ReviewNeuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders
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)
Neuroimaging studies of mood disorders
Biol Psychiatry
(2000)- et al.
Lithium at 50: have the neuroprotective effects of this unique cation been overlooked?
Biol Psychiatry
(1999) - et al.
Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression
Biol Psychiatry
(1999) - et al.
Treatment of psychiatric illness by stereotactic cingulotomy
Biol Psychiatry
(1987) Are different parts of the extended amygdala involved in fear versus anxiety?
Biol Psychiatry
(1998)Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression
Prog Brain Res
(2000)- et al.
Emotional memory: what does the amygdala do?
Curr Biol
(1997) - et al.
Sex-related difference in amygdala activity during emotionally influenced memory storage
Neurobiol Learn Mem
(2001) - et al.
Brain systems mediating aversive conditioning: an event-related fMRI study
Neuron
(1998) - et al.
Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study
Neuron
(1998)