intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in people with mdd. the antidepressants that do not act through the monoamine system, such as tianeptine and opipramol, have been known for a long time. there have also been inconsistent findings with regard to levels of serum 5-hiaa, a metabolite of serotonin. experiments with pharmacological agents that cause depletion of monoamines have shown that this depletion does not cause depression in healthy people. another problem that presents is that drugs that deplete monoamines may actually have antidepressants properties. further, some have argued that depression may be marked by a hyperserotonergic state. already limited, the monoamine hypothesis has been further oversimplified when presented to the general public. receptor binding as of 2012, efforts to determine differences in neurotransmitter receptor expression or for function in the brains of people with mdd using positron emission tomography (pet) had shown inconsistent results. using the pet imaging technology and reagents available as of 2012, it appeared that the d1 receptor may be underexpressed in the striatum of people with mdd. 5-ht1a receptor binding literature is inconsistent; however, it leans towards a general decrease in the mesiotemporal cortex. 5-ht2a receptor binding appears to be unregulated in people with mdd. results from studies on 5-htt binding are variable, but tend to indicate higher levels in people with mdd. results with d2/d3 receptor binding studies are too inconsistent to draw any conclusions. evidence supports increased mao activity in people with mdd, and it may even be a trait marker (not changed by response to treatment). muscarinic receptor binding appears to be increased in depression, and, given ligand binding dynamics, suggests increased cholinergic activity. four meta analyses on receptor binding in depression have been performed, two on serotonin transporter (5-htt), one on 5-ht1a, and another on dopamine transporter (dat). one meta analysis on 5-htt reported that binding was reduced in the midbrain and amygdala, with the former correlating with greater age, and the latter correlating with depression severity. another meta-analysis on 5-htt including both post-mortem and in vivo receptor binding studies reported that while in vivo studies found reduced 5-htt in the striatum, amygdala and midbrain, post mortem studies found no significant associations. 5-ht1a was found to be reduced in the anterior cingulate cortex, mesiotemporal lobe, insula, and hippocampus, but not in the amygdala or occipital lobe. the most commonly used 5-ht1a ligands are not displaced by endogenous serotonin, indicating that receptor density or affinity is reduced. dopamine transporter binding is not changed in depression. emotional processing and neural circuits emotional bias people with mdd show a number of biases in emotional processing, such as a tendency to rate happy faces more negatively, and a tendency to allocate more attentional resources to sad expressions. depressed people also have impaired recognition of happy, angry, disgusted, fearful and surprised, but not sad faces. functional neuroimaging has demonstrated hyperactivity of various brain regions in response to negative emotional stimuli, and hypoactivity in response to positive stimuli. one meta analysis reported that depressed subjects showed decreased activity in the left dorsolateral prefrontal cortex and increased activity in the amygdala in response to negative stimuli. another meta analysis reported elevated hippocampus and thalamus activity in a subgroup of depressed subjects who were medication naive, not elderly, and had no comorbidities. the therapeutic lag of antidepressants has been suggested to be a result of antidepressants modifying emotional processing leading to mood changes. this is supported by the observation that both acute and subchronic ssri administration increases response to positive faces. antidepressant treatment appears to reverse mood congruent biases in limbic, prefrontal, and fusiform areas. dlpfc response is enhanced and amygdala response is attenuated during processing of negative emotions, the former or which is thought to reflect increased top down regulation. the fusiform gyrus and other visual processing areas respond more strongly to positive stimuli with antidepressant treatment, which is thought to reflect the a positive processing bias. these effects do not appear to be unique to serotonergic or noradrenergic antidepressants, but also occur in other forms of treatment such as deep brain stimulation. neural circuits one meta analysis of functional neuroimaging in depression observed a pattern of abnormal neural activity hypothesized to reflect an emotional processing bias. relative to controls, people with mdd showed hyperactivity of circuits in the salience network (sn), composed of the pulvinar nuclei, the insula, and the dorsal anterior cingulate cortex (dacc), as well as decreased activity in regulatory circuits composed of the striatum and dlpfc. rendition of the limbic-cortical-striatal-pallidal-thalamic circuit as described by drevets et al. 2008 a neuroanatomical model called the limbic-cortical model has been proposed to explain early biological findings in depression. the model attempts to relate specific symptoms of depression to neurological abnormalities. elevated resting amygdala activity was proposed to underlie rumination, as stimulation of the amygdala has been reported to be associated with the intrusive recall of negative memories. the acc was divided into pregenual (pgacc) and subgenual regions (sgacc), with the former being electrophysiologically associated with fear, and the latter being metabolically implicated in sadness in healthy subjects. hyperactivity of the lateral orbitofrontal and insular regions, along with abnormalities in lateral prefrontal regions was suggested to underlie maladaptive emotional responses, given the regions roles in reward learning. this model and another termed "the cortical striatal model", which focused more on abnormalities in the cortico-basal ganglia-thalamo-cortical loop, have been supported by recent literature. reduced striatal activity, elevated ofc activity, and elevated sgacc activity were all findings consistent with the proposed models. however, amygdala activity was reported to be decreased, contrary to the limbic-cortical model. furthermore, only lateral prefrontal regions were modulated by treatment, indicating that prefrontal areas are state markers (i.e.,. dependent upon mood), while subcortical abnormalities are trait markers (i.e., reflect a susceptibility). reward while depression severity as a whole is not correlated with a blunted neural response to reward, anhedonia is directly correlated to reduced activity in the reward system. the study of reward in depression is limited by heterogeneity in the definition and conceptualizations of reward and anhedonia. anhedonia is broadly defined as a reduced ability to feel pleasure, but questionnaires and clinical assessments rarely distinguish between motivational "wanting" and consummatory "liking". while a number of studies suggest that depressed subjects rate positive stimuli less positively and as less arousing, a number of studies fail to find a difference. furthermore, response to natural rewards such as sucrose does not appear to be attenuated. general affective blunting may explain "anhedonic" symptoms in depression, as meta analysis of both positive and negative stimuli reveal reduced rating of intensity. as anhedonia is a prominent symptom of depression, direct comparison of depressed with healthy subjects reveals increased activation of the subgenual anterior cingulate cortex (sgacc), and reduced activation of the ventral striatum, and in particular the nucleus accumbens (nacc) in response to positive stimuli. although the finding of reduced nacc activity during reward paradigms is fairly consistent, the nacc is made up of a functionally diverse range of neurons, and reduced blood-oxygen-level dependent (bold) signal in this region could indicate a variety of things including reduced afferent activity or reduced inhibitory output. nevertheless, these regions are important in reward processing, and dysfunction of them in depression is thought to underlie anhedonia. residual anhedonia that is not well targeted by serotonergic antidepressants is hypothesized to result from inhibition of dopamine release by activation of 5-ht2c receptors in the striatum. the response to reward in the medial orbitofrontal cortex (ofc) is attenuated in depression, while lateral ofc response is enhanced to punishment. the lateral ofc shows sustained response to absence of reward or punishment, and it is thought to be necessary for modifying behavior in response to changing contingencies. hypersensitivity in the lofc may lead to depression by producing a similar effect to learned helplessness in animals. elevated response in the sgacc is a consistent finding in neuroimaging studies using a number of paradigms including reward related tasks. treatment is also associated with attenuated activity in the sgacc, and inhibition of neurons in the rodent homologue of the sgacc, the infralimbic cortex (il), produces an antidepressant effect. hyperactivity of the sgacc has been hypothesized to lead to depression via attenuating the somatic response to reward or positive stimuli. contrary to studies of functional magnetic resonance imaging response in the sgacc during tasks, resting metabolism is reduced in the sgacc. however, this is only apparent when correcting for the prominent reduction in sgacc volume associated with depression; structural abnormalities are evident at a cellular level, as neuropathological studies report reduced sgacc cell markers. the model of depression proposed from these findings by drevets et al. suggests that reduced sgacc activity results in enhanced sympathetic nervous system activity and blunted hpa axis feedback. activity in the sgacc may also not be causal in depression, as the authors of one review that examined neuroimaging in depressed subjects during emotional regulation hypothesized that the pattern of elevated sgacc activity reflected increased need to modulate automatic emotional responses in depression. more extensive sgacc and general prefrontal recruitment during positive emotional processing was associated with blunted subcortical response to positive emotions, and subject anhedonia. this was interpreted by the authors to reflect a downregulation of positive emotions by the excessive recruitment of the prefrontal cortex. neuroanatomy while a number of neuroimaging findings are consistently reported in people with major depressive disorder, the heterogeneity of depressed populations presents difficulties interpreting these findings. for example, averaging across populations may hide certain subgroup related findings; while reduced dlpfc activity is reported in depression, a subgroup may present with elevated dlpfc activity. averaging may also yield statistically significant findings, such as reduced hippocampal volumes, that are actually present in a subgroup of subjects. due to these issues and others, including the longitudinal consistency of depression, most neural models are likely inapplicable to all depression. structural neuroimaging gmv reductions in mdd and bd meta analyses performed using seed-based d mapping have reported grey matter reductions in a number of frontal regions. one meta analysis of early onset general depression reported grey matter reductions in the bilateral anterior cingulate cortex (acc) and dorsomedial prefrontal cortex (dmpfc). one meta analysis on first episode depression observed distinct patterns of grey matter reductions in medication free, and combined populations; medication free depression was associated with reductions in the right dorsolateral prefrontal cortex, right amygdala, and right inferior temporal gyrus; analysis on a combination of medication free and medicated depression found reductions in the left insula, right supplementary motor area, and right middle temporal gyrus. another review distinguishing medicated and medication free populations, albeit not restricted to people with their first episode of mdd, found reductions in the combined population in the bilateral superior, right middle, and left inferior frontal gyrus, along with the bilateral parahippocampus. increases in thalamic and acc grey matter was reported in the medication free and medicated populations respectively. a meta analysis performed using "activation likelihood estimate" reported reductions in the paracingulate cortex, dacc and amygdala. using statistical parametric mapping, one meta analysis replicated previous findings of reduced grey matter in the acc, medial prefrontal cortex, inferior frontal gyrus, hippocampus and thalamus; however reductions in the ofc and ventromedial prefrontal cortex grey matter were also reported. two studies on depression from the enigma consortium have been published, one on cortical thickness, and the other on subcortical volume. reduced cortical thickness was reported in the bilateral ofc, acc, insula, middle temporal gyri, fusiform gyri, and posterior cingulate cortices, while surface area deficits were found in medial occipital, inferior parietal, orbitofrontal and precentral regions. subcortical abnormalities, including reductions in hippocampus and amygdala volumes, which were especially pronounced in early onset depression. mdd is associated with reduced fa in the alic and genu/body of the cc multiple meta analysis have been performed on studies assessing white matter integrity using fractional anisotropy (fa). reduced fa has been reported in the corpus callosum (cc) in both first episode medication naive, and general major depressive populations. the extent of cc reductions differs from study to study. people with mdd who have not taken antidepressants before have been reported to have reductions only in the body of the cc and only in the genu of the cc. on the other hand, general mdd samples have been reported to