Hippocampal neuroplasticity in major depressive disorder.

Please cite this article in press as: Malykhin NV, Coupland NJ. Hippocampal neuroplasticity in major depressive disorder. Neuroscience (2015), http:// dx.doi.org/10.1016/j.neuroscience.2015.04.047

Neuroscience xxx (2015) xxx–xxx

REVIEW HIPPOCAMPAL NEUROPLASTICITY IN MAJOR DEPRESSIVE DISORDER N. V. MALYKHIN a,b,c* AND N. J. COUPLAND b

Contents Introduction 00 HC volume changes in MDD: focus on HC subregions 00 Neuroplasticity of HC subfields: insights from preclinical and post-mortem studies 00 Measurement of HC subfields in vivo using high-field MRI 00 Metabolic and white matter changes in the HC associated with MDD 00 Functional specialization of the HC 00 HC neuroplasticity and memory function in MDD 00 Conclusion 00 Acknowledgments 00 References 00

a

The Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada b Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada c Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada

Abstract—One of the most replicated findings has been that hippocampus volume is decreased in patients with major depressive disorder (MDD). Recent volumetric magnetic resonance imaging (MRI) studies suggest that localized differences in hippocampal volume may be more prominent than global differences. Preclinical and postmortem studies in MDD indicated that different subfields of the hippocampus may respond differently to stress and may also have differential levels of plasticity in response to antidepressant treatment. Advances in highfield MRI allowed researchers to visualize and measure hippocampal subfield volumes in MDD patients in vivo. The results of these studies provide the first in vivo evidence that hippocampal volume reductions in MDD are specific to the cornu ammonis and dentate gyrus hippocampal subfields, findings that appear, on the surface, consistent with preclinical evidence for localized mechanisms of hippocampal neuroplasticity. In this review we discuss how recent advances in neuroimaging allow researchers to further understand hippocampal neuroplasticity in MDD and how it is related to antidepressant treatment, memory function, and disease progression. This article is part of a Special Issue entitled: Hippocampus. Ó 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

INTRODUCTION Major depressive disorder (MDD) is a major challenge for society affecting 2–5% of the population and is a major cause of disability worldwide (Murray and Lopez, 2013). At least 30% of patients do not remit after a year of multiple antidepressant trials (Warden et al., 2007) and this overestimates positive outcomes (Frank et al., 1991). The causes of MDD remain uncertain, although a number of factors are known to increase risk including abuse during childhood and chronic stress as an adult (Paolucci et al., 2001; Widom et al., 2007; Bradley et al., 2008; Danese et al., 2009; Risch et al., 2009). The welldescribed effects of stress on risk of developing MDD have been supported by findings that there are abnormalities in the hypothalamic–pituitary–adrenal (HPA) axis in patients with MDD, and this may impact the release of glucocorticoids. That the HPA axis is dysregulated is evidenced by studies examining cortisol hypersecretion, dexamethasone non-suppression, and exaggerated responses to dex amethasone–corticotropin-releasing hormone challenges (Barden, 2004). In particular several components of the HPA axis have been implicated in the development of MDD, specifically the hippocampus (HC), amygdala and prefrontal cortex (PFC) (Pittenger and Duman, 2008; Ulrich-Lai and Herman, 2009). One of the most replicated findings has been that HC volume is decreased in patients with MDD, with the degree of change having been confirmed by several meta-analyses of magnetic resonance imaging (MRI) studies (Videbech and Ravnkilde, 2004; McKinnon et al., 2009). Based on preclinical studies, several mechanisms, including neuronal and glial remodeling or loss,

Key words: hippocampus, memory, major depressive disorder, antidepressant treatment, dentate gyrus, cornu ammonis.

*Correspondence to: N. V. Malykhin, Research Transition Facility 1069, University of Alberta, Edmonton, Alberta T6G 2V2, Canada. Tel: +1-(780)-248-1120; fax: +1-(780)-492-8259. E-mail address: [email protected] (N. V. Malykhin). Abbreviations: BDNF, brain-derived neurotrophic factor; CA, childhood adversity; CA1-3, cornu ammonis; Cho, choline; DG, dentate gyrus; DTI, diffusion tensor imaging; FA, fractional anisotropy; Glx, glutamate–glutamine; GR, glucocorticoid receptor; HC, hippocampus; HPA, hypothalamic–pituitary–adrenal axis; MDD, major depressive disorder; MI, myo-inositol; MRI, magnetic resonance imaging; NAA, N-acetyl-aspartate; PFC, prefrontal cortex; SSRI, selective serotonin reuptake inhibitors; UF, uncinate fascicles. http://dx.doi.org/10.1016/j.neuroscience.2015.04.047 0306-4522/Ó 2015 IBRO. Published by Elsevier Ltd. All rights reserved. 1

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N. V. Malykhin, N. J. Coupland / Neuroscience xxx (2015) xxx–xxx

neuronal death and suppressed adult neurogenesis, apparently involving elevated levels of glucocorticoids, have been suggested as potential causative factors in low HC volume (Sapolsky, 2000; Cze´h and Lucassen, 2007). MRI studies have consistently shown that the reductions in HC volumes in MDD have been associated with episode recurrence (MacQueen et al., 2003; McKinnon et al., 2009), history of childhood maltreatment (Vythilingam et al., 2002; Frodl et al., 2010) deficits in memory performance (Lee et al., 2012). Only a few MRI studies have analyzed the HC in medication-free MDD (MacQueen et al., 2003; Posener et al., 2003; Vythilingam et al., 2004; Frodl et al., 2010) while the majority of studies included participants on antidepressant treatment (Videbech and Ravnkilde, 2004; McKinnon et al., 2009). Several genetic associations have been suggested to play an important role with associations between mood, memory and HC volume (Eker et al., 2011; Kohli et al., 2011; Price et al., 2013; Dunn et al., 2015). There is preclinical evidence that stress and glucocorticoids negatively impact HC neuroplasticity, neuronal survival, and glial survival (Cze´h and Lucassen, 2007; Pittenger and Duman, 2008). Other preclinical studies have suggested that antidepressants have stress-protective effects on HC neuroplasticity (Pittenger and Duman, 2008), and such a positive effect also appears to occur in humans (Boldrini et al., 2009). Therefore, these findings might suggest that stress, possibly acting via glucocorticoids, may negatively affect HC neuronal plasticity, which in turn is reflected in decreased HC volumes (Dranovsky and Hen, 2006). This information may also suggest that one effect of antidepressant treatment would be to reverse some of these changes. Clearly, if this were known to be the case it could open up significant new possibilities for both the etiology and treatment of MDD. However, the information from most previous MRI studies has been inadequate to allow measurement of any such effects (McKinnon et al., 2009). In this review we discuss how recent advances in neuroimaging allow researchers to further understand HC neuroplasticity in MDD and how it is related to antidepressant treatment, memory function, and disease progression.

HC VOLUME CHANGES IN MDD: FOCUS ON HC SUBREGIONS Most MRI studies in MDD reported differences in global HC volume (Videbech and Ravnkilde, 2004; McKinnon et al., 2009). However, the HC can be further subdivided along its longitudinal axis into ventral–dorsal (rodent) and head–body–tail (human) subregions (Fig. 1). A new development in volumetric MRI analysis has been to segment the HC head, body and tail, and/or to include the tail in volume calculations (Maller et al., 2006; Malykhin et al., 2007). These anatomically and functionally different subregions (Duvernoy, 2005) are not uniformly affected by disease (Maller et al., 2007; Bouchard et al., 2008; Malykhin et al., 2008a,b). Until recently it was unclear whether HC subregions are differentially affected in

MDD, or in association with specific risk factors or treatment. Neumeister and colleagues (2005) first reported that posterior HC (posterior to the head; i.e. body + tail), rather than the HC head was smaller bilaterally in remitted, recurrent MDD (Table 1). Maller and colleagues (2007) found that low HC volume was limited primarily to the tail in treatment resistant MDD, particularly in females, with more anterior (i.e. body + head) changes also present in males. Next MacQueen and colleagues (2008) reported that MDD participants who met criteria for clinical remission at 8 weeks of treatment had larger pre-treatment HC body/tail volumes bilaterally than those who did not achieve remission. de Geus and colleagues (2007), using voxel-based morphometry and a twin design, reported a volume reduction in the left posterior HC region in monozygotic co-twins discordant for having high environmental risk factors for depression. Posener and colleagues (2003), using high-dimensional brain mapping, did not find differences in total HC volume between MDD and controls, but did report localized differences in HC surface deformation. The most prominent inward deformation of the HC was located in the head (asymmetrically more prominent on the right) and tail, whereas the most prominent outward deformation was in the HC body. Vythilingam and colleagues (2004) did not find significant differences in HC subregion volumes between untreated MDD and healthy subjects. In our own cross-sectional study (Malykhin et al., 2010b) we reported that MDD patients had a smaller HC tail bilaterally and unilaterally smaller right HC and right head volumes, compared with controls. A history of multiple types of child abuse was associated with more extensive and bilateral reductions in HC head and tail volume, but also with more recurrent depression. Despite the increasing number of MRI studies in MDD, only a few have included medication-free participants and with sometimes brief washout periods, such that data on medication effects were not considered adequate for meta-analysis (McKinnon et al., 2009). Several studies have suggested that lower total HC volume in MDD predicts worse treatment outcomes (Vakili et al., 2000; Frodl et al., 2008; MacQueen et al., 2008), but only one study has demonstrated that global HC volume increases after treatment (Frodl et al., 2008). A significant increase in the left HC volume was shown in participants who continued antidepressants for 3 years, but was not dependent on clinical response (Frodl et al., 2008) and changes after not been shown after shorter treatment duration (Vythilingam et al., 2004). In our study (Malykhin et al., 2010b) we did not confirm that unmedicated participants were more vulnerable to low HC head or tail volumes; although differences from controls were marginally more significant, unmedicated and medicated MDD did not differ. However, we demonstrated that long-term antidepressant treatment may affect total HC volume in MDD with the most notable difference in HC body, which was increased above that in controls, as well as unmedicated MDD. Although interpretation of this finding was limited by the cross-sectional design, the medicated patients were symptomatic and the data appear more consistent with evidence that increased HC volume



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Fig. 1. (a) Intraventricular aspect of the hippocampus (HC) (from Duvernoy, 2005): 1, HC body; 2, HC head; 3, HC tail; 4, fimbria; 5, crus of fornix; 6, subiculum; 7, splenium of the corpus callosum; 8, calcar avis; 9, collateral trigone; 10, collateral eminence; 11, uncal recess of the temporal horn. (b) 3D reconstruction of HC subfields from a healthy subject.

with long-term treatment may not depend on clinical response (Frodl et al., 2008) than evidence that low HC volume predicts subsequent adverse outcome (Vakili et al., 2000; Frodl et al., 2008; MacQueen et al., 2008). The median 3 years of treatment in our study was also consistent with the time course of volume changes in longitudinal follow up (Frodl et al., 2008). In agreement with several studies (Frodl et al., 2002; Lange and Irle, 2004; Hastings et al., 2004) we did not find correlations between HC total or subregion volumes and current symptom severity. Despite inconsistencies between sampling, methodology and findings, results to date suggest that localized differences in HC volume particularly in the posterior HC may be more prominent than global differences.

NEUROPLASTICITY OF HC SUBFIELDS: INSIGHTS FROM PRECLINICAL AND POST-MORTEM STUDIES The major subfields across the HC transverse axis are the cornu ammonis (CA1-3), dentate gyrus (DG) and subiculum (Duvernoy, 2005; Fig. 2a, b). Stress and glucocorticoid overexposure affect HC neuroplasticity via mechanisms that are at least in part localized to specific HC subfields (Sapolsky, 2000; Cze´h and Lucassen, 2007; Pittenger and Duman, 2008). Preclinical models of adult chronic stress have shown death of CA3 pyramidal cells (Sapolsky, 2000), but milder chronic psychogenic stress and glucocorticoid exposure typically lead to neuroplastic changes, with a widespread loss of spine synapses (Hajszan et al., 2009), dendrite retraction in CA3 pyramidal neurons and loss of CA3 volume (Pittenger and Duman, 2008; Leuner and Gould, 2010). Dendrite retraction occurs less often in CA1 pyramidal and DG granule cells, but CA1 becomes susceptible to

acute stress after stress-sensitization (Alfarez et al., 2003). Adult neurogenesis is specific to the DG. A reduction in the rate of neurogenesis in the DG has been suggested to play a role in low HC volumes in MDD (Jacobs et al., 2000). The neurogenic hypothesis of MDD suggests a pathogenic role of decreased neurogenesis and critical involvement of enhanced neurogenesis in antidepressant response (Kempermann and Kronenberg, 2003). The DG consists of molecular, granular and polymorphic layers, surrounding the hilus. Neurogenesis derives from neural progenitor cells that can divide into proliferative cells with the potential to survive, mature and integrate into HC circuits (van Praag et al., 2002). The proliferating cells in the subgranular zone of the DG of the HC migrate to the granular cell layer where they give rise to mature neurons. In rodents, proliferative cells migrate from a subgranular zone into the granular layer, whereas in primates a subgranular zone is less easily defined and proliferative cells appear in the polymorphic and granular layers and hilus (Boldrini et al., 2009; Lavenex et al., 2009). Chronic stress suppresses adult neurogenesis (Balu and Lucki, 2009; Leuner and Gould, 2010). The rate of neurogenesis declines across the lifespan and whereas suppression in adults is transient, early adversity leads to a developmental deficit in adult DG volume and to lasting suppression of the rate of neurogenesis (Lemaire et al., 2000; Mirescu et al., 2004; Lucassen et al., 2009). Many signaling systems regulate different aspects of neuroplasticity (Pittenger and Duman, 2008; Leuner and Gould, 2010): involvement of glucocorticoids is evidenced by findings that stress-induced dendrite retraction and suppression of neurogenesis are prevented by glucocorticoid receptor (GR) antagonists. However, it is interesting that specific suppression of HC neurogenesis does not in itself produce depression-like behavior in


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Table 1. MRI studies of HC subfields and subregions in MDD High-field MRI studies of HC subfields Study

Sample n (MDD/ Ctrl)

Medicated/ unmedicated with AD

HC subregions/subfields

Findings

Huang et al. (2013)

20/27

11/9

Head, body, tail; CA1-3, DG, Sub

Travis et al. (2014)

15/15

12/3

Head, body, tail; CA1-3, DG, Sub

Lindqvist et al. (2014)

16/19

–/16

Wisse et al. (2015)

17/30

n/a

Body; CA1, CA1-2 transition zone, CA3&DG Body and head; CA1, CA2, CA3, DG&CA4, Sub, ERC

Unmedicated MDD patients had a lower DG volume than control subjects or medicated MDD participants and a lower CA1–3 volume in the HC body subregion than control subjects. Both the subfield and posterior HC volume reductions were limited to unmedicated MDD: they were not present in MDD patients on longterm antidepressants. Global HC volumes were similar between groups; MDD patients showed significantly reduced DG volumes within the HC body. Duration of depression correlated with MDD patients’ total volumes in the HC body and CA1-3 and DG subfields within it. There were no significant between-group differences in HC subfields volumes.

Neumeister et al. (2005)

31/51

Maller et al. (2007)

45/30

8 – medication naı¨ ve, 23 – medication free n/a

Anterior HC (head), posterior HC (body + tail) Anterior HC (head– body), tail

MacQueen et al. (2008)

46/–

46/–

HC head, HC body– tail

Malykhin et al. (2010)

39/34

16/23

Head, body, tail

Maller et al. (2012)

182/76

n/a

Anterior HC (head– body), tail

All subfield volumes were smaller in the ever MDE group, but none of the differences were statistically significant. Multiple episodes were associated with smaller Sub volumes, but not with the other HC subfield volumes, ERC, or total HC volume.

MRI studies of HC subregions Patients showed smaller total and posterior HC volume relative to controls. Anterior HC volume did not differ between patients and controls. Compared to healthy controls both anterior and posterior HC were significantly smaller in males with MDD, but only the tail section in females with MDD was significantly smaller. Patients who remitted had larger pretreatment HC body/tail volumes bilaterally compared with those who were not in remission at 8 weeks. This difference was not apparent in either the right or left HC head. Significant reduction in the volume of the HC tail bilaterally, right HC head and right total HC in MDD patients. Medicated MDD patients showed increased HC body volume compared with both healthy controls and unmedicated MDD patients. Control subjects had significantly larger total HC and anterior HC volume than treatment-resistant MDD patients. HC tail volumes were also significantly smaller in the MDD group compared to controls.

AD, antidepressants; Ctrl, controls.

animals (Shors et al., 2002; Santarelli et al., 2003; Saxe et al., 2006; Airan et al., 2007). Chronic stress may reduce the number, size and processes of HC astrocytes, but this is under studied (Cze´h et al., 2006). In preclinical studies, stress- and glucocorticoid-induced suppression of DG neurogenesis can be prevented or reversed by antidepressant treatments, which also have direct neurogenic effects (Cze´h et al., 2001, 2002; Pham et al., 2003; Pittenger and Duman, 2008). Interference with the neurogenic effects of antidepressants can block their effects on depressive-like behaviors (Santarelli et al., 2003). In contrast, the CA, particularly the pyramidal cells of CA3, are most vulnerable to neuronal remodeling and cell loss following chronic stress or glucocorticoid overexposure and

antidepressant treatments can also prevent or reverse dendritic remodeling in CA3 (Sapolsky, 2000; McEwen, 2001; Joe¨ls et al., 2004; Lucassen et al., 2006; Cze´h and Lucassen 2007; Conrad, 2008; Schubert et al., 2008; McKernan et al., 2009) and glial loss. It also has been confirmed by several studies that the subiculum is likely to be the primary mode of HC interactions with HPA axis (Herman and Mueller, 2006; O’Mara, 2006). Furthermore, the ventral subiculum is critical for stress responsiveness (i.e. inhibition of the HPA axis), whereas the dorsal component may gate information concerning basal secretory patterns (Herman and Mueller, 2006; O’Mara, 2006). All of this suggests that different subfields of the HC especially CA and DG may respond differently



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Fig. 2. Coronal sections of the HC body: (a) explanatory diagram (from Duvernoy, 2005), (b) intravascular india ink injection (from Duvernoy, 2005): 1, cornu ammonis (CA); 2, dentate gyrus (DG); 3, subiculum (Sub); 4, margo denticulatus; 5, lateral part of the transverse fissure; 6, fimbria; 7, lateral geniculate body; 8, choroid plexuses and temporal horn of lateral ventricle; 9, caudate nucleus. (c) 4.7 T MRI view.

to stress and may also have differential levels of plasticity in different circumstances. The potential role of glucocorticoids in antidepressantinduced neurogenesis is also consistent with extant literature, which shows that antidepressants directly regulate the function of the GRs (Anacker et al., 2011). Furthermore, the antidepressant-induced changes in neurogenesis are dependent on the GR. Antidepressants regulate differentiation and proliferation of human HC progenitor cells by a GR-dependent mechanism that requires protein kinase A (PKA) signaling (Anacker et al., 2011). High levels of GRa protein are present in human hippocampal neurons and glia throughout the DG and CA subfields (Wang et al., 2013). This confirms that the human hippocampus can be sensitive to glucocorticoid exposure, consistent with a variety of effects of glucocorticoid or stress exposure on human HC cognitive functions (Wang et al., 2013). Antidepressants can also enhance brain-derived neurotrophic factor (BDNF) release in the PFC and HC (Sairanen et al., 2005). Human post-mortem studies (Table 2) have not provided evidence for neuronal death as a significant factor in MDD (Lucassen et al., 2001; Muller et al., 2001). Although the neurogenic effects of antidepressant treatment have been well established in rodents, there are very few studies to date demonstrating antidepressant effects in humans. One of the largest studies (n = 19) reported thinning of CA1-3 and DG with increased neuronal and glial densities and decreased pyramidal cell size (Stockmeier et al., 2004). Low HC volume in MDD may therefore be determined by loss of neuropil, including dendritic branches, spine complexity and astrocyte processes (Stockmeier et al., 2004). More recently this group reported that despite the fact that there was no significant difference between MDD and controls in total number or density of pyramidal neurons/granule cells or glial cells in CA1, CA2/3, hilus, or DG, however, CA1 pyramidal neuron density increased and total HC volume decreased with duration of illness in recurrent/chronic MDD (Cobb et al., 2013). In addition, granule cell and glial cell numbers increased with age in those MDD patients taking antidepressant medication. Increasing DG granule cell and glial cell numbers with age in antidepressant-treated subjects may reflect proliferative effects of antidepressant medications. Decreasing total volume and increasing CA1 pyramidal neuron density with duration of illness in recurrent/chronic MDD lends support to the neuropil

hypothesis of MDD (Cobb et al., 2013). This observation was further supported in an animal study (Bessa et al., 2009) where the reestablishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the HC and PFC, rather than neurogenesis, was the basis for the restoration of behavioral homeostasis by antidepressants. Post-mortem studies of neural progenitor and proliferative cell markers have shown DG neurogenesis throughout the human lifespan, decreasing sharply in adulthood, then gradually with aging (Boldrini et al., 2009; Knoth et al., 2010). Neural progenitor and proliferative cells were not reduced significantly in DG in MDD, within limitations of sample power and medication history (Reif et al., 2006; Boldrini et al., 2009). In a recent postmortem study of MDD, the volume of histologically defined DG was 68% larger in selective serotonin reuptake inhibitors (SSRI) - treated MDD subjects (Boldrini et al., 2012). SSRI treatment also substantially increased neural progenitor cells (NPCs) in the DG (Boldrini et al., 2009), although this was not replicated when prescription, rather than toxicology data were used to confirm treatment (Reif et al., 2006). Therefore involvement of DG proper would be consistent with the neurogenic hypothesis of depression (Jacobs et al., 2000; Kempermann and Kronenberg, 2003), in that preclinical studies have demonstrated that chronic, repeated or multiple psychological stressors are associated with suppression and antidepressants with enhancement of adult DG neurogenesis (Cze´h et al., 2001, 2002; Pham et al., 2003; Santarelli et al., 2003; Dranovsky and Hen, 2006; Leuner and Gould, 2010; Balu and Lucki, 2009). However, neither postmortem study provided evidence for reduced DG volume or neural progenitor cell numbers in unmedicated MDD. Furthermore, differences in cellular differentiation, maturation, survival, or neuropil volume could also contribute to DG volume differences at post-mortem (Stockmeier et al., 2004; Boldrini et al., 2012). In addition, some of the discrepancies between preclinical and post-mortem studies might be at least partially explained by sample power and medication history.

MEASUREMENT OF HC SUBFIELDS IN VIVO USING HIGH-FIELD MRI The spatial resolution of conventional MR imaging (1.5 Tesla scanners) in MDD has been insufficient for measurement of HC subfields in vivo, although some


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Table 2. Post-mortem studies examining HC structure in MDD Post-mortem studies Study



HC subregions/subfields

Findings

Lucassen et al. (2001) Muller et al. (2001)

15/16

10/5

Mid-body

15/16

10/5

Mid-body

Stockmeier et al. (2004)

19/21

7/12

Right HC body

Boldrini et al. (2009)

12/7

7/5

Entire HC


18/12

6/12

Entire right HC


25/17

10/15

Entire right HC

Cobb et al. (2013)

17/17

10/7

Entire left HC

No obvious massive cell loss was observed in MDD. In 11 of 15 depressed patients, rare, but convincing apoptosis was found in entorhinal cortex, Sub, DG, CA1, and CA4. There was no evidence of neuronal cell loss in MDD patients. Changes in B-50 and GFAP staining were observed in MDD patients in areas CA1 and CA2 only. In MDD, HC sections shrink in depth a significant 18% greater amount than in control subjects. The density of granule cells and glia in the DG and pyramidal neurons and glia in all CA subfields was significantly increased by 30–35% in MDD. The average soma size of pyramidal neurons was significantly decreased in MDD. MDDT receiving SSRIs had more NPCs than untreated MDD and controls, NPCs were not different in SSRI- and TCA-treated MDDT. Dividing cell number was greater in MDDT receiving TCAs than in untreated MDD, SSRI-treated MDD, and controls. The increase of NPCs and dividing cells in MDDT was localized to the rostral DG. MDDT had a larger DG volume compared with untreated MDD or controls. The MDD*SSRI had a larger capillary area and more NPCs versus MDDs and control subjects in the whole DG, more NPCs in the anterior and central (mid-body) DG, and greater capillary area in the pes and mid-body. The NPC number and capillary area correlated positively in the whole sample and in treated subjects. No NPCs or antidepressantrelated angiogenesis in CA1 and parahippocampal gyrus. The DG volume correlated positively with NPC number and capillary area and differed between groups in whole hippocampus and mid-body. Fewer GNs in the anterior DG were present in unmedicated MDDs compared with controls. Younger age of MDD onset correlated with fewer GNs. Unmedicated-MDDs had fewer mid-DG GNs than MDD*SSRIs and controls. Anterior GCL glial number did not differ between groups. Anterior/mid GCL volume was smaller in unmedicatedMDDs vs. controls and larger in MDD*SSRIs vs. unmedicated-MDDs, MDD*TCAs, and controls. Anterior GCL volume and GN number, and mid DG volume and GN number were correlated. Anterior DG capillary density correlated with GN number, and with GCL and DG volumes. Posterior DG volume and GN number did not differ between groups. HC volumes in all MDD subjects did not differ from controls. In recurrent/ chronic MDD, total volume decreased with duration of illness. There was no significant difference between MDD and controls in total number or density of pyramidal neurons/granule cells or glial cells in CA1, CA2/3, hilus, or DG. CA1 pyramidal neuron density increased with duration of illness in recurrent/chronic MDD. Granule and glial cell numbers increased with age in those taking AD.

GCL, granule cell layer; GFAP, glial fibrillary acidic protein; GN, granule neurons; MDDT, antidepressant-treated MDD; NPC, neural progenitor cells; SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants.

studies have mapped deformations in HC thickness to make probabilistic estimates of which subfields may be affected in MDD (Posener et al., 2003). The improved spatial resolution of high-field strength MRI has recently enabled measurements of subfield volumes in vivo across the entire HC structure (Malykhin et al., 2010b; Fig. 2c). In our study of HC subfields in healthy subjects we demonstrated that the differences in vulnerability of HC parts might be partially explained by their different structural organization (Malykhin et al., 2010a). We found that the HC head and tail have the largest proportion of the CA, and therefore processes that preferentially affect the CA may have a greater impact on the HC head and tail. In

addition, since the HC body has the largest part of the DG and the highest DG/CA ratio, we speculated that it might also play a major role in HC neurogenesis. However, the most convincing evidence for changes in CA subfields and alterations in the DG came from visualization of these structures directly in MDD (Huang et al., 2013; Lindqvist et al., 2014; Travis et al., 2014a; Wisse et al., 2015). Despite preclinical evidence that stress and antidepressant treatments affect HC subfields differently, clinical studies of MDD patients where HC subfields were visualized and manually measured are still very limited (Table 1). The first high-field MRI (4.7 Tesla



scanner) study of HC neuroplasticity in MDD patients reported that mean DG volume and volume of CA1-3 in the HC body were smaller in medication-naive or recently unmedicated MDD participants than in healthy controls (Huang et al., 2013). In addition, consistent with other recent MRI studies, there was also topographical variation along the longitudinal axis of the HC, with a smaller volume posteriorly, in the HC body and tail in unmedicated MDD, rather than anteriorly in the HC head. Finally, both the subfield and posterior HC volume reductions were limited to unmedicated MDD: they were not present in participants on long-term antidepressants. Since, we were not able to directly evaluate the rate of neurogenesis within the DG or estimate the production of new neurons in the HC as it can only be done postmortem (Boldrini et al., 2009), therefore, these findings might only indirectly provide evidence on altered HC neurogenesis in MDD, suggesting that the size of the DG is related to its function. Although we did not find a reduction in the volume of the CA1-3 subfield throughout the entire HC formation, its volume was lower in the unmedicated MDD, more than medicated MDD, in HC body (Huang et al., 2013). This finding is in line with the post-mortem and animal studies that demonstrated the greater vulnerabilities of the CA and DG (Sapolsky, 2000; McEwen, 2001; Joe¨ls et al., 2004; Lucassen et al., 2006; Cze´h and Lucassen, 2007; Conrad, 2008; Schubert et al., 2008; Leuner and Gould, 2010). Surprisingly, the antidepressant treatment was associated with larger volumes in both the DG and the CA1-3 subfields, suggesting that the effects of antidepressants are not limited to the DG. This is in agreement with previous animal studies that found that antidepressant treatment can prevent the CA and DG spine loss (Norrholm and Ouimet, 2001; Bessa et al., 2009; Hajszan et al., 2009), CA and DG dendritic retraction (Magarinõs et al., 1999; Bessa et al., 2009), and astrocyte loss (Cze´h et al., 2006). However, whether those reductions are directly related to glucocorticoidinduced neuronal damage of the HC in MDD remains to be determined. The only HC subfield that did not differ between MDD patients and controls was the subiculum. In addition, we found that, antidepressant treatment was associated with a larger volume of subiculum in the HC tail and a trend toward larger volumes in the HC body in medicated MDD patients, which mirrored the overall effects of antidepressants on the volumes of the DG and CA1-3 subfields in those HC subregions. This could be an indication that the effects of antidepressant treatment are not limited to the previously discovered effects on reduced CA and DG subfields, but might also involve neuroplastic changes in the subiculum. However, effects of antidepressants on the subiculum have been understudied. Although the subiculum contributes a relatively small amount of volume to the HC (Malykhin et al., 2010a), anatomically it represents the main output of the HC formation (and is likely a primary mode of HC interactions with HPA axis (O’Mara, 2006; Herman and Mueller, 2006). Additional studies are needed to determine whether larger volumes of the posterior subiculum are associated with normalization of basal cortisol level in MDD.

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In another high-field MRI (4 Tesla) study Lindqvist et al. (2014) did not find any difference in subfield volumes between controls and MDD patients. However, the authors reported that across both groups, the antioxidant score was significantly and positively correlated with total HC volume and CA3&DG subfield volume. Recently, in the different cohort of MDD patients our group discovered that despite the fact that global HC volumes were similar between controls and MDD patients, MDD patients showed significantly reduced DG volumes within the HC body (Travis et al., 2014a). In addition, duration of depression correlated with MDD patients’ total volumes in the HC body and both CA1-3 and DG subfields within it. In conclusion, the results of these studies provide the first in vivo evidence that HC volume reductions in MDD are specific to the CA1-3 and DG HC subfields, findings that appear, on the surface, consistent with preclinical evidence for localized mechanisms of HC neuroplasticity. However, it remains unclear why animal models show prevention and rapid reversal of psychological stress impact after brief (2 week) treatment, whereas any such effects seem to require a long period (>3 years) of treatment in humans and may therefore not involve the same mechanisms. Also, the impact of early-life stress on adult HC neuroplasticity needs more preclinical study.

METABOLIC AND WHITE MATTER CHANGES IN THE HC ASSOCIATED WITH MDD Proton magnetic resonance spectroscopy (1H-MRS) is a non- invasive imaging technique used to assess the levels of in vivo metabolites in different brain regions. 1 H-MRS can quantify the levels of specific bioactive molecules which are considered indicative of tissue viability, integrity and metabolic turnover in a specified location (Burtscher and Holtas, 2001). For instance, N-acetyl-aspartate (NAA) is a marker of neuronal density and integrity (Stanley, 2002), while choline (Cho) is often considered to be a marker of cellular membrane turnover and active neurodegeneration (Burtscher and Holtas, 2001). In addition, myo-inositol (MI), is commonly considered a marker for glial cell loss and glutamate– glutamine (Glx, it includes glutamate, glutamine and gamma-aminobutyric acid (GABA)) index is a marker of glutamatergic neurotransmission (Kato et al., 1998). As a consequence, elevated glutamate levels may result in increases in lactate (Lac) which is neurotoxic (Glitz et al., 2002). The measurement of these metabolites using 1H-MRS therefore, allows to indirectly examine neuronal and glial alterations in the HC of patients with depression (Table 3). Lower levels of Glx (Block et al., 2009; de Diego-Adelinõ et al., 2013) and lower levels of NAA (Block et al., 2009; de Diego-Adelinõ et al., 2013) have been reported in HC of MDD patients. In addition, several studies (Milne et al., 2009; de Diego-Adelinõ et al., 2013) reported increased Cho level in HC of depressed patients (Block et al., 2009) and decreased Lac/creatine (Cr) ratio (Husarova et al., 2012). Antidepressant treatment was associated with increased NAA level (Block et al., 2009; de Diego-Adelinõ et al., 2013), and increased Cho (Block et al., 2009).


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Table 3. 1H-MRS studies examining metabolic changes in HC structure in MDD 1

H-MRS studies

Study



HC subregions

Findings

Block et al. (2009)

18/10

–/18

Left HC body and head

Milne et al. (2009)

28/27

12/16

Left HC body and head

Husarova et al. (2012)

18/-

4/14

Left/right HC body and head

de Diego-Adelinõ et al. (2013)

52/16

47/5

Left/right HC head

Zhong et al. (2014)

26/13

–/26

Left/right HC body

Significant reduction of the metabolic ratios Glx/Cr and Gln/Cr in the patient group. The individual effect of treatment correlated with an increase in the absolute concentrations of NAA and of Cho compounds. Low baseline NAA and Cho levels predicted positive treatment effects. Cho-containing compounds were significantly increased in MDD patients with a high past illness burden relative to controls. The group presenting for first treatment had only increases in MI levels compared with matched controls. A significantly decreased Lac/Cr ratio in the left HC after treatment. The MI/Cr ratio showed a significant negative correlation with the severity of depression as assessed by the MADRS at baseline. Patients with treatment-resistant/chronic and remittedrecurrent depression had significantly lower levels of Glx and NAA than controls, especially in the right HC region. Diminished levels of Glx were correlated with longer illness duration. Cho levels were significantly higher in patients with treatment-resistant/chronic depression than those with firstepisode depression or controls in the right and left HC and were consistently related to longer illness duration and more previous episodes. No significant difference in the ratios of NAA/Cr and Cho/Cr in the bilateral HC among the MDD group, and the healthy controls.

Glx, glutamate–glutamine (it includes glutamate, glutamine (Gln) and gamma-aminobutyric acid (GABA)); Cho, choline; Cr, creatine; MI, myo-inositol; NAA, N-acetylaspartate.

Furthermore, low baseline NAA and Cho levels predicted positive treatment effects (Block et al., 2009). Metabolite alterations within the hippocampus were more pronounced in MDD patients whose clinical evolution is characterized by recurrences and/or chronicity (de Diego-Adelinõ et al., 2013). Overall, these findings provide further evidence to support the link between HC and the potential neuroplastic effects of stress and depression, suggesting that abnormalities in Glx, NAA and Cho spectra are closely related to the past burden of illness. Changes in glial/neuronal integrity and membrane turnover may underlie the metabolic changes reported in these studies, although further research is needed to establish the specific cellular processes involved in MDD over the course of the illness and their relationship with HC volumetric changes. In addition to MRI and 1H-MRS studies, diffusion tensor imaging (DTI) methods have been used in order to understand changes in HC white matter connections in MDD patients. There are three major white matter fiber tracts connecting HC with different prefrontal and limbic brain areas, namely uncinate fascicles (UF), fornix, and parahippocampal cingulum (Malykhin et al., 2008a,b). There are very few DTI studies of HC connections in MDD patients. Carballedo and colleagues (2012) found significant reduction in fractional anisotropy (FA) in MDD patients carrying the BDNF met-allele (rs6265) in the UF compared to those patients homozygous for val-allele and compared to healthy subjects

carrying the met-allele. Another study did not find changes in FA in HC white matter tracts (UF and fornix) in MDD patients (Korgaonkar et al., 2014). Ugwu and colleagues (2014) reported that in the UF, and parahippocampal cingulum, FA was greater in the left hemisphere in the subjects with history of childhood adversity (CA) when compared with those without CA. However, depression did not have any effects on the diffusivity measures. Additional DTI studies are needed to examine HC connections particularly in unmedicated MDD patients and the effects of treatment on their structural integrity.

FUNCTIONAL SPECIALIZATION OF THE HC Subsequent volumetric MRI studies of the HC have found that its volume can predict performance on a number of common neuropsychological tests and episodic memory paradigms. This is true for healthy controls with intact HC tissue (Foster et al., 1999; Hackert et al., 2002; Convit et al., 2003; Rosen et al., 2003) and in patients with Alzheimer’s disease; (Ko¨hler et al., 1998), schizophrenia (Seidman et al., 2002), and temporal lobe epilepsy (Griffith et al., 2004). It seems that these relationships are most obvious in individuals with significant cognitive impairments, neurological disorders, or age-related neurodegeneration which result in abnormal reductions in HC volume. It was discovered in lesion studies in rats that dorsal and ventral subregions of the HC are associated with a distinct set of behaviors (Bannerman et al.,



2004). It has been suggested that the dorsal HC – referred to as the posterior HC in primates – has a preferential role in spatial learning. In contrast, the ventral HC – equivalent to the primate anterior HC – may have a preferential role in anxiety-related behaviors (Bannerman et al., 2004). In human studies which examine the HC in just two antero-posterior subdivisions, it has been suggested that the anterior HC may have a preferential role in anxiety-related behaviors (Szeszko et al., 2006) and verbal memory (Hackert et al., 2002; Chen et al., 2010), while the posterior HC has a preferential role in spatial learning (Woollett and Maguire, 2011). The functional specificity of these studies conceivably reflects an underlying structural differentiation along the anteroposterior axis. Overall, the extant literature illustrates a specialization of HC subregions, a finding which could be overlooked when examining the HC as a whole. For example, Poppenk and Moscovitch (2011) reported that better performance on tasks of word pair, word-picture pairings and scene recognition was associated with positively with posterior and negatively with anterior HC volume, while overall HC volume was not sensitive to these measures. Therefore, the importance of separating a global volume of the HC into connectively-distinct subregions in studies of relationships between HC volume and memory is vital (Travis et al., 2014b). Recently using high-field MRI, several groups reported that HC subfield volumes might contribute differently to memory performance on standard memory tasks (Mueller et al., 2011; Travis et al., 2014b). It has been shown that HC subfield volumes were considerably more sensitive to reflect memory performance than global HC volume (Travis et al., 2014b). Furthermore, the performance on visuospatial tasks was associated with the volumes of the CA and DG subfields in the HC body and tail, while performance on verbal tasks was associated with CA and DG in the HC head. These findings provided further evidence of the functional specialization of the HC subregions and HC subfields. Given that HC volume reductions in MDD can be localized to specific posterior HC subregions or subfields it is very possible that memory deficit often observed in MDD patients could be linked to volumetric reductions in particular HC subregions and subfields. The main question is if such relationships exist in MDD patients, and whether or not they can be affected by the disease itself or by antidepressant treatment.

HC NEUROPLASTICITY AND MEMORY FUNCTION IN MDD MDD is associated with a number of cognitive deficits (Lee et al., 2012). Thus, patients with MDD have consistently demonstrated worse performance than healthy controls in verbal memory (Sheline et al., 1999; MacQueen et al., 2003; Vythilingam et al., 2004; Kaymak et al., 2010), recollection memory (Sheline et al., 1999; MacQueen et al., 2003; Kaymak et al., 2010), and in tests of visual memory (Reischies and Neu, 2000; Grant et al., 2001; Neu et al., 2005; Kaymak et al., 2010; van Wingen et al., 2010). Similar deficits have been reported in

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patients with late-onset depression in some (Hickie et al., 2005), but not all (Ballmaier et al., 2008; Greenberg et al., 2008), studies. The majority of the studies investigating cognitive deficit in MDD have focused on patients with multiple episodes of depression (Lee et al., 2012), rather than those with first onset. Thus, despite significant evidence for both cognitive/memory deficits in MDD patients and smaller HC volumes, the link between these two pathologies is much less documented. Furthermore, a number of studies suggested a possible impact of antidepressant medication on HC volumes in MDD. For example, we have shown in a cross-sectional study that long-term antidepressant treatment may be protective against volume loss and may even reverse it, a finding that was supported by other labs and longitudinal studies (Frodl et al., 2008; Malykhin et al., 2010a; Schermuly et al., 2011). However, whether antidepressant medication has a mediating function on the relationship between cognition and HC volumes in MDD is not clear. Interestingly, although the relationship between HC volume reductions in MDD and poorer memory performance appears to be a straightforward one, in reality only two studies reported a direct correlation between reduced HC volume and verbal/logical memory performance in MDD patients (Kaymak et al., 2010; Turner et al., 2012). Since measuring the relationship between global HC volume and memory performance might not reveal significant results we recently conducted high-field MRI study to determine if memory deficit often observed in MDD patients is associated with volumetric reductions in particular HC subregions and subfields (Travis et al., 2014a). We found that MDD patients underperformed in several episodic visual memory tasks, as well as in visual working memory, compared to healthy controls despite the absence of morphological changes in total volume of the HC. Consistent with findings from this study, several groups also reported poor performance on several hippocampus-related memory tests in MDD patients including recollection memory tasks (MacQueen et al., 2003), logical (verbal), and visual memory tasks (Vythilingam et al., 2004), despite finding that HC volumes in these patients did not differ from controls. All such findings suggest that the memory deficits found in MDD patients can predate volumetric changes that are subsequently seen in the HC. In addition, HAM-D scores do not predict memory performance in MDD patients, again findings that are consistent across several studies (Sheline et al., 1999; MacQueen et al., 2003; Travis et al., 2014a). Despite the facts that global HC volumes were similar between groups, MDD patients showed significantly reduced DG volumes within the HC body. We have previously found this particular volume to be correlated with episodic visual memory tasks (Travis et al., 2014b) in younger healthy individuals. However, DG volumes did not directly predict memory performance on visualspatial tests in MDD patients. Previous meta-analysis demonstrated that verbal learning in MDD patients did not differ from healthy subjects; however a higher proportion of MDD patients


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on antidepressant medications was associated with poorer verbal learning and memory performance (Lee et al., 2012). In contrast deficits in visual-spatial and visual-object memory might be particularly affected in MDD patients (Lee et al., 2012). Our volumetric findings were consistent with morphological changes in MDD patients observed in our previous studies (Malykhin et al., 2010a; Huang et al., 2013) and several others studies (Maller et al., 2007; MacQueen et al., 2008; Schermuly et al., 2011), suggesting that more posterior HC subregions (i.e. body and tail) might be particularly affected in MDD. Both the duration of depression and antidepressant treatment (Malykhin et al., 2010a; Huang et al., 2013; Travis et al., 2014a) demonstrated opposite effects on the HC body and DG (and CA) subfields within it, suggesting a complex dynamic relationship between those factors and HC structure. Although in those cross-sectional studies the authors could not eliminate the effects of antidepressant treatment on memory performance in MDD patients, several previous studies suggested that antidepressant use was associated with poorer verbal learning and memory functioning (Lee et al., 2012). Several studies reported that correlations between memory performance and HC volumes were found only in controls, but not MDD patients (Hviid et al., 2010; Turner et al., 2012). It has also been suggested that since depression severity and medication are highly correlated, patients who are currently on antidepressant medication could be those patients who are more severely depressed, and therefore more likely to be cognitively impaired (Lee et al., 2012). In contrast Vythilingam et al. (2004) found that both delayed memory, and retention on verbal memory subtests, significantly improved in MDD patients after successful antidepressant treatment even though there was no significant improvement in visual subtests of WMS-R in their study. In conclusion, while MDD disease duration is related to DG reductions in MDD patients, their memory deficits are not. This potentially implies temporally separable pathological processes of memory deficits in MDD on the one hand, and DG volume reductions in posterior HC regions on the other hand. Our findings suggest that DG volumes in particular may be worthy of further study to further elucidate their precise role in MDD, both by itself as well as in relation to memory.

CONCLUSION Recent volumetric MRI studies suggest that localized differences in HC volume may be more prominent than global differences. Preclinical and post-mortem studies in MDD indicated that different subfields of the HC may respond differently to stress and may also have differential levels of plasticity in response to antidepressant treatment. Advances in high-field MRI allowed researchers to visualize and measure HC subfield volumes in MDD patients in vivo. The results of these studies provide the first in vivo evidence that HC volume reductions in MDD are specific to the CA and DG HC subfields, findings that appear, on the surface,

consistent with preclinical evidence for localized mechanisms of HC neuroplasticity. Furthermore, in agreement with recent post-mortem studies, these studies indicate that antidepressant treatment can increase DG volume in MDD patients. These findings are consistent with the suggestion that stimulating DG neurogenesis with antidepressants might play an important role in reversing HC volume reduction in MDD patients. However, it is not clear when these increases in DG volume occur, or exactly how this might be related to memory function. In addition, reported significant correlations between memory performance and HC volumes often found in healthy subjects are not necessarily to be observed in MDD patients where other factors such as depression itself, antidepressant treatment, and disease duration can significantly affect both HC subfield volumes and memory function. Future longitudinal studies can answer these questions directly. Acknowledgments—This work was supported by Canadian Institutes of Health Research (CIHR).

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(Accepted 21 April 2015) (Available online xxxx)


Hippocampal volume and serotonin transporter polymorphism in major depressive disorder.

Physical Activity Modulates Common Neuroplasticity Substrates in Major Depressive and Bipolar Disorder.

Major depressive disorder.

Hippocampal and subcortical alterations of first-episode, medication-naïve major depressive disorder with panic disorder patients.

Neurobiology of major depressive disorder.

Hyperthermia for Major Depressive Disorder?

Association between glucocorticoid receptor methylation and hippocampal subfields in major depressive disorder.

Insular and hippocampal gray matter volume reductions in patients with major depressive disorder.

Seasonal variation of depressive symptoms in unipolar major depressive disorder.

Gene expression in major depressive disorder.

Risks for suicidality in major depressive disorder.

Advances in biomarkers of major depressive disorder.

Patient-reported functioning in major depressive disorder.

Temporal discounting in major depressive disorder.

Autobiographical episodic memory in major depressive disorder.

Prodromal symptoms in primary major depressive disorder.

Resting state networks in major depressive disorder.

Delayed mood transitions in major depressive disorder.

Depressive rumination alters cortisol decline in Major Depressive Disorder.

Glutamate metabolism in major depressive disorder.

Physical anhedonia in major depressive disorder.

Fluoxetine in tricyclic refractory major depressive disorder.

Major depressive disorder and cognitive impairment.

Chipping away at major depressive disorder.