral superior frontal cortex and regions of middle frontal cortex previously implicated in emotional suppression [Beauregard, M., Levesque, J., and Bourgouin, P. (2001). Neural correlates of conscious self-regulation of emotion. J. Neurosci., 21 (18), RC165.; Levesque, J., Eugene, F., Joanette, Y., Paquette, V., Mensour, B., Beaudoin, G., et al. (2003). Neural circuitry underlying voluntary suppression of sadness. Biol. Psychiatry, 53 (6), 502-510.; Ohira, H., Nomura, M., Ichikawa, N., Isowa, T., Iidaka, T., Sato, A., et al. (2006). Association of neural and physiological responses during voluntary emotion suppression. NeuroImage, 29 (3), 721-733] and negative connectivity with bilateral amygdala. These data suggest that processes involved in emotional regulation are recruited during task performance in the context of emotional distractors.

Blair K, Marsh AA, Morton J, Vythilingam M, Jones M, Mondillo K, Pine DC, Drevets WC, Blair JR. · Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-2670, USA. · J Neurosci. · Pubmed #17079666 links to  free full text

Abstract: The ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortices (ACd) are considered important for reward-based decision making. However, work distinguishing their individual functional contributions has only begun. One aspect of decision making that has received little attention is that making the right choice often translates to making the better choice. Thus, response choice often occurs in situations where both options are desirable (e.g., choosing between mousse au chocolat or crème caramel cheesecake from a menu) or, alternatively, in situations where both options are undesirable. Moreover, response choice is easier when the reinforcements associated with the objects are far apart, rather than close together, in value. We used functional magnetic resonance imaging to delineate the functional roles of the vmPFC and ACd by investigating these two aspects of decision making: (1) decision form (i.e., choosing between two objects to gain the greater reward or the lesser punishment), and (2) between-object reinforcement distance (i.e., the difference in reinforcements associated with the two objects). Blood oxygen level-dependent (BOLD) responses within the ACd and vmPFC were both related to decision form but differentially. Whereas ACd showed greater responses when deciding between objects to gain the lesser punishment, vmPFC showed greater responses when deciding between objects to gain the greater reward. Moreover, vmPFC was sensitive to reinforcement expectations associated with both the chosen and the forgone choice. In contrast, BOLD responses within ACd, but not vmPFC, related to between-object reinforcement distance, increasing as the distance between the reinforcements of the two objects decreased. These data are interpreted with reference to models of ACd and vmPFC functioning.