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Learning as a Model for Neural Plasticity in MajorDepressionChristoph Nissen, Johannes Holz, Jens Blechert, Bernd Feige, Dieter Riemann, Ulrich Voderholzer, andClaus Normann

Background: The neuroplasticity hypothesis of depression proposes that a dysfunction of neural plasticity—the basic ability of livingorganisms to adapt their neural function and structure to external and internal cues—might represent a final common pathway underlyingthe biological and clinical characteristics of the disorder. This study examined learning and memory as correlates of long-term synapticplasticity in humans to further test the neuroplasticity hypothesis of depression.

Methods: Learning in three tasks, for which memory consolidation has been shown to depend on local synaptic refinement in areas ofinterest (hippocampus-dependent declarative word-pair learning, amygdala-dependent fear conditioning, and primary-cortex-dependentvisual texture discrimination), was assessed in 23 inpatients who met International Classification of Disease, 10th Revision, criteria for severeunipolar depression and 35 nondepressed comparison subjects.

Results: Depressed subjects showed a significant deficit in declarative memory consolidation and enhanced fear acquisition as indicatedby skin conductance responses to conditioned stimuli, in comparison with nondepressed subjects. Depressed subjects demonstratedimpaired visual discrimination at baseline, not allowing for valid group comparisons of gradual improvement, the plasticity-dependentphase of the task.

Conclusions: The results of the study are consistent with the neuroplasticity hypothesis of depression, showing decreased synapticplasticity in a dorsal executive network that comprises the hippocampus and elevated synaptic plasticity in a ventral emotional network thatincludes the amygdala in depression. Evaluation of further techniques aimed at modulating synaptic plasticity might prove useful for
developing novel treatments for major depressive disorder.
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Key Words: Depression, fear conditioning, human, memory, syn-aptic plasticity, texture discrimination

Major depressive disorder (MDD) is the leading cause ofyears of life lived with disability across all ages world-wide. Still, less than 50% of all individuals with MDD

how full remission with optimized first-line treatment, indicatinghe need for additional research (1).

The Neuroplasticity Hypothesis of Depression

A novel but as yet unconfirmed concept for the etiology ofMDD proposes that a dysfunction of neural plasticity—the basicability of living organisms to adapt their neural function andstructure to external and internal cues in a changing environ-ment—might represent a final common pathway underlying thebiological and clinical characteristics of the disorder (2).

Some data suggest that changes in neurogenesis might belinked to the pathophysiology of MDD. A decrease in neurogen-esis has been shown in animal models of depression (3,4) andtreatment with antidepressants increased the number of surviv-ing newborn neurons in adult rodents (5–7). Research onneurogenesis might ultimately lead to new therapies for neuraldegeneration or lesions. However, it is unlikely that neurogenic

From the Department of Psychiatry (CN, JH, BF, DR, UV, CN), UniversityMedical Center Freiburg, Freiburg, Germany; Department of Psychology(JB), University of Freiburg, Freiburg, Germany; Department of Psychol-ogy (JB), Stanford University, Palo Alto, California; and Schön Klinik Rose-neck (UV), Prien am Chiemsee, Germany.

Address corespondence to Christoph Nissen, M.D., Department of Psychia-try and Psychotherapy, University Medical Center Freiburg, Haupt-strasse 5, 79104 Freiburg, Germany; E-mail: [email protected].

tReceived Feb 2, 2010; revised May 17, 2010; accepted May 19, 2010.

0006-3223/$36.00doi:10.1016/j.biopsych.2010.05.026

rocesses, which have been demonstrated to be limited to theentate gyrus of the hippocampus and the olfactory bulb in adultodents (8), represent a sufficient mechanism to explain theroad spectrum of biological and clinical alterations in MDD (9).

More recently, the idea has been put forward that shifts inynaptic plasticity and related network activity might be criticalor the development of MDD (2,10–13). In contrast to neurogen-sis, long-term potentiation (LTP) and long-term depressionLTD)—two basic mechanisms for experience-dependent modi-ication of synaptic strength—have been described in virtuallyvery brain region across species, including humans (14–17).lectrophysiological studies revealed that chronic mild stressacilitates hippocampal LTD in an animal model of depression3). Other models of chronic stress have also demonstrated anmpairment in LTP (18–20).

Recently, our group reported that the modulation of earlyomponents of the visual evoked potential shares propertiesith Hebbian forms of synaptic plasticity and is altered inepressed subjects relative to nondepressed ones (13). This haseen interpreted as the first evidence for reduced LTP-dependentlasticity in the cortex of patients with MDD (21). Despite theromise of this line of research, fundamental questions persistegarding the subtypes of plasticity, the distribution of plastichanges across brain networks, and the relationship of thesehanges to the clinical symptoms of the disorder.

eurocircuitry Models of Depression

Current models emphasize the relevance of two neuralystems in emotional behavior: a ventral emotional system,omprising the amygdala, insula, ventral striatum, and ventralarts of the anterior cingulate cortex and prefrontal cortex anddorsal executive system, comprising the hippocampus, theorsal anterior cingulate cortex, and the dorsolateral prefron-
al cortex (22). Studies have suggested that the ventral system
BIOL PSYCHIATRY 2010;68:544–552© 2010 Society of Biological Psychiatry

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has increased activity, whereas the dorsal system has de-creased activity in MDD (23). These changes have been linkedto clinical characteristics of the disorder, including emotionalhyperarousal (ventral system) and executive deficits (dorsalsystem) (24,25).

Notably, stress, one of the main precipitating factors of MDD(26) and a strong modulator of long-term synaptic plasticity(19,27–29), has been shown to both impair LTP and facilitate LTDin the hippocampus but increase LTP in the amygdala (30),providing a potential link between features of neuroplasticityand brain circuitry models of MDD.

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ere presented 12 times, 4 in each block (early, middle, and late blocks). Imlectric shock (unconditioned stimulus [US]). The intertrial interval was 18xpectancy was assessed on a visual analogue scale. An electrical stimulatoilver/silver chloride electrodes for 100 msec in the right lower arm. Skin condf 500 Hz using the Neuroscan Synamps 1 system (Neuroscan Compumed

he middle phalanx of the index and the middle fingers of the left hand, ulectrode paste. Respiration was measured to allow for the detection andubtracting the average skin conductance level within 1 sec before CS onsetormalized using a log-transformation. (C) Trial sequence in the texture disc

he screen and activated the target frame consisting of a central fixation learray of three diagonal bars). Subjects had to discriminate whether the thrnsures good fixation and shows only modest improvement with practice,ependent component, with improved discrimination after practice. An immxation. No feedback was given for the target-texture discrimination. Each ponfiguration) appearing in the lower left quadrant of the visual field (2.5°–5°

.76° apart). The display size was 13 � 13° of visual angle, on either side of theead movements, using a 1024 � 768 pixel screen resolution with a 60 Hzresenting stimuli and recording responses with precise timing. The time in
ask-onset asynchrony) was decreased in a stepwise fashion, depending on
timulus; SOA, stimulus-to-mask-onset asynchrony; US, unconditioned stimulus.

earning As a Model for Synaptic Plasticity

Long-term synaptic plasticity is believed to be the molecular basis ofearning and memory (14,31,32). Here, we examined learning andemory as an accessible correlate of synaptic plasticity in humans

14,31) to further test the synaptic plasticity hypothesis of MDD.Three well-described memory tasks for which learning has been

hown to depend on local synaptic refinement in areas of interestave been selected: hippocampus-dependent declarative word-pairearning (33), amygdala-dependent classical fear conditioning (FC)34), and primary cortex-dependent visual texture discrimination

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re required to study 40 word-pairs until they correctly recalled at least 24 oflearning. (B) Fear conditioning. During acquisition, both the CS� and CS�iately at the stimulus offset, each CS� (but not CS�) was followed by ansec (determined at random). Before and after acquisition, subjective US

-7D, Digitimer, Ltd., Hertfordshire, England) was used to deliver the US viance responses (SCRs) and rating information were recorded at a sample rateharlotte, North Carolina). Skin conductance responses were recorded for

11-mm inner diameter silver/silver chloride electrodes filled with isotoniclusion of spurious SCRs. Skin conductance responses were calculated byhe maximum SCR recorded in the first 4 sec after CS onset. Amplitudes wereation task. During each trial, participants fixated on a circle in the center ofa randomly rotated L or T (e.g., here L)—and the peripheral target textureget bars were vertical or horizontal (e.g., here horizontal). The central taskeas the detection of the peripheral target texture represents the learning-te auditory feedback was provided for letter identification to ensure centraleral target consisted of three diagonally oriented bars (horizontal or verticalcenter) on a background of 17 � 17 horizontal bars (.43 � .07° each, spaced

n (2.8° gap). Sessions were performed in a dark environment, with restrictedsh rate and a MATLAB toolbox (Keithley Instruments, Cleveland, Ohio) forl between the target frame and the onset of the mask pattern (stimulus-to-

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546 BIOL PSYCHIATRY 2010;68:544–552 C. Nissen et al.

(35). We hypothesized that patients with MDD would show 1)reduced declarative memory consolidation indicative of reducedhippocampal plasticity, 2) enhanced fear conditioning consistentwith increased amygdala-dependent plasticity, and 3) impairedvisual discrimination learning as a correlate of attenuated corticalplasticity, in comparison with healthy subjects.

Method and Materials

SubjectsTwenty-three patients with MDD and 35 healthy control (HC)

subjects aged 20 to 55 years participated in the study (n � 58). Afterbeing given a complete description of the study, written informedconsent was obtained from all participants. The procedures hadbeen approved by the local institutional review board. Depressedsubjects were inpatients at the Department of Psychiatry, Freiburg,and met ICD-10 criteria for severe unipolar depression (36). Theywere excluded if they met ICD-10 criteria for bipolar disorder,schizophrenia, schizoaffective disorder, lifetime history of substanceabuse, or borderline or antisocial personality disorder. Routineblood tests and magnetic resonance scanning were used to excludeorganic affective disorders. Four patients presented with a firstepisode, 19 with a recurrent disorder. The average age of MDDonset was 30.1 � 11.8 years, the duration of illness at the time ofparticipation was 9.3 � 9.0 years, the number of episodes was 4.1 �.1, the duration of the current episode was 20.5 � 16.7 weeks, and

the overall duration of antidepressive medication was 1.9 � 2.8ears. At the time of participation, all patients were receivingsychotherapy and stable medication (�2 weeks) with one or morentidepressants (nine selective serotonin reuptake inhibitors [SSRIs],ight venlafaxine, four mirtazapine, two bupropione, three tricyclicntidepressants, four lithium, one lamotrigine). None of the patientseceived any antipsychotics, tranquilizers, or other central nervousystem active compounds.

Healthy control subjects matched for sex, age, and IQ wereecruited from the community and reimbursed for their partici-ation. To rule out any comorbid physical or mental disorders,ll participants underwent an extensive diagnostic examination,ncluding a Composite International Diagnostic Interview. Allubjects had normal or corrected-to-normal vision. Participantsid not consume alcohol or caffeine during the study andmoked �10 cigarettes per day.

tudy DesignAll participants underwent a 2-day experimental protocol.

fter initial screening, a learning session of the word-pair andexture discrimination tasks took place on day 1 (4:00 PM–6:00

PM), which was followed by a retrieval session of the word-pairnd texture discrimination tasks 24 hours later on day 2 (4:00

PM–6:00 PM). The order of the word-pair and texture discrimina-ion tasks was balanced across subjects. A single fear-condition-ng session was performed after completion of the last word-air/texture discrimination task on day 2 to minimize the impactf interference related to arousal during fear conditioning.

linical AssessmentsThe following assessments were used to control for mental

ealth status, stress, sleep, IQ, and attention: Composite Interna-ional Diagnostic Interview (37), 21-item Hamilton Rating Scaleor Depression (38), Beck Depression Inventory (39), Becknxiety Inventory (40), Perceived Stress Questionnaire (41),ittsburgh Sleep Quality Index (42), a standard German teststimating premorbid intelligence (43), and the Test for Atten-
ional Performance (44). r

ord-Pair TaskThe word-pair task (Figure 1A) consisted of the sequential

resentation of 40 semantically related pairs of German nounsn a monitor, with a presentation rate of 5 sec and annterstimulus interval of 100 msec (Presentation Software,eurobehavioral Systems, Albany, California). Two additionalord pairs at the beginning and end of the task served touffer primacy and recency effects (33). Subjects were re-uired to recall the second word upon presentation of the firstcued recall, e.g., bird – eagle). Immediately after recall, theorrect paired-associate was revealed on the screen. On day 1,he list was presented repeatedly in different orders until theubject correctly recalled �24 words (60% criterion). On day, recall was assessed without further learning. Memoryonsolidation was calculated as the percentage of correctlyetrieved words on day 2 with respect to the number oforrectly encoded words on day 1 (retention rate, %).

ear ConditioningA classical differential fear conditioning paradigm was used

Figure 1B). A mild electric shock served as unconditionedtimulus (US). Equally sized, red color, geometric shapessquare, circle, triangle, ellipse) presented on a computer mon-tor served as conditioned (CS�) and nonconditioned (CS�)timuli. After attachment of the electrodes for skin conductanceeasurement and shock application, the intensity of the shocksas customized for each individual to a level described as

aversive but not painful.”During the 24 acquisition trials, each CS� was followed by an

lectric shock (CS�, 12 trials), whereas the CS� was not followedy the shock (CS�, 12 trials). In a slight modification of standardifferential tasks, we presented two different shapes for the CS�e.g., square and circle) and two shapes for the CS� (e.g., trianglend ellipse), expecting that this would lengthen the acquisitionrocess. This was done because in differential fear conditioning,aradigms learning occurs rapidly in neurologically intact humanubjects (e.g., [45] and J.B., unpublished data, 2010) and wexpected to detect more subtle group differences in acquisitionpeed and strength under these conditions. To control for shapeharacteristics, the assignment of shapes to the CS-type was coun-erbalanced across participants.

Before and after acquisition, subjective US expectancy wasssessed on a visual analogue scale, i.e., “How much do youxpect that this picture will be followed by a shock?” (46). As aelated but distinct test of explicit contingency learning, contin-ency awareness (the explicit knowledge that a specific CSredicts a specific US) was assessed verbally for each CS after FC,ifferentiating between subjects that were fully aware (both CS�nd CS� identified correctly), partially aware (at least one CS�dentified correctly), and unaware (no CS identified correctly).ecording and processing of skin conductance followed estab-

ished guidelines (47).

exture Discrimination TaskThe texture discrimination task (Figure 1C) closely followed

he procedures described by Karni and Sagi (35), who providedhe original software. On day 1, all participants were trained inlocks of 15 trials at 1000 msec and 400 msec time intervalsetween the target display and the mask (stimulus-to-mask-onsetsynchrony [SOA]) until they reached a criterion of �90% correctesponses. Then, successive blocks of 40 trials each were pre-ented with decreasing SOAs. Starting from 400 msec, SOA was
educed by 40 msec (�90% correct responses) or 20 msec (�90%

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correct responses) until a criterion of two blocks with � 70%correct responses was reached. On day 2, a block of 15 trials ata SOA of 400 msec was presented to keep conditions compara-ble. Then, successive blocks of 40 trials each were presentedwith decreasing SOAs, starting at 400 msec as described forday 1.

For every subject and day, the learning curve, correct (%)versus SOA, was fitted with a logistic function between thechance level of 50% and 100% with the parameters of the SOA atwhich 75% of the responses were correct (SOA75) and scale(describing the inverse slope at SOA75). Between-session im-provement was expressed in a reduction of SOA75. For visual-ization, group average curves were obtained by using theaveraged parameters for each group.

Data AnalysisDescriptive presentation of the data includes mean values and

standard deviations. Group comparisons of demographic andclinical characteristics were performed with t tests. A 2 � 2, timelearning, retrieval) � group (MDD, HC) analysis of varianceANOVA) with repeated measures on time was computed to testor differences in word-pair and texture discrimination learning.

2 � 3 � 2, stimulus (CS�, CS�) � time (early, middle, latelock) � Group (MDD, HC), ANOVA with repeated measures onS type and time was used to test for skin conductance responseSCR) differences in fear conditioning. Due to technical prob-ems, word-pair data were lost for three patients and five healthyubjects, texture discrimination task (TDT) data were lost for sixatients and six healthy subjects, and FC data were lost for fiveatients and none of the healthy subjects. The level of signifi-ance was set at p � .05.

Results

Demographic and Clinical CharacteristicsDemographic and clinical characteristics of the participants are

summarized in Table S1 in Supplement 1. Patients with MDD andhealthy subjects did not differ in the distribution of sex, age, and IQ.Patients with MDD reported significantly higher levels of depres-sion, anxiety, stress, and sleep complaints compared with healthysubjects. Neuropsychological testing revealed that MDD patientshad longer reaction times than healthy control subjects, pointing todifferences in attentional performance between the experimentalgroups.

Word-Pair TaskOn day 1, MDD patients and healthy control subjects did not

differ in the number of trials to criterion [patients 1.6 � .6, controlsubjects 1.8 � .6; F (1,48) � .8, p � .382] or in the final numberf correctly encoded word-pairs [patients 30.0 � 3.8, controlubjects 30.4 � 4.1; F (1,48) � 1.0, p � .759]. In the retrieval

session on day 2, depressed patients correctly recalled 25.2 � 5.7words and healthy subjects 27.4 � 4.7 words [F (1,48) � 2.3, p �139]. The repeated measures ANOVA showed a highly signifi-ant session � group interaction [F (1,48) � 8.2, p � .006; Figure], indicating a significant reduction in declarative memoryonsolidation in depressed patients (retention rate 82.3 � 11.8%)ompared with healthy subjects [91.3 � 10.6%; F (1,48) � 7.7,� .008].

Fear ConditioningTo capture the time course of differential fear conditioning,

SCRs were averaged in an early, middle, and late block, each
block containing four CS� and four CS� (Figure 3A). An
mnibus 2 � 3 � 2 CS type (CS�, CS�) � time (early, middle,ate) � group (HC, MDD) ANOVA with repeated measures on CSype and time yielded a significant CS type � group interactionF (1,50) � 5.2, p � .027], with the time � group interactionpproaching significance [F (1,49) � 2.4, p � .097]. To follow upn the CS type � group interaction, we collapsed across thehree levels of the time factor and used paired-sample t tests tovaluate CS type effects separately for both groups. Majorepressive disorder patients responded stronger to the CS� thano the CS� (t � -2.3, p � .037), whereas the control participantsid not show differential SCRs to the CSs (t � .6, p � .532)Figure 3B).

Unconditioned stimulus expectancy was analyzed in a 2 �� 2 CS type (CS�, CS�) � time (before, after acquisition) �

roup (HC, MDD) ANOVA. Both groups showed comparablexplicit learning of the CS–US contingencies, as evidenced by aignificant CS type � time interaction [F (3,48) � 8.3, p � .001]nd the absence of group effects (all Fs � 1.5) (Figure 3C).1

exture Discrimination TaskPatients with MDD demonstrated a significantly reduced

aseline performance compared with healthy subjects [F (2,42) �.6, p � .016], driven by a significant increase in the number of

Additional analyses revealed that healthy subjects (3.4 � .6 log �S) andMDD patients (3.2 � .7 log �S) did not differ in their SCR to the US(F � .8, p � .390), indicative for comparable levels of shockaversiveness. Twenty-three healthy subjects (65.7%) and 13 MDDpatients (76.5%) were fully aware of the CS-US contingency (that is,they correctly identified both CS� and both CS�). Percentages ofaware participants did not differ between the groups (X2 � .6, p �.430). Because it has been argued that differential skin conductanceconditioning may require awareness, we repeated the SCR analysisonly for fully aware participants. The critical CS type � groupinteraction remained significant (p � .044). Similarly, when skinconductance nonresponders (measurable signal but no responses toany stimulus) were excluded (1 HC and 2 MDD patients), the CS

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type � group interaction remained almost unchanged (p � .022).


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rials needed to reach the 90% criterion of correctly detectedargets in MDD patients (6.0 � 7.0) compared with healthyubjects [2.4 � 1.6; F (1,43) � 7.5, p � .009] and a significantlyrolonged SOA75 in patients (255.0 � 66.9 msec) relative toealthy subjects [206.7 � 76.1 msec; F (1,43) � 4.5, p � .039]. Theumber of correctly identified letters did not differ between theroups (p � .2).

Both groups showed a highly significant improvement inisual discrimination (SOA75) from day 1 to day 2 [F (1,43) �7.2, p � .001]. However, no significant session � groupnteraction was observed [F (1,43) � 2.3, p � .134]. Temporaliscriminative threshold performance curves for MDD patientsnd healthy subjects on days 1 and 2 are shown in Figure S1 inupplement 1.

orrelation AnalysesPearson correlation analyses within the group of MDD pa-

ients revealed a significant negative correlation between theord-pair retention rate and the total duration of illness (R �.5, p � .026). No other significant correlation between param-

ters of memory consolidation (word-pair retention, strength ofonditioning, improvement in visual discrimination) and clinicalharacteristics (Hamilton Rating Scale for Depression, Beckepression Inventory, duration of illness, duration of currentpisode, number of episodes) was observed (p � .1). Noorrelations between the main outcome parameters of the mem-ry tasks were observed (p � .1).

iscussion

This study investigated learning and memory as a model ofong-term synaptic plasticity in humans (14,31) to further test theeuroplasticity hypothesis of MDD (2). The results of the studyre consistent with the idea that patients with MDD showlterations in long-term synaptic plasticity. To probe plasticity inifferent brain networks, memory consolidation was assessedsing three tasks for which learning has been shown to stronglyepend on local synaptic refinement in brain regions of interest.

™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™igure 3. (A) Skin conductance response (SCR) levels during fear condition-

ng. The lines depict mean SCRs across single blocks (early, middle, and late).atients with major depressive disorder (MDD) (red dashed lines), but notealthy control subjects (black solid lines), showed a significant increase inCR to the CS� (bold line) in the late block relative to the CS� (slim line). Allalues were normalized using log-transformation. Data represent means.p � .05, by analysis of variance (ANOVA). (B) Skin conductance responseevels to conditioned stimuli. The bars depicted represent SCRs to both theS� and CS�. Reactions to the conditioned stimuli were different for pa-

ients with MDD (red bars) compared with healthy control subjects (blackars), as evidenced by the significant interaction between conditioned stim-lus (CS) type � group. Within the MDD group, reactions to the CS� wereignificantly higher to the CS� than to the CS�. All values were normalizedsing log-transformation. Bars represent means � SEM. *p � .05, by ANOVA.

C) Unconditioned stimulus (US) expectancy ratings. The lines depict subjectiveS expectancy ratings before and after acquisition. Positive values represent

he expectancy that a CS will be followed by the US and negative values that theS will not be followed by the US. Both groups showed comparable explicit

earning of the CS–US contingencies, as evidenced by a significant CS type �ime interaction and the absence of group effects. Data represent means.**p � .001, by ANOVA. CS�, conditioned stimulus; CS�, nonconditionedtimulus; HC, healthy control subjects; MD, major depression; Post, after acqui-

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Declarative MemoryDeclarative memory consolidation refers to a process by

which the newly encoded and initially unstable memory traces offacts or knowledge, such as the word-pairs used in this study,become stabilized and integrated into long-term representations(48–50). Converging evidence from animal and human studies(51) indicates that declarative learning depends on synapticrefinement in a hippocampal-neocortical network (52,53).

Patients with MDD have shown cognitive deficits (54,55) thatmight be pronounced in domains that depend on hippocampaland medial temporal lobe function (56,57). In this study, weobserved a significant deficit in declarative memory consolida-tion in depressed compared with nondepressed subjects. Ofnote, both experimental groups showed virtually identical levelsof initial encoding and retrieval. The deficit was limited to thestage of consolidation. This finding poses difficulties for expla-nations suggesting that the results might be solely driven bygeneral cognitive or motivational deficits. Our findings areinstead more consistent with the initial hypothesis of attenuatedlong-term synaptic plasticity in a brain network that comprisesthe hippocampus under conditions of MDD. The observednegative correlation between declarative memory consolidationand the duration of illness is consistent with previous workshowing deficits in hippocampal volume size with an increasingnumber of past days depressed (58). However, our correlationanalysis has been exploratory in nature (not controlled formultiple testing) and requires further investigation.

Fear ConditioningIt is now widely believed that the association between a

conditioned and unconditioned stimulus that is formed in fearconditioning involves local synaptic plasticity in the form oflong-term synaptic potentiation in pathways of the lateral amyg-dala (34,59,60). The lateral nucleus of the amygdala serves as asensory interface that receives input from the sensory thalamusand cortical structures (61,62). Via the central nucleus, the lateralamygdala projects to areas responsible for mediating fear reac-tions, such as elevated SCR assessed in this study (63,64).

To our knowledge, this is the first study that investigated fearonditioning in MDD and showed enhanced conditioning inepressed compared with nondepressed subjects. Uncondi-ioned stimulus expectancy ratings and contingency awarenessests indicated high and comparable levels of cognitive represen-ations of the association between the CS and US in both groups.owever, only MDD patients showed a differential SCR to theonditioned stimuli.

The dissociation between physiological responses and ex-licit knowledge of the CS–US pairing in healthy subjects isonsistent with the existence of multiple, partly independentortical and subcortical systems in emotional learning (34,65).

The absence of a group difference in explicit learning suggeststhat increased autonomic FC in MDD relies on enhancedsubcortical learning and underlying synaptic long-term plas-ticity, presumably at the level of the lateral amygdala. Thatsaid, it has to be acknowledged that FC in humans likelyinvolves other brain structures such as the hippocampus,insula, and prefrontal regions (66,67). However, brain imagingstudies in healthy humans (68) and findings in patients withamygdala lesion (65,69) indicate that, even though otherstructures are involved, the amygdala represents the centrallocation of fear acquisition and the expression of autonomic
responses (70).
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exture DiscriminationIn texture discrimination, performance improves with practice

perceptual learning) (71). This learning has been shown to be 1)ocal (in a retinotopic sense), 2) specific to the trained stimulus,nd 3) strongly monocular (there is little intraocular transfer ofearning) (35). These features indicate that this type of learningust emerge from experience-dependent synaptic modification

n the cortex, presumably at the level of orientation-gradientensitive cells in primary visual cortex (V1) (72). The locationpecificity of learning has been shown to be paralleled bynhancement in functional magnetic resonance imaging signal inhe trained region of V1 after retinotopic training (73,74).

Assuming stereotyped algorithms of cortical operations, theurrent study attempted to use texture discrimination as anccessible method to study cortical plasticity in MDD. However,n contradiction to our prediction, we observed significanterformance deficits in depressed compared with nondepressedubjects already in the initial training phase at baseline. Fromhere, we detected no significant difference between the exper-mental groups in the gradual improvement from day 1 to day 2,he plasticity-dependent phase of the task.

Whereas early work has emphasized that TDT improvementtrongly depends on plastic changes in low-level V1 (35,75), ouresults are consistent with recent studies pointing to an involve-ent of higher-level cortical processes in tuning activity and

ynaptic refinement in V1 (76,77). Thus, the attenuated baselineerformance in MDD patients might reflect higher-level cognitiveeficits, e.g., shown for attention in the present sample, withoutroviding evidence for alterations of synaptic plasticity at the

evel of the primary cortex.

trengths and Limitations of the StudyTo our knowledge, this is the first study exploring basic forms

f learning to further test the neuroplasticity hypothesis of MDD.trengths include a well-defined sample of severely depressednpatients and healthy comparison subjects matched accordingo sex, age, and IQ. A limitation is that the changes observed inepression might not be specific to learning and neural plasticityut instead rely on a general neurocognitive dysfunction. How-ver, the differential finding of attenuated declarative memoryonsolidation and enhanced fear conditioning in MDD patientsannot be explained by general cognitive or motivational dys-unction but rather points to more specific changes in synapticeorganization in distinct neural networks.

An additional limitation stems from the fact that all patientseceived treatment with antidepressant medication (restricted to

igure 4. Depression model. The neuroplasticity hypothesis of depressionroposes that a dysfunction in neural plasticity plays a key role in thetiology of depression. We propose that genetically determined and envi-onmentally modulated alterations in brain plasticity differentially affecteural circuits of interest for depression, resulting in elevated plasticity in anmotional neural system that includes the amygdala and attenuated plas-
icity in a control system that occludes the hippocampus and broad corticalreas.

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stable medication with mainly SSRIs) following standard guidelinesfor MDD (78). All participants were free of any antipsychotic orsedative substances. Because discontinuing medication for experi-mental procedures would contravene the evidence-based and eth-ical consensus for the treatment of severe depression, an alternativestrategy to control for effects of medication would be to exposehealthy subjects to antidepressant treatments (e.g. [13]). In thecurrent study, we decided against this for two reasons: first, admin-istration of antidepressants to healthy subjects might differ in itseffects compared with those in MDD patients, which limits thevalidity of such a control. Second, there is strong evidence thatadministration of antidepressants, including SSRIs, leads to anupregulation of long-term synaptic plasticity in the hippocampus(3,79) and declarative learning in rats (80). Successful SSRI treatmentsignificantly improved verbal declarative memory in patients withMDD (81). Conversely, studies indicate that chronic SSRI treatmentimpairs the acquisition of conditioned fear (82–84). This is consis-tent with clinical data showing that long-term treatment is anxiolytic(85). These findings are contradictory to the results observed in thecurrent sample of patients and lead us to assume that the mainfindings of our study are not driven by the effects of medication.Instead, it might be that the effects in MDD patients would be evenmore pronounced in the absence of pharmacological treatment.

Additional animal and human studies will be needed 1) tofurther characterize the specific subtypes of plastic alterationsthat are occurring in MDD (e.g., different types of long-termsynaptic plasticity, neurogenesis), 2) to investigate plasticityprocesses across different brain structures (e.g., examining cor-tical areas using tools that are more independent from attention,such as transcranial magnetic stimulation), and 3) to furtherelucidate the impact of various factors intimately linked todepression and brain plasticity, such as the impact of sleep(86,87) (e.g., experimental sleep disruptions in healthy subjects)and stress (19,27–29) (e.g., stress paradigms in healthy subjects).

The Neuroplasticity Hypothesis of DepressionTogether, the data provide support for the neuroplasticity

hypothesis of MDD. The results corroborate previous findings ofattenuated synaptic long-term plasticity in MDD (13) and extendthis work by adding a neurocircuitry perspective (Figure 4). Thedata support the notion that, in MDD, there is an elevation insynaptic plasticity in an emotional system that includes theamygdala, concurrent with decreased plasticity in a more exec-utive network subserved by the hippocampus (23,25).

Chronic synaptic shifts might mediate modifications of neuralmorphology (88). These might include reduced synaptic densityand volume of the hippocampus (58,89,90) and enhanced syn-aptic growth and volume of the amygdala in MDD (91–94),perhaps due to opposite, stress-related neurotoxicity of glu-cocorticoids in both structures (95,96). Lastly, this pattern mightcontribute to clinical symptoms of the disorder, such as elevatedanxiety and executive deficits in MDD.

The presence of residual neuroplastic deficits in antidepressant-treated patients highlights a potentially important limitation of theefficacy of SSRI treatment of MDD, consistent with the results fromthe Sequenced Treatment Alternatives to Relieve Depression trial(97). As a result, further exploring strategies to modulate synapticplasticity beyond the level of aminergic/cholinergic neurotransmis-sion, based on a broad preclinical body of evidence, might proveuseful for developing novel treatments for MDD.

The study was funded by intramural funds of the Department
of Psychiatry and Psychotherapy, Freiburg; a Research Grant
1


rovided by the Research Committee, University Medical Centerreiburg; and a J. Christian Gillin, M.D., Research Grant pro-ided by the American Sleep Research Society Foundation to Dr.issen.

The authors thank Yoram Bonneh and Dov Sagi for providinghe software for texture discrimination learning. The authors alsohank the doctoral students and technical staff at the Department ofsychiatry and Psychotherapy, Freiburg, for their help in conduct-

ng the study.Dr. Nissen has received speaker honoraria from Sanofi-

ventis and Lundbeck. In the past 2 years, Dr. Normann haseceived research support from Lundbeck. He has served as annvestigator on trials sponsored by Janssen, Hoffmann-La Roche,nd Lundbeck. He has served on an advisory board for Bristol-yers Squibb and has received speaker honoraria from Pfizer,laxoSmithKline, AstraZeneca, and Lilly. Dr. Voderholzer has

eceived speaker honoraria from Sanofi-Aventis, Lundbeck,fizer, Cephalon, and Lilly. He has been principal investigator ofn investigator initiated trial sponsored by Lundbeck. Dr. Ri-mann has served as an advisory board member of Sanofi-ventis, Lundbeck, and GlaxoSmithKline. He has received speakeronoraria from Sanofi-Aventis, Lundbeck, GlaxoSmithKline,nd Servier and has received research support from Sanofi-ventis, Omron, Organon, Takeda, and Actelion. J. Holz, Dr.lechert, and Dr. Feige have indicated no biomedical financial

nterests or potential conflicts of interest.

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