Converging evidence for the proposed framework comes from research in neuroscience and psychiatry. First, that successful treatment of depression seems to be conditional upon a concomitant volume increase in the adult hippocampus [29
]. Second, that electrically stimulating prefrontal regions implicated in associative processing alleviates depression symptoms [30
]. These two lines of findings will be elaborated next.
Associative processing and the ability to learn associations between previously unrelated items have been attributed primarily to structures of the MTL, particularly the hippocampus [31
], and the parahippocampal cortex in the MTL [4
]. Several recent studies have demonstrated both functional disturbances and volume reduction of the hippocampal formation in depression [34
]. Importantly, the severity of depressive symptoms is directly increased by such hippocampal structural disturbances [36
], as well as with a decrease in hippocampal activity [37
]. Additionally, successful antidepressant treatment can halt the progression of hippocampal damage [35
], and is associated with recovery of hippocampal volume [38
]. These results demonstrate the close relationship between depression and the functional and structural integrity of the MTL.
One of the most effective medications for treating depression relies on selective serotonin reuptake inhibitors (SSRI) such as fluoxetine (e.g., Prozac). In recent years it has been observed that SSRIs have a direct influence on adult neurogenesis [39
], particularly in the dentate gyrus within the hippocampus [35
]. Importantly serotonin has also been shown to play a central role in learning and memory formation [41
], which is widely believed to be mediated by the MTL and to rely on associations.
Adult hippocampal neurogenesis is still a new and controversial topic. Nevertheless, the possibilities, especially for our understanding of mental disorder, are profound and thus warrant further attention. There is accumulating evidence that hippocampal neurogenesis is not merely an epiphenomenon of the SSRIs' chemical effect, but actually has a causal effect on the success of SSRI treatment: The newly generated neurons have direct effect on the state of depression, whereby successful antidepressant treatment is conditional upon a successful hippocampal neurogenesis. Indeed, blocking hippocampal neurogenesis substantially reduces the efficiency of antidepressants [29
Computational modeling work [42
] shows that such neurogenesis could be critical for establishing new contexts for behavior in memory, and such contexts, we have argued [4
], are based on associative representations and activations. Indeed, associative long-term potentiation (LTP) can be induced in new neurons more readily than in older neurons [43
], and the magnitude of LTP can be modulated by serotonin [44
]. These converging findings, together, provide a potential mechanism for mediating the increase in associative processing with neurogenesis and SSRI-based therapy (see Box 1
Box 1. Some qualifications regarding hippocampal neurogenesis and depression
First, it is worth noting that loss of neurogenesis seems neither sufficient nor necessary for developing depression symptoms, but neurogenesis can nevertheless be critical for treatment success. Within the framework proposed here, one can imagine a thinking pattern that is broadly associative because the infrastructure that affords broad associative processing is in place, and can remain so even without neurogenesis. However, for a depressed individual such infrastructure presumably needs to be rebuilt, which can only be done with new neurons and new connections. Furthermore, the birth of new hippocampal neurons will exert no behavioral and clinical influence if these new neurons do not integrate and survive; neurogenesis without associative activity that will promote the survival of the new neurons will not be sufficient for alleviating the symptoms of mood disorders, according to this proposal. Therefore, in thinking about the reciprocal relation between neurogenesis and associative activation, neurogenesis can be seen as providing the medium, but this medium needs to be used by broadly associative activation to survive and generate the webs of associations that mediate the non-ruminative activation required for a healthy mood.
Second, neurogenesis is not always beneficial, as for example is the case in temporal lobe epilepsy [75
], where new cells might migrate incorrectly. Third, depression might be accompanied by cognitive impairments that might go beyond associative processing. For example, the MPFC has been implicated in thinking about self and in reward related processing. However, these other functions rely on associative processing; for example, rumination is associated with self-reflections and reward relies on learned associations. Finally, this is not to suggest that all types of depression can be treated in the same fashion [76
], or that all stem from hippocampal/prefrontal processes.
In a second line of research that is related to the proposal presented here, findings indicate that electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) exhibit anti-depressant effects [45
]. How these treatments exert their effects remains an open question. Recently, Mayberg and colleagues [30
] demonstrated successfully that electrically stimulating the deep Brodmann area 25 () can alleviate the symptoms of major depression patients. Area 25, the subgenual cingulate, is situated in the MPFC, which is activated in associative cognitive tasks (). One possible mechanism by which such deep brain stimulation (DBS) in MPFC can affect depression symptoms might be through the regulation of inhibition. Our memory consists of a web of representations that are connected with each other, within several degrees of separation. While this makes for an efficient framework for encoding and retrieval, it is crucial that the activation of one mental representation (e.g., a chair, when we see an image of a chair) would not result in the activation of representations that are irrelevant in the specific context. Inhibition is proposed to play this central role of limiting the extent of related representations that are activated at a given instance (e.g., seeing an image of a chair would activate “chair,” “table” and perhaps “legs,” but should not activate “chicken legs”), thereby giving rise to associations and predictions that are most relevant. In the context of inhibition and mood, an abnormally activated MPFC, as in depression [47
], can result in over-inhibition from MPFC to MTL, which might then significantly constrain the scope of associative activation in MTL [48
]. Excessive inhibition from MPFC could explain the inability of depressed patients to disengage from debilitating rumination (). Indeed, inhibitory dysfunction can exacerbate depression through rumination [49
]. DBS might therefore operate by bringing MPFC back to its normal level of activity (), which brings back inhibition to a level where MTL can resume broader associative activation.
- Converging activations in MPFC
It is particularly interesting to note that the pattern of brain activity typically observed at “rest” (i.e., default brain activity) in healthy individuals differs in patients with depression symptoms. The MPFC and the neighboring anterior cingulate cortex in particular exhibit abnormal activity during periods of “rest” in depressed individuals compared with non-depressed individuals [50
], and activation in these regions seems to predict treatment success [51
]. Furthermore, the structure, function and connectivity of the same default/associative network () are compromised in depression [52
], and the integrity of this network is improved with antidepressants-related clinical improvement [53
]. A therapeutic approach that promotes activation of those regions via intense associative processing can be seen as a cognitively generated analogue of DBS, and thus might elicit similar mood benefits. While cognitive, endogenous triggering of associations and regulation of inhibition is likely to be less intense than direct electrical deep stimulation, it is expected to be considerably more focused on the presumed circuitry of interest. In addition, DBS is primarily applied in cases of severe major depressive disorder (MDD), when most other methods have failed. It is possible that for less severe cases of depression, a reduced intensity of stimulation in the same area will suffice for observing a significant symptomatic improvement.