Review
Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders

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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.

Introduction

Major depressive episodes (MDE) are several-week- to several-year-long periods in which conscious mental activity is dominated by persistent dysphoric emotions and thoughts, which coexist with disturbances of motivated and psychomotor behavior, sleep, appetite, energy, and libido [1]. Despite the application of the descriptive term ‘depression’, the dominant emotional symptoms of MDE can instead include anxiety, irritability, or anhedonia (inability to experience pleasure or reward) [1]. Such episodes may occur secondary to specific medical or neurological illnesses, other psychiatric disorders, or pharmacological agents. They may also arise in the absence of medical or psychiatric antecedents as primary, idiopathic disorders, termed ‘major depressive disorder’ (MDD) when only depressive episodes occur, or ‘bipolar disorder’ (BD; also known as ‘manic-depressive illness’) when manic episodes also occur. The most common mood disorder, MDD, rivals hypertension as the most frequently treated illness in primary health care, and is a leading cause of disability worldwide [2].

The etiology and pathophysiology of MDE remain poorly understood. Twin, adoption and family studies indicate that both genetic and environmental factors contribute to the risk for developing MDD and BD [1]. The environmental factors commonly proposed to be involved in the pathogenesis of MDE are psychosocial stressors, although causal links between stressors and MDE have been difficult to establish. Patients with recurrent MDE usually conclude that their pattern of depressive symptoms is not coupled to stressful life situations (with the exception of childbirth, as the post-partum period is the epoch of greatest risk in females). Nevertheless, stress plays a prominent role in the clinical phenomenology of MDD and BD, as ordinary work-demands and interpersonal interactions are perceived as being exceedingly stressful during MDE.

Primary mood disorders (in which the onset of MDD or BD temporally precedes that of other major medical or psychiatric disorders) have been associated with a variety of neuroendocrine, neurochemical, neurophysiological, and neuromorphometric abnormalities [1]. It is not known, however, whether these abnormalities cause a vulnerability to abnormal mood episodes, or whether they are compensatory changes to other pathogenic processes or sequelae of recurrent illness. The neurobiological systems affected by these abnormalities nevertheless suggest intriguing hypotheses for the development of the cognitive-emotional manifestations of mood disorders, which are discussed in this review.

Section snippets

Neuroimaging studies of mood disorders

Neuroimaging technology has afforded the ability to investigate neurophysiological, neuroanatomical and neurochemical correlates of mood disorders in vivo 1., 3.. The results of such studies are being complimented by converging data from post mortem studies, some of which have been specifically guided by neuroimaging data, to elucidate interactions between abnormalities of brain structure and function in primary mood disorders [3]. These experimental approaches are also being combined to

Elevated physiological activity in the amygdala: implications for emotional behavior

Abnormal elevations of resting CBF and glucose metabolism in the amygdala have been consistently reported in depressives who have familial MDD or melancholic subtype, and have been inconsistently reported in BD (Fig. 1, Fig. 23., 14.). The magnitude of this abnormality as measured by positron emisson tomography (PET) has ranged from 5% to 7% (Fig. 2), which, when corrected for spatial-resolution effects, would reflect an increase in the actual CBF and metabolism of about 50 to 70% 14., 20..

Implications for the pathogenesis of depressive thought content

Neuroimaging, electrophysiological and lesion analysis studies in humans and experimental animals have demonstrated that the amygdala is involved in the recall of emotional or arousing memories 28., 29., 30.. In humans, bursts of electroencephalographic (EEG) activity have been recorded in the amygdala during recollection of specific emotional events [31]. Moreover, electrical stimulation of the human amygdala can evoke emotional experiences (especially fear or anxiety) [32] and recall of

Role of the prefrontal cortex in modulating emotional behavior

Multiple areas of the medial and orbital PFC appear to play roles in modulating emotional behavior. These structures are thought to participate in modifying behavioral responses based upon competing or changing reinforcement contingencies 47., 48., 49.. Some of these areas also participate in modulating autonomic and endocrine responses to stress 50., 51., 52., 53••., 54••.. These areas share extensive, reciprocal projections with the amygdala, through which the amygdala modulates PFC neuronal

The orbital and ventrolateral prefrontal cortex

In the posterior and lateral orbital cortex, the anterior insula, and the ventrolateral PFC (VLPFC), metabolic activity is abnormally elevated in resting, unmedicated subjects with primary MDD [3]. Physiological activity also increases in these areas during experimentally induced anxiety states in healthy subjects and in subjects with obsessive-compulsive disorder (OCD), simple phobia or panic disorder 6., 23., 75.. Although CBF and metabolism increase in these areas in the depressed relative

Dysfunction of neural systems involved in processing motivation and reward

Another core feature of MDE is a pervasive absence of behavioral incentive. This is clinically manifested by apathy, anhedonia, amotivation, and loss of interest in hobbies, socialization, work, food, and sex. This condition renders positive life-events ineffective at altering the depressed state and causes potentially enjoyable or rewarding activities to be curtailed or engaged in only through extraordinary effort.

This symptom cluster appears to be phenomenologically related to the putative

Conclusions

The neuroimaging and neuropathological data recently acquired in studies of primary mood disorders have identified both structural and functional abnormalities in the orbital and medial PFC, the amygdala, and related parts of the striatum and thalamus. The areas where such studies demonstrate persistent metabolic abnormalities, reductions in cortex volume, and histopathological changes in primary mood disorders appear to modulate emotional behavior and stress responses, based upon evidence from

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • •of special interest

  • ••of outstanding interest

References (106)

  • K Rasmussen et al.

    Single unit activity of locus coeruleus neurons in the freely moving cat. I. During naturalistic behaviors and in response to simple and complex stimuli

    Brain Res

    (1986)
  • B Ferry et al.

    Role of norepinephrine in mediating stress hormone regulation of long-term memory storage: a critical involvement of the amygdala

    Biol Psychiatry

    (1999)
  • R.J Frysztak et al.

    The effect of medial frontal cortex lesions on cardiovascular conditioned emotional responses in the rat

    Brain Res

    (1994)
  • J.L Price et al.

    Networks related to the orbital and medial prefrontal cortex, a substrate for emotional behavior?

    Prog Brain Res

    (1996)
  • G.R Leichnetz et al.

    The efferent projections of the medial prefrontal cortex in the squirrel monkey (Saimiri sciureus)

    Brain Res

    (1976)
  • A.R Damasio et al.

    Individuals with sociopathic behavior caused by frontal damage fail to respond autonomically to social stimuli

    Behav Brain Res

    (1990)
  • R.J Dolan et al.

    Neural activation during covert processing of positive emotional facial expressions

    Neuroimage

    (1996)
  • F Schneider et al.

    Mood effects on limbic blood flow correlate with emotional self-rating: a PET study with oxygen-15 labeled water

    Psychiatry Res

    (1995)
  • B.J Everitt et al.

    Interactions between the amygdala and ventral striatum in stimulus–reward associations: studies using a second-order schedule of sexual reinforcement

    Neuroscience

    (1989)
  • R Spanagel et al.

    The dopamine hypothesis of reward: past and current status

    Trends Neurosci

    (1999)
  • E.A Kiyatkin et al.

    Fluctuations in nucleus accumbens dopamine during cocaine self-administration behavior: an in vivo electrochemical study

    Neuroscience

    (1995)
  • W.C Drevets et al.

    Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria

    Biol Psychiatry

    (2001)
  • W Schultz

    Dopamine neurons and their role in reward mechanisms

    Curr Opin Neurobiol

    (1997)
  • P Redgrave et al.

    Is the short-latency dopamine response too short to signal reward error?

    Trends Neurosci

    (1999)
  • S Murase et al.

    Prefrontal cortex regulates burst firing and transmitter release in rat mesolimbic dopamine neurons studied in vivo

    Neurosci Lett

    (1993)
  • W.C Drevets et al.

    Depression, mania and related disorders

  • Murray C.J.L., Lopex A.D., World Health Organization Monograph. World Health Organization,...
  • R.S Duman et al.

    A molecular and cellular theory of depression

    Arch Gen Psychiatry

    (1997)
  • W.C Drevets et al.

    Reciprocal suppression of regional cerebral blood flow during emotional versus higher cognitive processes: implications for interactions between emotion and cognition

    Cognit Emotion

    (1998)
  • D Ongur et al.

    Glial reduction in the subgenual prefrontal cortex in mood disorders

    Proc Natl Acad Sci USA

    (1998)
  • W.C Drevets et al.

    Subgenual prefrontal cortex abnormalities in mood disorders

    Nature

    (1997)
  • K.R Krishnan et al.

    Neuroanatomical substrates of depression in the elderly

    Eur Arch Psychiatry Clin Neurosci.

    (1993)
  • H.S Mayberg et al.

    Selective hypometabolism in the inferior frontal lobe in depressed patients with Parkinson's disease

    Ann Neurol

    (1990)
  • S.E Starkstein et al.

    Affective disorders and cerebral vascular disease

    Br J Psychiatry

    (1989)
  • H.A Ring et al.

    Depression in Parkinson's disease. A positron emission study

    Br J Psychiatry

    (1994)
  • W.C Drevets et al.

    A functional anatomical study of unipolar depression

    J Neurosci

    (1992)
  • J Corsellis et al.

    Neuropathological observations on yttrium implants and on the undercutting in the orbito-frontal areas of the brain

  • W.J.H Nauta et al.

    Afferent and efferent relationships of the basal ganglia

  • R Newcombe

    The lesion in stereotactic suscaudate tractotomy

    Br J Psychiatry

    (1975)
  • G Knight

    Stereotactic tractotomy in the surgical treatment of mental illness

    J Neurol Neurosurg Psychiatry

    (1965)
  • J.M Links et al.

    Influence of spatially heterogeneous background activity on ‘hot object’ quantitation in brain emission computed tomography

    J Comput Assist Tomogr

    (1996)
  • J.E LeDoux et al.

    Local cerebral blood flow increases during auditory and emotional processing in the conscious rat

    Science

    (1983)
  • Abercrombie H.C., Larson C.L., Ward R.T., Metabolic rate in the amygdala predicts negative affect and depression...
  • W.C Drevets et al.

    Regional blood flow changes in response to phobic anxiety and habituation

    J Cereb Blood Flow Metab

    (1995)
  • W.C Drevets

    Prefrontal cortical–amygdalar metabolism in major depression

    Ann NY Acad Sci

    (1999)
  • Nofzinger E.A., Nichols T.E., Meltzer C.C., Price J., Steppe D.A., Miewald J.M., Kupfer D.J., Moore R.Y., Changes in...
  • T Canli et al.

    Event-related activation in the human amygdala associates with later memory for individual emotional experience

    J Neurosci

    (2000)
  • J.E LeDoux

    The Emotional Brain

    (1996)
  • E Halgren

    The amygdala contribution to emotion and memory: current studies in humans

  • P Gloor et al.

    The role of the limbic system in experiential phenomena of temporal lobe epilepsy

    Ann Neurol

    (1982)
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