Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression.

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.

The subgenual anterior cingulate cortex in mood disorders.

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.

Prefrontal cortical gamma-aminobutyric Acid levels in panic disorder determined by proton magnetic resonance spectroscopy.

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).

Neural basis of abnormal response to negative feedback in unmedicated mood disorders.

Depressed individuals show hypersensitivity to negative feedback during cognitive testing, which can precipitate subsequent errors and thereby impair a broad range of cognitive abilities. We studied the neural mechanisms underlying this feedback hypersensitivity using functional magnetic resonance imaging (fMRI) with a reversal learning task that required subjects to ignore misleading negative feedback on some trials. Thirteen depressed subjects with major depressive disorder (MDD), 12 depressed subjects with bipolar disorder (BD) and 15 healthy controls participated.

A neural model of voluntary and automatic emotion regulation: implications for understanding the pathophysiology and neurodevelopment of bipolar disorder.

The ability to regulate emotions is an important part of adaptive functioning in society. Advances in cognitive and affective neuroscience and biological psychiatry have facilitated examination of neural systems that may be important for emotion regulation. In this critical review we first develop a neural model of emotion regulation that includes neural systems implicated in different voluntary and automatic emotion regulatory subprocesses.

Reduced posterior hippocampal volume in posttraumatic stress disorder.

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.

Response to emotional expressions in generalized social phobia and generalized anxiety disorder: evidence for separate disorders.

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.

Neural response to catecholamine depletion in unmedicated subjects with major depressive disorder in remission and healthy subjects.

Context: The pathophysiologic mechanism of major depressive disorder (MDD) has been consistently associated with altered catecholaminergic function, especially with decreased dopamine neurotransmission, by various sources of largely indirect evidence. An instructive paradigm for more directly investigating the relationship between catecholaminergic function and depression has involved the mood response to experimental catecholamine depletion (CD).

Objectives: To determine whether catecholaminergic dysfunction represents a trait abnormality in MDD and to identify brain circuitry abnormalities involved in the pathophysiologic mechanism of MDD.

Neurophysiological responses to traumatic reminders in the acute aftermath of serious motor vehicle collisions using [15O]-H2O positron emission tomography.

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.

Plasma NPY concentrations during tryptophan and sham depletion in medication-free patients with remitted depression.

Background: Neuropeptide Y (NPY) and serotonergic systems have been implicated in the pathophysiology of depression but have not yet been linked together.

Methods: In a randomized, double-blind crossover study, 28 medication-free patients with remitted depression and 26 healthy control subjects underwent tryptophan depletion (TD) and sham depletion. Plasma NPY concentrations were determined at baseline and at +5, +7, and +24 h during TD and sham depletion, respectively.

The role of 5-HTTLPR in choosing the lesser of two evils, the better of two goods: examining the impact of 5-HTTLPR genotype and tryptophan depletion in object choice.

Rationale: The serotonin (5-HT) system is considered important for decision-making. However, its role in reward- and punishment-based processing has not yet been clearly determined.

Objectives: The present study examines the effect of 5-HTTLPR genotype and tryptophan depletion on reward- and punishment-related processing, using a task that considers decision-making in situations of subtlety of choice.

Serotonin-1A receptor imaging in recurrent depression: replication and literature review.

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.

The effect of acute tryptophan depletion on the neural correlates of emotional processing in healthy volunteers.

The processing of affective material is known to be modulated by serotonin (5-HT), but few studies have used neurophysiological measures to characterize the effect of changes in 5-HT on neural responses to emotional stimuli. We used functional magnetic resonance imaging to investigate the effect of acute tryptophan depletion, which reduces central 5-HT synthesis, on neural responses to emotionally valenced verbal stimuli. Though no participants experienced significant mood change, emotional information processing was substantially modified following 5-HT depletion.

Orbitofrontal cortex function and structure in depression.

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.

Distinct profiles of neurocognitive function in unmedicated unipolar depression and bipolar II depression.

Background: Studies have demonstrated neuropsychological deficits across a variety of cognitive domains in depression. Few studies have directly compared depressed subjects with major depressive disorder (MDD) and bipolar disorder (BD), and many are confounded by medication status across subjects. In this study, we compared the performance of unmedicated currently depressed MDD and BD groups on a battery of neuropsychological tests that included measures of risk taking and reflection impulsivity.

Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder.

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.

5-HT1A receptor binding in temporal lobe epilepsy patients with and without major depression.

Background: Major depressive disorder (MDD) is the most common comorbid psychiatric condition associated with temporal lobe epilepsy (TLE). Preclinical and clinical studies suggest that 5-HT(1A) receptors play a role in the pathophysiology of both TLE and MDD. There is preliminary evidence for an association between decreased 5-HT(1A) receptor binding in limbic brain areas and affective symptoms in TLE patients.

Cerebral blood flow in immediate and sustained anxiety.

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.

Serotonin 1A receptor reductions in postpartum depression: a positron emission tomography study.

Objective: To measure brain serotonin-1A (5HT1A) receptor binding potential (BP) in healthy and depressed postpartum women.

Design: 5HT1A receptor BP was measured with positron emission tomography by using [(11)C]WAY100635 a single time. Multivariate analysis of variance was used to determine depression effects on 5HT1A receptor BP in relevant brain regions.

Selective effects of cholinergic modulation on task performance during selective attention.

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.

Measurement of 5-HT1A receptor binding in depressed adults before and after antidepressant drug treatment using positron emission tomography and [11C]WAY-100635.

Objective: To assess effects of chronic antidepressant drug treatment on serotonin type-1A receptor (5-HT(1A)R) binding potential (BP) in major depressive disorder.

Methods: Depressed subjects (n = 27) were imaged using PET and [(11)C]WAY-100635 at baseline and following a median of 9.4 weeks of treatment with selective serotonin reuptake inhibitor or dual reuptake inhibitor antidepressant agents.

Reduced hippocampal 5HT1A PET receptor binding and depression in temporal lobe epilepsy.

Purpose: To study the relation of hippocampal 5HT1A receptor binding to symptoms of depression in patients with temporal lobe epilepsy. Depression is common in people with epilepsy, and reduced 5HT1A binding has been reported in patients with primary depressive disorders.

Methods: We studied 45 patients with temporal lobe epilepsy confirmed by ictal video-EEG recording.

Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy.

Context: Increasing evidence indicates that major depressive disorder (MDD) is associated with altered function of the major excitatory and inhibitory neurotransmitters glutamate and gamma-aminobutyric acid (GABA), respectively. A recently developed magnetic resonance spectroscopy method allows for reliable measurement of glutamate/glutamine (Glx) and GABA concentrations in prefrontal brain regions that have been implicated in the pathophysiologic mechanisms of MDD by studies using other neuroimaging and postmortem techniques.

Objective: To measure Glx and GABA levels in 2 regions of the prefrontal brain tissue in unmedicated adults with MDD.

Modulation of emotion by cognition and cognition by emotion.

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.