Anatomical and functional correlates in major depressive disorder: The contribution of neuroimaging studies

Several studies suggested the neural networks modulating aspects of emotional behaviour to be implicated in the pathophysiology of mood disorders. 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 MPFC and related limbic and striato-pallido-thalamic structures organize emotional expression. The aim of this paper is to review the contribution of the most relevant studies with single photon emission tomography (SPECT), positron emission tomography (PET) and magnetic resonance imaging (MRI) to the understanding of pathophysiology of major depressive disorder (MDD), with particular focus on the reversibility of functional correlates with treatment.     

Volumetric MRI studies of mood disorders: do they distinguish unipolar and bipolar disorder?

The authors reviewed magnetic resonance imaging volumetric imaging results in major mood disorders, particularly comparing similarities and differences from studies of bipolar disorder and unipolar major depression. Abnormalities of cerebral brain regions appear inconsistently in mood disorders and, when present, typically consist of decreased frontal or prefrontal cortical volumes in both unipolar depression and bipolar disorder. In contrast, subcortical and medial temporal abnormalities are more commonly observed and are different between these two major classes of affective illness. Specifically, whereas structural enlargement of the basal ganglia and amygdala have been observed in bipolar disorder, in unipolar depression, these structures appear to be smaller in patients than healthy subjects. These findings suggest that affective illnesses may share in common an underdeveloped or atrophied prefrontal region, leading to loss of cortical modulation of limbic emotional networks. The effect of this loss results in unipolar depression or cycling (mania with depression) depending on the abnormalities of the subcortical structures involved. The cerebellum may also play a role in the presentation of mood disorders. This hypothesis remains speculative as much more research is needed to specifically examine how morphometric brain abnormalities translate into the neurophysiologic deficits that produce mood disorders.     

Reciprocal modulation and attenuation in the prefrontal cortex: an fMRI study on emotional-cognitive interaction

Everyday and clinical experience demonstrate strong interactions between emotions and cognitions. Nevertheless the neural correlates underlying emotional-cognitive interaction remain unclear. Using event-related fMRI, we investigated BOLD-signal increases and decreases in medial and lateral prefrontal cortical regions during emotional and non-emotional judgment of photographs taken from the International Affective Picture System (IAPS). Emotional and non-emotional judgment conditions were compared to each other as well as with baseline allowing for distinction between relative signal changes (comparison between conditions) and true signal changes (referring to baseline). We have found that: (1) both emotional and non-emotional judgment of IAPS pictures were characterized by signal increases in ventrally and dorsally located lateral prefrontal cortical areas and concurrent signal decreases in ventro- and dorsomedial prefrontal cortex; (2) direct comparison between emotional and non-emotional judgment showed relative signal increases in ventro- and dorsomedial prefrontal cortex, and in contrast, relative signal increases were detected in ventrally and dorsally located lateral prefrontal cortical areas when comparing non-emotional to emotional judgment; and (3) as shown in separate comparisons with baseline, these relative signal changes were due to smaller signal decreases in ventro- and dorsomedial prefrontal cortex and smaller signal increases in ventrally and dorsally located lateral prefrontal cortical areas during emotional judgment. Therefore, the emotional load of a cognitive task lead to both less deactivation of medial prefrontal regions and, at the same time, less activation of lateral prefrontal regions. Analogous patterns of reciprocal modulation and attenuation have previously been described for other cortical regions such as visual and auditory areas. Reciprocal modulation and attenuation in medial and lateral prefrontal cortex might constitute the neurophysiologic basis for emotional-cognitive interaction as observed in both healthy and psychiatric subjects.     

The neural basis of mood-congruent processing biases in depression

BACKGROUND: Mood-congruent processing biases are among the most robust research findings in neuropsychological studies of depression. Depressed patients show preferential processing of negatively toned stimuli across a range of cognitive tasks. The present study aimed to determine whether these behavioral abnormalities are associated with specific neural substrates. METHODS: Ten depressed patients and 11 healthy control subjects underwent scanning during performance of an emotional go/no-go task using functional magnetic resonance imaging. The task allowed comparison among neural response to happy, sad, and neutral words, in the context of these words as targets (ie, stimuli to which subjects were required to make a motor response) or distractors (ie, stimuli to which the motor response was withheld). RESULTS: Depressed patients showed attenuated neural responses to emotional relative to neutral targets in ventral cingulate and posterior orbitofrontal cortices. However, patients showed elevated responses specific to sad targets in rostral anterior cingulate extending to anterior medial prefrontal cortex. Unlike controls, patients showed differential neural response to emotional, particularly sad, distractors in the lateral orbitofrontal cortex. CONCLUSIONS: These findings suggest a distinct neural substrate for mood-congruent processing biases in performance. The medial and orbital prefrontal regions may play a key role in mediating the interaction between mood and cognition in affective disorder.     

Neuroplasticity in mood disorders

Neuroimaging and neuropathological studies of major depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities of brain structure in areas of the prefrontal cortex, amygdala, striatum, hippocampus, parahippocampal gyrus, and raphe nucleus. These structural imaging abnormalities persist across illness episodes, and preliminary evidence suggests they may in some cases arise prior to the onset of depressive episodes in subjects at high familial risk for MDD. In other cases, the magnitude of abnormality is reportedly correlated with time spent depressed. Postmortem histopathological studies of these regions have shown abnormal reductions of synaptic markers and glial cells, and, in rare cases, reductions in neurons in MDD and BD. Many of the regions affected by these structural abnormalities show increased glucose metabolism during depressive episodes. Because the glucose metabolic signal is dominated by glutamatergic transmission, these data support other evidence that excitatory amino acid transmission is elevated in limbic-cortical-striatal-pallidal-thalamic circuits during depression. Some of the subject samples in which these metabolic abnormalities have been demonstrated were also shown to manifest abnormally elevated stressed plasma cortisol levels. The co-occurrence of increased glutamatergic transmission and Cortisol hypersecretion raises the possibility that the gray matter volumetric reductions in these depressed subjects are partly accounted for by processes homologous to the dendritic atrophy induced by chronic stress in adult rodents, which depends upon interactions between elevated glucocorticoid secretion and N-meihyl-D-aspartate (NMDA)-glutamate receptor stimulation. Some mood-stabilizing and antidepressant drugs that exert neurotrophic effects in rodents appear to reverse or attenuate the gray matter volume abnormalities in humans with mood disorders. These neurotrophic effects may be integrally related to the therapeutic effects of such agents, because the regions affected by structural abnormalities in mood disorders are known to play major roles in modulating the endocrine, autonomic, behavioral, and emotional experiential responses to stressors.     

Midline and intralaminar thalamic connections with the orbital and medial prefrontal networks in macaque monkeys

Although the midline and intralaminar thalamic nuclei (MITN) were long believed to project "nonspecifically," they are now known from rat studies to have restricted connections to the prefrontal cortex. This has not been studied thoroughly in primates, however, and it is not known how MITN are associated with the "orbital" and "medial" prefrontal networks. This study examined the connections of MITN in cynomolgus monkeys (Macaca fascicularis). Experiments with retrograde and anterograde tracer injections into the orbital and medial prefrontal cortex (OMPFC) showed that MITN are strongly connected with the medial prefrontal network. The dorsal nuclei of the midline thalamus, including the paraventricular (Pa) and parataenial nuclei (Pt), had heavy connections with medial network areas 25, 32, and 14c in the subgenual region. Areas 13a and 12o, which are associated with both networks, were strongly connected with the Pt and the central intermedial nucleus, respectively. Otherwise, orbital network areas had weak connections with MITN. Anterograde tracer injections into the dorsal midline thalamus resulted in heavy terminal labeling in the medial prefrontal network, most notably in areas ventral to the genu of the corpus callosum (25, 32, and 14c), but also in adjacent areas (13a and 13b). Retrograde tracer injection into the dorsal midline labeled similar areas. The medial network, particularly the subgenual region, is involved in visceral and emotional control and has been implicated in mood disorders. The strong connections between the subgenual cortex and the Pa provide a pathway through which stress signals from the Pa may influence these prefrontal circuits.     

L’analyse des visages dans la dépression

Depression is a mood disorder associated with impairments in the processing of social and emotional messages. This article presents a review of the literature of behavioral, clinical, pharmacological, and neuro-imaging studies dealing with a particular kind of stimuli: faces. Overall, these studies report on the existence of deficits in the processing of emotional faces in patients with major depressive disorder, especially for happiness and sadness. At the behavioral level, studies show a reduction in the recognition of positive expressions together with an enhancement in the recognition of negative emotions, in particular sadness. Attentional and memory biases have also been observed with these stimuli. At the clinical level, impairments in facial expression processing seem to improve following antidepressant treatment. However, subtle deficit may remain, which might also be present in subjects at risk for major depressive disorder. Pharmacological studies suggest that anomalies in the serotonin signalling may be involved. Finally, these deficits have been associated with structural and functional anomalies in a network of brain regions including the amygdala, prefrontal cortex (medial, orbitofrontal and anterior cingulate) and hippocampus. Studies investigating the neural dynamics of facial expression processing in depression are consistent with anomalies in the early stages of attentional orienting toward emotional stimuli in depressed patients. Recent advances in pharmacogenetics and genetic neuro-imaging relating functional and pharmacological anomalies with cognitive or emotional disorders observed in depressed patients offer new promising perspectives.     

Neural bases of reappraisal regulatory effect on negative emotion in high reappraisers

Previous studies have reported that individual differences in reappraisal use are associated with particular patterns of neural activity. We hypothesized that if ’high reappraisers’ (individuals who use reappraisal well in a behavioral experiment) completed two training sessions, they would exhibit more reliable patterns of neural activity related to cognitive reappraisal. In the present study, 13 high reappraisers were selected from 27 healthy volunteers through an initial behavioral experiment (first training) followed by a functional MRI experiment (second training). Emotional images selected from the International Affective Picture System were used for both the behavioral and functional MRI sessions of the experiment. The behavioral results revealed that reappraisal reduced subjective unpleasantness. The functional MRI results revealed that the cognitive reappraisal used by high reappraisers decreased the activation of emotion-responsive regions, including the amygdala, insula, and cingulate gyrus, and increased the activation of regulation-related regions, including the inferior prefrontal cortex, orbital prefrontal cortex, and dorsal medial prefrontal cortex. These findings suggest the involvement of inferior orbital and dorsal medial prefrontal cortex in constructing reappraisal strategies that modulate activity in emotion-processing systems.     

Bases neurales de l’apathie dans les maladies dégénératives

Apathy is widely recognized as a lack of motivation, which expresses through the cognitive, behavioral and emotional dimensions of living. It is described within several neuropsychiatric syndromes such as degenerative disorder and is associated with poorer outcomes. In order to better understand the underpinnings of apathy and to develop specific treatment strategies, much research has been conducted to define its neural bases. In the present review, perfusion, metabolic, pathologic and functional results of apathy neural bases in Alzheimer's and Parkinson's diseases are displayed. Methods and strategies to control for confounding factors such as depression, cognitive impairments and other behavioral disorders are described. Results are not strictly identical between disorders and even within disorders. Variation of methods employed on assessment tools and control for confounding factors such as cognitive disorders, depression, other behavioral disorders and medical treatment is thought to be the main reason for this discrepancy. However, it seems that the inferior prefrontal cortex, especially the orbitofrontal cortex, the lateral prefrontal cortex and the anterior cingulate are of particular interest. The second part of the review discusses the literature in these three areas in conditional learning essentially via the reward characteristic encoding, auto-initiated and perseverance behaviors and emotional experience and its regulation.     

Using fMRI to dissociate sensory encoding from cognitive evaluation of heat pain intensity

Neuroimaging studies of painful stimuli in humans have identified a network of brain regions that is more extensive than identified previously in electrophysiological and anatomical studies of nociceptive pathways. This extensive network has been described as a pain matrix of brain regions that mediate the many interrelated aspects of conscious processing of nociceptive input such as perception, evaluation, affective response, and emotional memory. We used functional magnetic resonance imaging in healthy human subjects to distinguish brain regions required for pain sensory encoding from those required for cognitive evaluation of pain intensity. The results suggest that conscious cognitive evaluation of pain intensity in the absence of any sensory stimulation activates a network that includes bilateral anterior insular cortex/frontal operculum, dorsal lateral prefrontal cortex, bilateral medial prefrontal cortex/anterior cingulate cortex, right superior parietal cortex, inferior parietal lobule, orbital prefrontal cortex, and left occipital cortex. Increased activity common to both encoding and evaluation was observed in bilateral anterior insula/frontal operculum and medial prefrontal cortex/anterior cingulate cortex. We hypothesize that these two regions play a crucial role in bridging the encoding of pain sensation and the cognitive processing of sensory input.     

Telomere length as a predictor of emotional processing in the brain

Shorter telomere length (TL) has been associated with the development of mood disorders as well as abnormalities in brain morphology. However, so far, no studies have considered the role TL may have on brain function during tasks relevant to mood disorders. In this study, we examine the relationship between TL and functional brain activation and connectivity, while participants (n = 112) perform a functional magnetic resonance imaging (fMRI) facial affect recognition task. Additionally, because variation in TL has a substantial genetic component we calculated polygenic risk scores for TL to test if they predict face‐related functional brain activation. First, our results showed that TL was positively associated with increased activation in the amygdala and cuneus, as well as increased connectivity from posterior regions of the face network to the ventral prefrontal cortex. Second, polygenic risk scores for TL show a positive association with medial prefrontal cortex activation. The data support the view that TL and genetic loading for shorter telomeres, influence the function of brain regions known to be involved in emotional processing.     

Differences between effects of psychological versus pharmacological treatments on functional and morphological brain alterations in anxiety disorders and major depressive disorder: a systematic review

The most prevalent mental disorders, anxiety and mood disorders, are associated with both functional and morphological brain changes that commonly involve the ‘fear network’ including the (medial) prefrontal cortex, hippocampus and amygdala. Patients suffering from anxiety disorders and major depressive disorder often show excessive amygdala and reduced prefrontal cortex functioning. It is, however, still unclear whether these brain abnormalities disappear or diminish following effective treatment. This review aims to compare the effects of psychotherapy and pharmacotherapy on functional and morphological brain measures in these disorders. Sixty-three studies were included, 30 investigating psychotherapy effects and 33 investigating pharmacotherapy effects. Despite methodological differences, results suggest a functional normalization of the ‘fear network’. Pharmacotherapy particularly decreases over-activity of limbic structures (bottom-up effect) while psychotherapy tends to increase activity and recruitment of frontal areas (top-down effect), especially the anterior cingulate cortex. Additionally, pharmacotherapy, but not psychotherapy, has been associated with morphological changes, depending on the disorder. These findings suggest that both types of treatments normalize (functional) brain abnormalities each in specific ways.     

Evaluating Prefrontal Activation and Its Relationship with Cognitive and Emotional Processes by Means of Hemoencephalography (HEG)

The main aim of this study is to determine the efficacy of the method of diagnosis known as hemoencephalography (HEG), which measures hemodynamic changes in the prefrontal cortex by determining differences in oxygen flow to show patterns of neuronal activity. Of the 5 tests designed for this purpose, 2 are strictly cognitive, while the other 3 have primarily emotional or sensitive content. The tests were applied to a sample of 70 university students. The Wilcoxon nonparametric signed rank test was applied to test the paired differences between the HEG baseline result and the HEG result of the task. Results show, first, that the HEG method successfully determines oxygen flow to the prefrontal cortex and clearly differentiates the subject's baseline from HEG activation during the task (Wilcoxon, p < .05); second, that HEG results vary depending on the type of activity, whether cognitive (low emotional load) or emotional (high emotional load) in such a way that cognitive areas, those located higher in the cortex (dorsolateral prefrontal), show less activity during emotional tests and more activity during cognitive tests, thus associating higher areas (dorsolateral prefrontal) with cognition and deeper areas (medial temporal, medial prefrontal, and cingulate) with emotion. The HEG procedure is effective in detecting states or situations of ailment or suffering not always accompanied by evident external manifestations. Furthermore, the procedure can differentiate between cognitive and emotional processing. The HEG method can help diagnosis in clinical settings due to its ability to detect painful-feeling processing independently of both body and verbal language.     

Right brain,left brain in depressive disorders: Clinical and theoretical implications of behavioral,electrophysiological and neuroimaging findings

The right and left side of the brain are asymmetric in anatomy and function. We review electrophysiological (EEG and event-related potential), behavioral (dichotic and visual perceptual asymmetry), and neuroimaging (PET, MRI, NIRS) evidence of right-left asymmetry in depressive disorders. Recent electrophysiological and fMRI studies of emotional processing have provided new evidence of altered laterality in depressive disorders. EEG alpha asymmetry and neuroimaging findings at rest and during cognitive or emotional tasks are consistent with reduced left prefrontal activity in depressed patients, which may impair downregulation of amygdala response to negative emotional information. Dichotic listening and visual hemifield findings for non-verbal or emotional processing have revealed abnormal perceptual asymmetry in depressive disorders, and electrophysiological findings have shown reduced right-lateralized responsivity to emotional stimuli in occipitotemporal or parietotemporal cortex. We discuss models of neural networks underlying these alterations. Of clinical relevance, individual differences among depressed patients on measures of right-left brain function are related to diagnostic subtype of depression, comorbidity with anxiety disorders, and clinical response to antidepressants or cognitive behavioral therapy.     

Topographic organization of connections between the hypothalamus and prefrontal cortex in the rhesus monkey

Prefrontal cortices have been implicated in autonomic function, but their role in this activity is not well understood. Orbital and medial prefrontal cortices receive input from cortical and subcortical structures associated with emotions. Thus, the prefrontal cortex may be an essential link for autonomic responses driven by emotions. Classic studies have demonstrated the existence of projections between prefrontal cortex and the hypothalamus, a central autonomic structure, but the topographic organization of these connections in the monkey has not been clearly established. We investigated the organization of bidirectional connections between these areas in the rhesus monkey by using tracer injections in orbital, medial, and lateral prefrontal areas. All prefrontal areas investigated received projections from the hypothalamus, originating mainly in the posterior hypothalamus. Differences in the topography of hypothalamic projection neurons were related to both the location and type of the target cortical area. Injections in lateral eulaminate prefrontal areas primarily labeled neurons in the posterior hypothalamus that were equally distributed in the lateral and medial hypothalamus. In contrast, injections in orbitofrontal and medial limbic cortices labeled neurons in the anterior and tuberal regions of the hypothalamus and in the posterior region. Projection neurons targeting orbital limbic cortices were more prevalent in the lateral part of the hypothalamus, whereas those targeting medial limbic cortices were more prevalent in the medial hypothalamus. In comparison to the ascending projections, descending projections from prefrontal cortex to the hypothalamus were highly specific, originating mostly from orbital and medial prefrontal cortices. The ascending and descending connections overlapped in the hypothalamus in areas that have autonomic functions. These results suggest that specific orbitofrontal and medial prefrontal areas exert a direct influence on the hypothalamus and may be important for the autonomic responses evoked by complex emotional situations. J. Comp. Neurol. 398:393–419, 1998. © 1998 Wiley-Liss, Inc.     

Mood alters amygdala activation to sad distractors during an attentional task.

BACKGROUND: A behavioral hallmark of mood disorders is biased perception and memory for sad events. The amygdala is poised to mediate internal mood and external event processing because of its connections with both the internal milieu and the sensory world. There is little evidence showing that the amygdala's response to sad sensory stimuli is functionally modulated by mood state, however. METHODS: We investigated the impact of mood on amygdala activation evoked by sad and neutral pictures presented as distractors during an attentional oddball task. Healthy adults underwent functional magnetic resonance imaging during task runs that were preceded by sad or happy movie clips. Happy and sad mood induction was conducted within-subjects on consecutive days in counterbalanced order. RESULTS: Amygdala activation to sad distractors was enhanced after viewing sad movies relative to happy ones and was correlated with reaction time costs to detect attentional targets. The activation was higher in female subjects in the right hemisphere. The anterior cingulate, ventromedial and orbital prefrontal cortex, insula, and other posterior regions also showed enhanced responses to sad distractors during sad mood. CONCLUSIONS: These findings reveal brain mechanisms that integrate emotional input and current mood state, with implications for understanding cognitive distractibility in depression.     

Stroop performance in bipolar disorder: further evidence for abnormalities in the ventral prefrontal cortex

OBJECTIVES: Bipolar patients are impaired in Stroop task performance, a measure of selective attention. Structural and functional abnormalities in task-associated regions, in particular the prefrontal cortex (PFC), have been reported in this population. We aimed to examine the relationship between functional abnormalities, impaired task performance and the severity of depressive symptoms in bipolar patients. METHODS: Remitted bipolar patients (n = 10; all medicated), either euthymic or with subsyndromal depression, and age-matched control subjects (n = 11) viewed 10 alternating blocks of incongruent Stroop and control stimuli, naming the colour of the ink. Neural response was measured using functional magnetic resonance imaging. We computed between-group differences in neural response and within-group correlations with mood and anxiety. RESULTS: There were no significant between-group differences in task performance. During the Stroop condition, controls demonstrated greater activation of visual and dorsolateral and ventrolateral prefrontal cortical areas; bipolar patients demonstrated relative deactivation within orbital and medial prefrontal cortices. Depression scores showed a trend towards a negative correlation with the magnitude of orbitofrontal cortex deactivation in bipolar patients, whereas state anxiety correlated positively with activation of dorsolateral PFC and precuneus in controls. CONCLUSIONS: Our findings confirm previous reports of decreased ventral prefrontal activity during Stroop task performance in bipolar patients, and suggest a possible negative correlation between this and depression severity in bipolar patients. These findings further highlight the ventromedial PFC as a potential candidate for illness related dysfunction in bipolar disorder.     

Neural correlates of affective processing in response to sad and angry facial stimuli in patients with major depressive disorder

Mood abnormalities related to major depressive disorder (MDD) seem to result from disturbances in pathways connecting the fronto-limbic and subcortical, both regions known to be involved in the processing of emotional information. Using functional magnetic resonance imaging (fMRI), we measured neural responses to viewing images of sad, angry and neutral faces in 21 patients with MDD and 15 healthy controls. When shown pictures of sad faces, patients with MDD relative controls showed decreased activations bilaterally in the dorsolateral prefrontal cortex, inferior orbitofrontal cortex (OFC), medial OFC, caudate, and hippocampus. We also found significant group differences under the angry face condition, bilaterally, in the inferior OFC and medial OFC areas. Our findings indicate that decreased activations in the fronto-limbic and subcortical regions in response to affectively negative stimuli may be associated with pathophysiology of MDD.     

Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates

The prefrontal cortex has been implicated in a variety of cognitive and executive processes, including working memory, decision-making, inhibitory response control, attentional set-shifting and the temporal integration of voluntary behaviour. This article reviews current progress in our understanding of the rodent prefrontal cortex, especially evidence for functional divergence of the anatomically distinct sub-regions of the rat prefrontal cortex. Recent findings suggest clear distinctions between the dorsal (precentral and anterior cingulate) and ventral (prelimbic, infralimbic and medial orbital) sub-divisions of the medial prefrontal cortex, and between the orbitofrontal cortex (ventral orbital, ventrolateral orbital, dorsal and ventral agranular cortices) and the adjacent medial wall of the prefrontal cortex. The dorso-medial prefrontal cortex is implicated in memory for motor responses, including response selection, and the temporal processing of information. Ventral regions of the medial prefrontal cortex are implicated in interrelated 'supervisory' attentional functions, including attention to stimulus features and task contingencies (or action-outcome rules), attentional set-shifting, and behavioural flexibility. The orbitofrontal cortex is implicated in lower-order discriminations, including reversal of stimulus-reward associations (reversal learning), and choice involving delayed reinforcement. It is anticipated that a greater understanding of the prefrontal cortex will come from using tasks that load specific cognitive and executive processes, in parallel with discovering new ways of manipulating the different sub-regions and neuromodulatory systems of the prefrontal cortex.     

Reductions in phenomenological, physiological and attentional indices of depressive mood after 2 Hz rTMS over the right parietal cortex in healthy human subjects

Research into emotion and emotional disorders by repetitive transcranial magnetic stimulation (rTMS) has largely been restricted to the prefrontal regions. There is, however, also evidence for the parietal cortex being implicated in emotional (dys-)functioning. Here we used rTMS to investigate a role of the right parietal cortex in depression. In a placebo-controlled design, 2 Hz rTMS at 90% of the individual motor threshold (MT) was applied over the right parietal cortex of eight healthy subjects for 20 min continuously. Effects on mood, autonomic activity and motivated attention were investigated. Significant reductions in depressive mood were observed immediately following and 30 min after stimulation. Moreover, these findings were objectified by a concurring pattern of autonomically mediated changes in the attentional processing of angry facial expressions. These data suggest a role for the right parietal cortex in affective brain circuits regulating phenomenological, physiological and attentional aspects of depressive functioning.