Memory related dysregulation of hippocampal function in major depressive disorder

Biological Psychology 85 (2010) 499–503

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Biological Psychology journal homepage: www.elsevier.com/locate/biopsycho

Brief report

Memory related dysregulation of hippocampal function in major depressive disorder Scott L. Fairhall a,b,c , Sindra Sharma d , Jane Magnusson d , Bernadette Murphy e,∗ a

Department of Psychology, Harvard University, Cambridge, MA, United States Centre for Mind and Brain, University of Trento, Trent, Italy c Neuroimaging Laboratory, Fondazione Santa Lucia, Rome, Italy d Department of Sports and Exercise Science, University of Auckland, New Zealand e Faculty of Health Sciences, University of Ontario Institute of Technology, Ontario, Canada b

a r t i c l e

i n f o

Article history: Received 5 February 2010 Received in revised form 31 August 2010 Accepted 1 September 2010 Available online 15 September 2010 Keywords: Depression Associative memory Encoding Faces Medial temporal lobes Functional magnetic resonance imaging fMRI

a b s t r a c t Hippocampal abnormalities have frequently been associated with major depressive disorder (MDD), however evidence of a functional hippocampal deficit has remained illusive. Here, functional magnetic resonance imaging (fMRI) is employed in conjunction with an associative memory paradigm to investigate functional irregularities of the hippocampus during the encoding process. The use of a focussed analytical approach and a behavioural task targeted to hippocampal function confirmed the hypothesis that the normal modulation of hippocampal activation by encoding strength is dysregulated in MDD. Further analysis demonstrated that this impairment of function was specific to the hippocampus. A double dissociation between groups in the hippocampus and intraparietal sulcus indicates that compensatory mechanisms may exist. These results show that MDD is associated with a dysregulation of hippocampal function that cannot be explained in terms of overall brain state or motivational stance and provides an important link between memory impairments and hippocampal changes in MDD. © 2010 Elsevier B.V. All rights reserved.

Major depressive disorder (MDD) is a widespread debilitative disorder, ranking in the top ten causes of disability worldwide (Murray and Lopez, 1996). To date, compelling evidence has linked MDD with hippocampal atrophy (Campbell et al., 2004; Hickie et al., 2005; McKinnon et al., 2009; Videbech and Ravnkilde, 2004; Vythilingam et al., 2004). Furthermore, alterations in hippocampal neurogenesis have been associated with MDD and the therapeutic efficacy of pharmaceutical agents that promote hippocampal neurogenesis is contingent on this neurogenic action (Campbell and Macqueen, 2004; Sahay and Hen, 2007; Santarelli et al., 2003). This implicates the hippocampus an aetiological, rather than purely symptomatic, role in MDD. However, a link between these reports of macro and microscopic changes and evidence for alterations in hippocampal function has remained illusive (Werner et al., 2009). Deficits in associative memory, a core function of the hippocampal complex (Brown and Aggleton, 2001; Scoville and Milner, 1957), have been reported in MDD (Burt et al., 1995; Dalgleish et al., 2007;

∗ Corresponding author at: Faculty of Health Sciences, University of Ontario Institute of Technology, 2000 Simcoe St. North, Oshawa, ON, Canada. Tel.: +1 905 721 8668 . E-mail address: [email protected] (B. Murphy). 0301-0511/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.biopsycho.2010.09.002

Gould et al., 2007; Vythilingam et al., 2004). One recent fMRI study compared patients with MDD to controls and did not find a difference in hippocampal activation (Werner et al., 2009). Therefore, to date no study has successfully linked these memory impairments to alterations of hippocampal function in MDD. Here we use functional magnetic resonance imaging (fMRI) to assess the functional integrity of the hippocampus during associative encoding in individuals with MDD. The present study is specifically designed to have sufficient sensitivity to identify MDD-associated functional abnormalities in the hippocampus while controlling for the tendency to make false positives due to poorly controlled multiple comparisons. Specifically, we: 1) formally test the a priori hypothesis that in MDD there is a dysregulation of the normal neurocognitive relationship between increased hippocampal activation and encoding success, 2) select an experimental paradigm previously shown to produce robust modulation of hippocampus activity with encoding success (Sperling et al., 2003), 3) use this specific paradigm to permit the a) separation of true encoding success from chance success, b) selection of a specific brain region-of-interest, 4) use an eloquent-voxels approach (Friston et al., 2006) as a further functional localizer to refine this hippocampal region, and 5) replicate this a priori analysis across brain regions active during the task to ensure that this effect was specific to the hippocampus.

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S.L. Fairhall et al. / Biological Psychology 85 (2010) 499–503 1.5. fMRI analysis Data were analyzed using SPM5 software (www.fil.ion.ucl.ac.uk/spm/). All functional volumes were slice time corrected, realigned, smoothed (5 mm kernel), high-pass (128 s) filtered and normalised to standard stereotactic (MNI) space (using the segmented grey matter). The analysis was based on a conventional general linear model (Friston et al., 1995). Three condition types were retrospectively nominated based upon whether the stimulus was matched to the correct name outside the scanner: with high confidence (HC correct), with low confidence (LC correct) or incorrectly. As the LC correct condition was uninformative, containing both truly correct responses and a high number of lucky guesses (chance = 50%), only HC correct and incorrect responses were taken to a second level factorial random effects design [group by encoding success] to permit inference at the population level.

Fig. 1. Experimental paradigm. During encoding, subjects viewed 240 face name pairs over two fMRI sessions. To ensure adequate encoding of the stimuli and subject engagements, subjects were asked to indicate whether they felt the name was a good match for the face (‘does this look like a “Sally” to you?; c.f. Sperling et al., 2003 for the first use of the paradigm). During the functional image acquisition participants were presented with the encoding task by way of a LCD projector and rear projection screen. They responded using a push-button response device. Stimuli were presented in two 8.5 min sequences. Each sequence consisted of the presentation of jittered event related face name pairs with 120 stimulus presentations of 3 s, interspersed with 34 fixations periods varying between 3 and 9 s. The retrieval task was performed outside the scanner. Participants were first asked to indicate which of the two names was originally paired with the presented face and subsequently asked to report the certainty of this judgment. This was used to retrospectively nominate the encoding trials as successful or unsuccessful encoding events.

1. Methods and materials 1.1. Subjects A convenience sample of sixteen participants was recruited through advertisement and clinical referral. Eight outpatients with a clinical diagnoses of MDD and no other co-existing DSM-IV Axis I disorders (four female, mean age 25.9) were compared with eight healthy controls of similar ages (five female, mean age 29.6). Medication in the MDD group was not an exclusion criterion provided they had been medicated for at least four weeks so that medication effects had stabilized. At the time of the scanning, three of the MDD group were on SSRIs (one of which was also on anxiolytics), two were on unspecified medication, one was on a Tricyclic, and two were non-medicated. All procedures were approved by the University of Auckland Ethics Committee.

1.2. Psychometric evaluation Participants were assessed with the Beck Depression Inventory II (BDI II; Beck et al., 1996), the Hospital Anxiety and Depression Scale (HADS; Pallant and Bailey, 2005) and the Perceived Stress Scale (PSS; Cohen et al., 1983). The MDD group scored significantly higher on the BDI II (¯x = 26.13, s = 9.49; controls = 8.00, s = 5.29, p < .001), HADS (¯x = 9.25, s = 2.60; controls: x¯ = 4.13, s = 2.64, p < .05) and also reported greater levels of stress (PSS, x¯ = 31.13, s = 5.14; controls: x¯ = 23.25, s = 6.16, p < .05). 1.3. Experimental procedure During two fMRI scanning sessions, subjects underwent an encoding session where faces were paired to names (see Fig. 1: encoding and caption for more details). After a 10-min delay, subjects underwent a recall test outside the scanner where in each trial they matched a presented face with the previously presented name and subsequently indicated whether or not they were confident in this judgement (Fig. 1: retrieval). This permitted the identification of encoding events that led to an increased chance of subsequent recall.

1.4. Scan acquisition Scan sequences were carried out on a 1.5 T Siemens Magnetron Avanto. Functional images were acquired in two sessions of 174 scans [3.5 mm slices with an interslice gap of 0.9 mm, 3 × 3 mm in-plane resolution, matrix 64 × 64 mm/FOV 192 mm, repetition time (TR) = 3 s, echo time (TE) = 50 ms, flip angle = 90◦ ]. To maximise hippocampal signal quality, slices were positioned in a coronal oblique orientation, with phase encoding in the foot to head direction. Additionally, a high-resolution structural sequence (MPRAGE) of 160 slices (1 mm × 1 mm × 1 mm voxels) was acquired.

2. Results 2.1. Task performance Both control and MDD groups performed significantly above chance in high confidence responses in the associative memory task (controls 65%, s = 4%, MDD 68%, s = 3%, p < .01) and performance did not differ between groups (t < 1). 2.2. Task-activated brain regions To identify the network of brain regions involved in attempted encoding (irrespective of subsequent recall-performance), the activation during the task (all conditions) was compared to baseline (fixation-events). Bilaterally, elements of fronto-parietal attention networks and the ventral visual stream and, critically, medial temporal lobe structures were activated (see Fig. 2A for full details). Within medial temporal lobe structures, activation was weighted towards the hippocampal complex rather than the parahippocampal gyrus, indicating that this task primarily recruited hippocampal structures. 2.3. A prior analysis of the anterior hippocampus This study was motivated by an a priori hypothesis of the role of anterior regions of the hippocampus in this form of associative memory encoding. To this end, a region-of-interest (ROI) approach was adopted and the peak voxel in left and right anterior hippocampi were selected from the contrast of task versus fixation-events (irrespective of group). This comparison to the loose fixation-baseline allowed the identification of eloquent-voxels in a way orthogonal to the effects of interest (condition, group, group by condition), ensuring a maximised signal to noise ratio while not biasing the values derived for inferential statistics (c.f. Friston et al., 2006). In accord with our hypothesis, a significant group by condition interaction was observed within bilateral anterior hippocampus (F(1,14) = 5.30, p < .05; see Fig. 2B). This interaction was driven by a positive relationship between hippocampal activity and successful encoding in controls (left: t(7) = 2.83, p < .05; right: t(7) = 3.00, p < .05) that was not present in individuals with depression (left: t(7) = −0.46, ns; right: t(7) = −0.44, ns.). To quantify the disparity in the relationship between encoding success and bilateral hippocampal activation in control and MDD groups, Cohen’s d [(¯xHCorrect − x¯ incorrect )/Spooled ] was calculated separately for each group. Controls exhibited a large effect size (d = 1.11) while depressed individuals demonstrated no relationship between anterior hippocampus activity and efficacy of stimulus encoding (d = −0.19). There was no main effect of group in the hippocampus. For this reason, these findings indicate a breakdown in memory related hippocampal function (dysregulation) rather than hypo- or hyperactivation of the hippocampus per se. These results formally demonstrate that the strong relationship between hippocampal

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activation and encoding success present in normal subjects is absent in individuals experiencing MDD. 2.4. Extended ROI analysis To ensure that effects were not equally present in other brain regions, a similar region-of-interest analysis was conducted over other task-activated brain regions (all conditions > baseline, irrespective of group). These ROIs comprised bilaterally, the dorsal lateral prefrontal cortex (DLPFC), intraparietal sulcus (IPS), anterior fusiform gyrus (FG) and amygdala (see Table 1). In terms of general effects of successful encoding (HC > incorrect, independent of group), the DLPFC, fusiform gyri and amygdalae trended towards more activation during successful encoding (all ps < .015, one tailed, uncorrected. See Fig. 2C for effect sizes). Significant hemisphere by condition interactions in the fusiform gyri (p < .001) reflected a stronger relationship between activation and successful encoding in the right ( = 4.48, p < .001) rather than the left ( = −0.78, n.s.) fusiform gyrus. The only region to show a significant relationship between encoding success and group was the IPS (p = .031). The relationship was inverted to that seen in the hippocampus (F(1,14) = 15.62, p < .002), with an increased encoding-sensitivity in the IPS in MDD (Fig. 2C). These results show that, using the same criterion, no evidence of encoding deficits was observed outside the hippocampus. Rather, in the right FG both groups showed a strong positive relationship activation with encoding success (and a trend to this effect in the DLPFC and amygdala). In contrast a reversal of the group by hippocampus effects was evident in the IPS. 3. Discussion

Fig. 2. fMRI results. A) Right hemispheric representation of the network of regions activated during encoding, irrespective of group or encoding success. A lateral surface-view and cut-away of medial temporal lobe structures reveals activation of the dorsal fronto-parietal system, the ventral visual stream and medial temporal lobe structures. Activation has been colour coded into cortical (orange), hippocampal (red), parahippocampal (blue) and amygdalic regions (green) using anatomical templates (Tzourio-Mazoyer et al., 2002). All activations are thresholded at p < .001 and corrected for multiple comparisons at the cluster level. The yellow dot in the hippocampus represents the region extracted for further analysis. B) A priori assessment of the regularity of hippocampal function during encoding. Controls show the expected pattern of increased activation in the anterior hippocampus during the associative encoding of stimuli that are later remembered with confidence compared to those that are not remembered. A significant interaction confirmed that

Using an associative encoding task known to involve the hippocampus we investigated the functional integrity of this structure in individuals with MDD. As hypothesised, a dysregulation of the normal relationship between hippocampal activation and encoding success was observed, providing the first evidence of a functional hippocampal abnormality in an MDD sample. In contrast to the specific deficit observed in the hippocampus of the MDD group, encoding success was associated with comparable activation in a network of regions and a positive regulation of right FG activation in both groups. Hippocampal dysregulation was observed in the absence of any overt behavioural difference in memory performance, suggesting that this deficit may be presymptomatic (at least with respect to the task used here) or may be mitigated by compensatory mechanisms. This second possibility is supported by the finding of a strong dissociation between the role of hippocampal and intraparietal cortex in this task between MDD and control groups. The increased activation of this section of the IPS during successful encoding in the MDD group is of particular interest as this region is associated with increasing task demands and effort (Culham et al., 2001) and suggests that the result reported here do not reflect a reduction in executive control (Dalgleish et al., 2007) or general motivational impairment. Together these results suggest a hippocampal dysregulation in MDD that is both specific

this pattern is absent in the MDD group. C) Specificity of effect. To ensure that any specificity of effect was not merely the result of a hippocampal analytic focus, this analysis was replicated across the network of regions active during attempted encoding. Bar plots show the effect size (Cohen’s d ) of the difference between successful and unsuccessful encoding, collapsed across hemisphere for control and MDD groups alongside the effect size in the hippocampus for comparison [*p < .05, **p < .005. Abbreviations: DLPFC, dorsolateral prefrontal cortex; IPS, intraparietal sulcus; FG, fusiform gyrus; amyg, amygdala; hipp, hippocampus; a.u., arbitrary units]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

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Table 1 Extended ROI analysis peak locations and t value for main effect of task (attempted encoding versus fixation) for both groups and for each group considered separately. Region

Subregion

MNI coordinate

Both

Control

MDD

DLPFC

Left Right

−51 51

12 18

30 30

7.1 10.26

4.23 6.66

5.89 7.93

IPS

Left Right

−30 36

−60 −57

54 54

8.64 6.88

4.69 4.97

7.65 4.75

FG

Left Right

−39 42

−51 −51

−21 −18

14.12 18.27

9.1 14.99

10.95 10.71

Amygdala

Left Right

−18 21

−6 −6

−15 −12

5.62 8.93

4.21 6.18

3.73 6.46

x

Main effect of attempted encoding (t value) y

z

to this brain region and not the result of overall network deficits or motivational disparities between MDD and control populations This finding is in contrast to a recent study of encoding which failed to observe functional modulation of the hippocampus (Werner et al., 2009). This null finding may be due to a less focussed analytical approach and because Werner and colleagues considered overall differences in hippocampal activation, conflating successful and unsuccessful encoding events. 4. Limitations While this study showed a clear and robust alteration in hippocampal function the sample size was modest (eight in each group). Empirical investigations of fMRI data have shown that smaller sample sizes tend to lead to an increase of type II errors but do not result in the increase of type I (false positive) errors (Murphy and Garavan, 2004; Thirion et al., 2007). These results must therefore be interpreted in the context that additional effects may be present that have not been revealed by this study. A stronger limitation of the modest sample size may be the ability to generalise the results of this experiment across the heterogeneous MDD population. In this initial study we used a convenience sample of depressed individuals and control subjects of similar age. This MDD sample was heterogeneous in severity (BDI s = 9.5), consisted of both first instance and recurrent depressive episodes and included patients on and off medication. While this broad sampling is indicative of good population validity, the effects reported here may be due to only a subgroup driving the observed hippocampal dysregulation. For example, number of depressive episodes has an influence on hippocampal volume and potential function (Campbell and Macqueen, 2004; McKinnon et al., 2009). Additionally, the majority of patients were on medication, three on SSRIs and two on unspecified medication (likely to be SSRIs as ∼82% of patients are prescribed with this medication; NZ Ministry of Health, 2007). SSRIs may serve to promote hippocampal neurogenesis (Santarelli et al., 2003), and thus hippocampal dysregulation may be even more pronounced in patients not taking medication. Furthermore, one patient was receiving anxiolytic medication. Anxiolytic medication such as benzodiazepines can have a negative impact on cognitive performance (Golombok et al., 1988) which may have contributed to the effects seen in this subject. Another limitation is that the control group scored moderately high on the BDI and thus may not have represented a true control. Although this does not compromise the internal validity of this study, ideally structured clinical interviews should have been performed in both the depressed group to confirm the clinician’s diagnosis and in the control group to rule out the presence of depression. Future studies with larger sample sizes subgrouped by illness duration with depression diagnosis confirmed by structured interview will help determine the degree to which memory related hippocampal dys-

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