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Human Brain Mapping 35:4293–4302 (2014)
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Altered Neural Function During Episodic Memory Encoding and Retrieval in Major Depression Bruno Dietsche,* Heidelore Backes, Mirjam Stratmann, Carsten Konrad, Tilo Kircher, and Axel Krug Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Germany r
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Abstract: Memory impairments are common in major depression. Neural processing during non-emotional episodic memory in depressed patients has only sparsely been investigated, since the majority of studies have focused on emotional stimuli. The aim of this study was to explore neural correlates of episodic memory in depressive patients and to assess brain regions related to subsequent memory performance. Forty-six participants (23 depressed patients) performed a non-emotional episodic memory encoding and retrieval task while brain activation was measured with functional magnetic resonance imaging. Patients with depression showed decreased activation in the right prefrontal cortex and right cingulate cortex during memory encoding, but increased activation in the right inferior frontal gyrus (IFG) during recognition memory. While a strong association between hippocampal and parahippocampal activation during memory encoding with subsequent memory performance became evident in healthy controls, this relationship was absent in patients with depression. Taken together, these findings demonstrate that memory related brain regions are affected in their appropriate functioning during memory encoding in depressed patients. Therefore, patients with depression may rely to a greater degree on other brain regions such as the IFG during episodic memory retrieval. Hum Brain Mapp C 2014 Wiley Periodicals, Inc. V 35:4293–4302, 2014. Key words: major depression; episodic memory; fMRI; hippocampal formation; prefrontal cortex r
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INTRODUCTION Contract grant sponsor: Deutsche Forschungsgemeinschaft (German Research Foundation); Contract grant number: KR 3822/2-1; Contract grant sponsor: Research Grant of the University Medical Center Gießen and Marburg (UKGM); Contract grant number: 11/2010 MR.; Contract grant sponsor: The authors report no conflict of interest. Conflict of Interest: The authors report no conflict of interest. *Correspondence to: Bruno Dietsche, Department of Psychiatry and Psychotherapy, Philipps-University Marburg, RudolfBultmann-Str. 8, 35039 Marburg, Germany. E-mail: Dietsche@ med.uni-marburg.de Received for publication 2 May 2013; Revised 20 December 2013; Accepted 13 January 2014. DOI 10.1002/hbm.22475 Published online 17 March 2014 in Wiley Online Library (wileyonlinelibrary.com). C 2014 Wiley Periodicals, Inc. V
Major depression is a common mental disorder, which is accompanied by cognitive deficits. Meta-analytical findings indicate that episodic memory problems are among the most impaired cognitive domains in patients with depression [Burt et al., 1995; Lee et al., 2012; McDermott and Ebmeier, 2009; Zakzanis et al., 1998]. Despite a strong neuropsychological tradition of non-emotional episodic memory research in major depression, only relatively few functional neuroimaging studies have previously been carried out using non-emotional stimuli [e.g., Fairhall et al., 2010; Kelley et al., 2013; Milne et al., 2012; van Eijndhoven et al., 2011]. Generally, episodic memory has been associated with a widespread network of brain regions including the medial temporal lobe (MTL) and the prefrontal cortex
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Dietsche et al.
(PFC) [Cabeza and Nyberg, 2000; Dickerson and Eichenbaum, 2010; Eichenbaum et al., 2007; Fernandez and Tendolkar, 2001; Nyberg et al., 2003]. Among MTL structures the hippocampus has been shown to be critically involved in episodic memory processing [Kircher et al., 2008; Kirwan and Stark, 2004; Wang and Morris, 2010]. Furthermore, meta-analytical findings indicate hippocampal activation during memory encoding to be highly predictive for successful memory formation [Kim, 2011; Spaniol et al., 2009]. The PFC, which is strongly connected with MTL structures, has been shown to be crucial for episodic memory processing. The various PFC subregions subserve selection and maintaining of incoming information, forming and organizing associations between items, as well as monitoring and evaluation of items [Blumenfeld and Ranganath, 2007; Cabeza and Nyberg, 2003; Spaniol et al., 2009]. Compared with healthy subjects, there is a growing consensus that patients with depression show neural alterations mainly in the MTL, PFC, and cingulate cortex during non-emotional episodic memory processing [Bremner et al., 2004; Fairhall et al., 2010; Kelley et al., 2013; Milne et al., 2012; Werner et al., 2009; van Eijndhoven et al., 2011]. In particular, functional neuroimaging studies have provided evidence that depression is associated with hippocampal and cingulate hypoactivity during memory processing [Bremner et al., 2004; Diener et al., 2012; Fairhall et al., 2010; Kelley et al., 2013; Milne et al., 2012; Young et al., 2012]. However, regarding the PFC, significant differences in the functional role of various subregions have been found in depressed patients, which demonstrated hypoactivity as well as hyperactivity during memory encoding and recognition [Aihara et al., 2007; Bremner et al., 2004; Kelley et al., 2013; van Eijndhoven et al., 2011; Werner et al., 2009]. While most studies have explored the neural correlates of non-emotional memory using verbal memory tasks, there are only two studies applying a face association learning paradigm [Fairhall et al., 2010; Werner et al., 2009]. Fairhall et al. [2010] investigated exclusively encoding processes and identified hippocampal dysregulations during a face-name association memory task in patients with major depression. However, only eight young depressed outpatients were included in this study, which limits the generalizability of the results. Besides, the authors focused on a priori selected regions-of-interest. In contrast, Werner et al. [2009] examined whole brain activation patterns between eleven outpatients with depression and eleven healthy controls during memory encoding and recognition in a face-profession association task. They found differences in memory-related brain regions between both groups, but did not show an involvement of the hippocampus. Again, only a small number of depressed outpatients were included. Moreover, the authors used emotional biased stimuli that might confound the outcome. Our study focused on two objectives. First, we explored the neural correlates of memory encoding and recognition
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of neutral faces in patients with major depression, in order to minimize an emotional related memory bias. Regarding previous findings, we expected neural alterations in prefrontal regions, hippocampal formation, and cingulate cortex during memory encoding and recognition in patients with depression compared with healthy controls [e.g., Bremner et al., 2004; Kelley et al., 2013; Werner et al., 2009]. Second, we assessed brain regions related to the individual memory performance. We expected a strong relationship between MTL structures and memory performance in healthy controls, but not in depressive patients due to disorder-related aberrant functioning of these structures.
MATERIALS AND METHODS Participants A total of 23 inpatients from the Department of Psychiatry and Psychotherapy at the Philipps-University Marburg, Germany, diagnosed with a current depressive disorder according to the International Classification of Diseases (ICD-10) and 23 healthy controls participated in this study (see Table I). Additional affective ratings were assessed with the German versions of the Beck Depression Inventory (BDI) [Hautzinger et al., 1994] and the Hamilton Depression Rating Scale (HAM-D) [CIPS, 2005]. Patients were included if they suffered primarily from either a first (n 5 5) or a recurrent episode (n 5 18) of unipolar depression. Ten patients did not have any comorbidities and seven patients additionally fulfilled the criteria for a dysthymic disorder (“double depression”). Patients with another comorbiditiy were only included if the depression was the reason for current hospitalization. Therefore, patients with the following comorbidities were included: social phobia (n 5 2), somatoform disorder (n 5 2), and dependent or narcissistic personality disorder (n 5 2). Three patients did not receive any medication and 20 patients were treated according to the current treatment guidelines at time of inclusion. Patients received an antidepressant monotherapy (n 5 13), combined antidepressant therapy (n 5 3), or combined antidepressant and antipsychotic pharmacotherapy (n 5 4). Patients with a history of manic or psychotic episodes as well as patients with comorbid alcohol or substance dependence (life time diagnosis) were excluded from this study. In general, participants were excluded if they had major medical or neurological disorders, mental retardation, medication likely to influence cognitive function, current alcohol or drug abuse, history of lifetime alcohol or drug dependence, were younger than 18 years or older than 60 years, or fulfilled general MRI exclusion criteria. Additional exclusion reasons for healthy controls were a current or a lifetime history of a psychiatric disorder assessed with the German version of the Structured Clinical Interview for DSM-IV (SCID-I) [Wittchen et al., 1997] or first-
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Neural Function During Episodic Memory in MDD
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TABLE I. Sociodemographic, clinical, and performance variables of the two groups
Age Gender (f/m) Years of education BDIa HAMDb,c VLMTd Immediate recall Delayed recall Correctly recognized items Performance during fMRI tasks Encoding task Reaction time (ms) Correct gender identification (%) Recognition task Reaction time (ms) Correctly recognized items
Patients
Controls
M (SD)
M (SD)
t -value
P
36.69 (10.35) 14/9 10.95 (1.71) 29.39 (5.86) 17.75 (3.64)
37.13 (10.42) 14/9 11.43 (1.53) 2.65 (2.20)
0.14
0.88
0.99 20.48
0.32
Human Brain Mapping 35:4293–4302 (2014)
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Altered Neural Function During Episodic Memory Encoding and Retrieval in Major Depression Bruno Dietsche,* Heidelore Backes, Mirjam Stratmann, Carsten Konrad, Tilo Kircher, and Axel Krug Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Germany r
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Abstract: Memory impairments are common in major depression. Neural processing during non-emotional episodic memory in depressed patients has only sparsely been investigated, since the majority of studies have focused on emotional stimuli. The aim of this study was to explore neural correlates of episodic memory in depressive patients and to assess brain regions related to subsequent memory performance. Forty-six participants (23 depressed patients) performed a non-emotional episodic memory encoding and retrieval task while brain activation was measured with functional magnetic resonance imaging. Patients with depression showed decreased activation in the right prefrontal cortex and right cingulate cortex during memory encoding, but increased activation in the right inferior frontal gyrus (IFG) during recognition memory. While a strong association between hippocampal and parahippocampal activation during memory encoding with subsequent memory performance became evident in healthy controls, this relationship was absent in patients with depression. Taken together, these findings demonstrate that memory related brain regions are affected in their appropriate functioning during memory encoding in depressed patients. Therefore, patients with depression may rely to a greater degree on other brain regions such as the IFG during episodic memory retrieval. Hum Brain Mapp C 2014 Wiley Periodicals, Inc. V 35:4293–4302, 2014. Key words: major depression; episodic memory; fMRI; hippocampal formation; prefrontal cortex r
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INTRODUCTION Contract grant sponsor: Deutsche Forschungsgemeinschaft (German Research Foundation); Contract grant number: KR 3822/2-1; Contract grant sponsor: Research Grant of the University Medical Center Gießen and Marburg (UKGM); Contract grant number: 11/2010 MR.; Contract grant sponsor: The authors report no conflict of interest. Conflict of Interest: The authors report no conflict of interest. *Correspondence to: Bruno Dietsche, Department of Psychiatry and Psychotherapy, Philipps-University Marburg, RudolfBultmann-Str. 8, 35039 Marburg, Germany. E-mail: Dietsche@ med.uni-marburg.de Received for publication 2 May 2013; Revised 20 December 2013; Accepted 13 January 2014. DOI 10.1002/hbm.22475 Published online 17 March 2014 in Wiley Online Library (wileyonlinelibrary.com). C 2014 Wiley Periodicals, Inc. V
Major depression is a common mental disorder, which is accompanied by cognitive deficits. Meta-analytical findings indicate that episodic memory problems are among the most impaired cognitive domains in patients with depression [Burt et al., 1995; Lee et al., 2012; McDermott and Ebmeier, 2009; Zakzanis et al., 1998]. Despite a strong neuropsychological tradition of non-emotional episodic memory research in major depression, only relatively few functional neuroimaging studies have previously been carried out using non-emotional stimuli [e.g., Fairhall et al., 2010; Kelley et al., 2013; Milne et al., 2012; van Eijndhoven et al., 2011]. Generally, episodic memory has been associated with a widespread network of brain regions including the medial temporal lobe (MTL) and the prefrontal cortex
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Dietsche et al.
(PFC) [Cabeza and Nyberg, 2000; Dickerson and Eichenbaum, 2010; Eichenbaum et al., 2007; Fernandez and Tendolkar, 2001; Nyberg et al., 2003]. Among MTL structures the hippocampus has been shown to be critically involved in episodic memory processing [Kircher et al., 2008; Kirwan and Stark, 2004; Wang and Morris, 2010]. Furthermore, meta-analytical findings indicate hippocampal activation during memory encoding to be highly predictive for successful memory formation [Kim, 2011; Spaniol et al., 2009]. The PFC, which is strongly connected with MTL structures, has been shown to be crucial for episodic memory processing. The various PFC subregions subserve selection and maintaining of incoming information, forming and organizing associations between items, as well as monitoring and evaluation of items [Blumenfeld and Ranganath, 2007; Cabeza and Nyberg, 2003; Spaniol et al., 2009]. Compared with healthy subjects, there is a growing consensus that patients with depression show neural alterations mainly in the MTL, PFC, and cingulate cortex during non-emotional episodic memory processing [Bremner et al., 2004; Fairhall et al., 2010; Kelley et al., 2013; Milne et al., 2012; Werner et al., 2009; van Eijndhoven et al., 2011]. In particular, functional neuroimaging studies have provided evidence that depression is associated with hippocampal and cingulate hypoactivity during memory processing [Bremner et al., 2004; Diener et al., 2012; Fairhall et al., 2010; Kelley et al., 2013; Milne et al., 2012; Young et al., 2012]. However, regarding the PFC, significant differences in the functional role of various subregions have been found in depressed patients, which demonstrated hypoactivity as well as hyperactivity during memory encoding and recognition [Aihara et al., 2007; Bremner et al., 2004; Kelley et al., 2013; van Eijndhoven et al., 2011; Werner et al., 2009]. While most studies have explored the neural correlates of non-emotional memory using verbal memory tasks, there are only two studies applying a face association learning paradigm [Fairhall et al., 2010; Werner et al., 2009]. Fairhall et al. [2010] investigated exclusively encoding processes and identified hippocampal dysregulations during a face-name association memory task in patients with major depression. However, only eight young depressed outpatients were included in this study, which limits the generalizability of the results. Besides, the authors focused on a priori selected regions-of-interest. In contrast, Werner et al. [2009] examined whole brain activation patterns between eleven outpatients with depression and eleven healthy controls during memory encoding and recognition in a face-profession association task. They found differences in memory-related brain regions between both groups, but did not show an involvement of the hippocampus. Again, only a small number of depressed outpatients were included. Moreover, the authors used emotional biased stimuli that might confound the outcome. Our study focused on two objectives. First, we explored the neural correlates of memory encoding and recognition
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of neutral faces in patients with major depression, in order to minimize an emotional related memory bias. Regarding previous findings, we expected neural alterations in prefrontal regions, hippocampal formation, and cingulate cortex during memory encoding and recognition in patients with depression compared with healthy controls [e.g., Bremner et al., 2004; Kelley et al., 2013; Werner et al., 2009]. Second, we assessed brain regions related to the individual memory performance. We expected a strong relationship between MTL structures and memory performance in healthy controls, but not in depressive patients due to disorder-related aberrant functioning of these structures.
MATERIALS AND METHODS Participants A total of 23 inpatients from the Department of Psychiatry and Psychotherapy at the Philipps-University Marburg, Germany, diagnosed with a current depressive disorder according to the International Classification of Diseases (ICD-10) and 23 healthy controls participated in this study (see Table I). Additional affective ratings were assessed with the German versions of the Beck Depression Inventory (BDI) [Hautzinger et al., 1994] and the Hamilton Depression Rating Scale (HAM-D) [CIPS, 2005]. Patients were included if they suffered primarily from either a first (n 5 5) or a recurrent episode (n 5 18) of unipolar depression. Ten patients did not have any comorbidities and seven patients additionally fulfilled the criteria for a dysthymic disorder (“double depression”). Patients with another comorbiditiy were only included if the depression was the reason for current hospitalization. Therefore, patients with the following comorbidities were included: social phobia (n 5 2), somatoform disorder (n 5 2), and dependent or narcissistic personality disorder (n 5 2). Three patients did not receive any medication and 20 patients were treated according to the current treatment guidelines at time of inclusion. Patients received an antidepressant monotherapy (n 5 13), combined antidepressant therapy (n 5 3), or combined antidepressant and antipsychotic pharmacotherapy (n 5 4). Patients with a history of manic or psychotic episodes as well as patients with comorbid alcohol or substance dependence (life time diagnosis) were excluded from this study. In general, participants were excluded if they had major medical or neurological disorders, mental retardation, medication likely to influence cognitive function, current alcohol or drug abuse, history of lifetime alcohol or drug dependence, were younger than 18 years or older than 60 years, or fulfilled general MRI exclusion criteria. Additional exclusion reasons for healthy controls were a current or a lifetime history of a psychiatric disorder assessed with the German version of the Structured Clinical Interview for DSM-IV (SCID-I) [Wittchen et al., 1997] or first-
4294
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Neural Function During Episodic Memory in MDD
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TABLE I. Sociodemographic, clinical, and performance variables of the two groups
Age Gender (f/m) Years of education BDIa HAMDb,c VLMTd Immediate recall Delayed recall Correctly recognized items Performance during fMRI tasks Encoding task Reaction time (ms) Correct gender identification (%) Recognition task Reaction time (ms) Correctly recognized items
Patients
Controls
M (SD)
M (SD)
t -value
P
36.69 (10.35) 14/9 10.95 (1.71) 29.39 (5.86) 17.75 (3.64)
37.13 (10.42) 14/9 11.43 (1.53) 2.65 (2.20)
0.14
0.88
0.99 20.48
0.32
