ventral anterior cingulate cortex (vACC) signals when things go well for us (it signals well-being: gaining safety, social and biological rewards, reaching a comfort zone or goals, feeling liked and accepted, satisfied, at ease), so it is underactive in depression. vACC induces serotonin release in DRN so has causal effect on feeling fine when upregulated and feeling down if suppressed. In contrast pregenual ACC (pgACC) is overactive in negative feelings of regret, when missing someone or feeling sorry. In addition worries and anxiety stimulate dorsal ACC (dACC) which further inhibits vACC.  dACC warns us about potential dangers and negative consequences such as pain, loss, harm. dACC signals to rest of brain when things go bad or wrong for us (i.e. getting negative feedback, rejection). So dACC and pgACC are overstimulated in depression.

DLPFC is known to be deactivated in depression because its neuronal spines get smaller and the lack of dopamine lowers DLPFC function. Thus the cognitive capability to learn new things and find out new ways to get out of current suboptimal state (pain, hurt, loss or failures) is weaker in depression. (when feeling down because of circumstances or because of drop in dopamine and serotonin signaling in brain).

more in :   https://www.scienceopen.com/document/vid/13e62385-1fb0-4a49-9a5d-e435baa5b95e;jsessionid=5oMo6amOM2jzVEuMv6V-7oa1.master:so-app1-prd?0

Thanks a lot Dr. Renzo Bianchi and Dr. Karin Vadovicova for the immense help and direction.

My impression is that dACC, dlPFC, and vmPFC are all abnormal in depression, but in unique ways:

-vmPFC tends to be hyperactive in depression, and successful remission is associated with deactivation. vmPFC is also activated during transient sadness and rumination. (Mayberg et al., 1999; Goldapple et al., 2004; Koenigs & Grafman 2009)

-dlPFC, by contrast, is hypoactive in depression, which may be related to impaired regulatory control over emotion (Hamilton et al., 2012)

-I find the dACC results harder to put into context for depression, but it definitely pops up just as often!

Dear Hemanth, the impact on the various regions mentioned above is also determined by the type and severity of depression (as well as co morbid disorders, such as anxiety/Cardiovascular disease etc),. i wrote a comprehensive review on treatment resistant MDD. I have provided a small excerpt below which I hope will be of help in shedding further light

"Morphological pathology.

Current evidence, in conjunction with post mortem evidence indicates thatwhite matter lesions and reductions in grey matter are present in patients with Depression. White matter lesions can be a normal aspect of the aging process (Peters, 2006), or related to pathophysiological processes, such as diabetes or cerebrovascular disease risk factors (Schmidt et al., 1992).  The relationship between Depression and white matter lesions is not well known, however de Groot et al. (2000) established that the degree of severity of subcortical white matter lesions  was related to late onset Depression and depressive symptoms in non- demented elderly people (n=1077).  The presence of severe subcortical white matter lesions in elderly people may be a risk factor for Depression. The evidence of grey matter reductions in the hippocampal region in Depressed patients has been previously noted (Rajkowska, 2000).  Bremner et al. (2000) conducted a study on MDD patients  in remission, (n=16) versus matched nondepressed controls (n=16). The MDD group presented with a 19% smaller left hippocampal volume than the controls, which was significant.  The amygdala, caudate, frontal lobe, and temporal lobe regions were similar in volume between the MDD group and the controls (Bremner et al., 2000). In TRD patients, (n=20) versus healthy controls, (n=20) Shah et al. (2002) found attenuated grey matter density in the left temporal cortex, inclusive of the left hippocampal region, as well as signs of attenuation in the right hippocampus. The possible role of subcortical white matter lesions and the reduction in volume of the hippocampus and left temporal cortex needs to be investigated. It is proposed that the severity of attenuation may not be fully reversible and this could contribute to the development of TRD.

Brain structure and connectivity pathology.

Dysfunction within the limbic-cortical network is associated with Depression.  Attenutation occurs in the dorsal neocortical regions, whilst increased activity occurs in ventral limbic and paralimbic regions. The Dorsal medial frontal (Mf9), Rostral anterior cingulate (rcG24) and the medial orbital frontal cortex (Of11) have been identified as critical regions for the integration and communication between systems involved in self- referential processes, (Drevets, Price & Furey, 2008; Mayberg, 1997, 2003; Pizzagalli, 2011) and play a key role in Depression. Pathology in the  Medial Prefrontal Cortex (MPFC) in conjunction with areas such as the DLPFC, the Anterior Cingulate cortex (ACC) which is inclusive of regions such as the rostral, dorsal, and posterior cingulate cortex) , the anterior temporal, entorhinal and parahippocampal cortices have been identified (Drevets et al, 2008). The subcallosal cingulate gyrus (SBCG), inclusive of Brodmann area 25 and parts of 24 and 32 and in particular the rostral anterior cingulate(RACC) have been an increasing focus of attention in imaging studies due to their dysfunctionality in Depression and TRD (Hamani et al, 2011; Lozano et al, 2012; Pizzagalli, 2011). “The rostral cingulate cortex is thought to mediate between the dorsal (dorsolateral pre-frontal cortex, dorsal anterior cingulate cortex, inferior parietal cortex, and striatum) and ventral (paralimbic cortex, subcortical hypothalamus, insula, subgenual cingulate cortex, and brainstem) areas of limbic-cortical dysregulation in depression” (Hauptman et al., 2008, p. E3). The importance of the RACC, (rcG24, 24a) as well as the SBCG in Depression and TRD requires further investigation, as these regions may provide biomarkers for those at risk of developing TRD. (Hauptman et al., 2008; Lozano et al., 2008; Mayberg, 2003;Pizzagalli, 2011 ).

Higher levels of activity  in the HPA Axis are known to be a feature of depressive disorders, (Gotlib et al., 2008).with the 5-HTTPLR being associated with amygdala activation (Aleman, Swart & van Rijn, 2008; Munafo, Brown  & Hariri, 2008).  Johnstone et al. (2007) in an fMRI study discovered that dysfunctional recruitment of the right prefrontal cortex (RPFC) and the attenuated recruitment of left lateral-ventromedial prefrontal regions (LLVMPFC), (which control amygdala activity) occurred in patients with MDD.  Rotenberg (2008) reviewed findings in relation to brain lateralization of function in Depression, and found that activity was attenuated in the left hemisphere, with dysfunctional processing occurring in the right.  These findings are consistent with the general finding that top down regulation of the HPA Axis is dysfunctional in Depression (Rotenberg, 2008). The relationships between anatomical areas and metabolic processes in Depression may occur on a continuum of severity, with TRD being most severe pathophysiologically.

 Hope this helps!

Some antidepressants (SSRI and other strong serotonergic drugs) decrease metabolism (acitivity?) in prefrontal cortex, some increase it (mirtazapine, other dopaminergic-noradrenergic drugs). I think in SSRI it's comes from agonism of 5-HT2c receptors on GABA interneurons > this cause decrease in firing of VTA dopamine neurons that projects to prefrontal cortex. That's why this drugs can cause some anhedonia, amotivational syndrome, sexual dysfunction ("rontal lobe syndrome").

Utilizing 

Utilizing EEG actuarials, I find consistent left prefrontal functioning in the low frequency theta range among my depressed patients. Often the right prefrontal readings are in the beta/gamma range. Among normal to positive mood individuals I find comparatively little difference between the right and left prefrontal frequencies. Other research seems to suggest that consistent beta/gamma registration are associated with cortical thinning a finding frequently noted among bipolar patients. I have more success recommending atypical mood stabilizers, e.g. lamotrigene for depressed patients or a combination of low dose SSRI's and lamotrigene which circumvents the tendency for SSRI's to lower glutamate levels which promotes amotivational anhedonia.

Dear Cheryl, that was quiet explanatory.  Thanx tons for the wonderful help

Thank you, Dr. Vadovicova. You answer was very illuminating. I have read many papers that focus of prefrontal areas, such as those responsible for mood and emotion regulation (subgenual cingulate, VACC), reward processing (OFC), self-referential processes and autobiographical memory (MPFC), as well as executive functioning (DLPFC), that are dysfunctional in depression.

However, your remark on the role of the DACC in situations that signal stress and threat and its implication on the genesis of depression wasn't something that I had stumbled on and I found it quite fascinating.

After all DACC is implicated in a wide variety of functions that require attention and cognitive control and is also a crucial structure for the formation on cortico-striatal loops during development (if I am not mistaken).

It is also a major node of the Salience network, that acts as an attentional switch between the DMN and CEN.

Given its wide connections, any abnormal firing of this structure could produce an effect on many other networks in the brain.

Do you know if DACC is impaired in other disorders, such as PTSD and anxiety?

I think the differentiation of functions in the PFC has an implication for the etiology and symptomatology of depression. As we know, depression is a heterogenous disease that manifests itself differently in individuals. There is anxious depression, characterized by a lack of sleep, loss of appetite and high anxiety levels.

But there is depression that presents itself with symptoms which are completely opposite - like hunger, constant sleepiness, anhedonia, social and emotional withdrawal.

I am not including all the other types of depression - such as manic, seasonal, cyclothymia, etc., just for simplicity.

Just between those two broad types of depression, we can see that we are probably looking and two different disorders, with different etiologies and different dysfunctional circuits.

The role of DACC is not clearly defined, as it is activated by many tasks and probably undergoes changes during development.

Depression is characterized by global network dysfunctions (poor deactivation of DMN), caused by hyper and hypo-activations in network nodes. Also it is often triggered by a traumatic life event and the probability for suffering from depression raises with the exposure to such events. However, it is clear that there are protecting factors (genetic and environmental) that provide resilience to an individual who is exposed to a traumatic event. The factors are expressed in the strength, integrity and connectivity of functional networks.

An insult or dysfunction in any crucial nodes of these networks is expected to have lasting and profound consequences on brain function. Perhaps the DACC is one such dysfunctional node.

That are just my thoughts on it. Back to reading ;)