Altered brain function underlying verbal memory encoding and retrieval in psychotic major depression Ryan Kelley a,b , Amy Garrett a,b,n , Jeremy Cohen a , Rowena Gomez b , Anna Lembke b , Jennifer Keller b , Allan L. Reiss a,b,c , Alan Schatzberg b a Center for Interdisciplinary Brain Sciences Research, Stanford University School of Medicine, Stanford, CA 94305, USA b Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA c Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA article info Article history: Received 15 July 2011 Received in revised form 10 May 2012 Accepted 12 June 2012 Keywords: Depression Psychosis Functional imaging Verbal declarative memory Hippocampus Encoding deficits abstract Psychotic major depression (PMD) is associated with deficits in verbal memory as well as other cognitive impairments. This study investigated brain function in individuals with PMD during a verbal declarative memory task. Participants included 16 subjects with PMD, 15 subjects with non-psychotic major depression (NPMD) and 16 healthy controls (HC). Functional magnetic resonance imaging (fMRI) data were acquired while subjects performed verbal memory encoding and retrieval tasks. During the explicit encoding task, subjects semantically categorized words as either ‘‘man-made’’ or ‘‘not man- made.’’ For the retrieval task, subjects identified whether words had been presented during the encoding task. Functional MRI data were processed using SPM5 and a group by condition ANOVA. Clusters of activation showing either a significant main effect of group or an interaction of group by condition were further examined using t-tests to identify group differences. During the encoding task, the PMD group showed lower hippocampus, insula, and prefrontal activation compared to HC. During the retrieval task, the PMD group showed lower recognition accuracy and higher prefrontal and parietal cortex activation compared to both HC and NPMD groups. Verbal retrieval deficits in PMD may be associated with deficient hippocampus function during encoding. Increased brain activation during retrieval may reflect an attempt to compensate for encoding deficits. & 2012 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Depression can be regarded as a heterogeneous condition, likely consisting of various subtypes associated with family psychiatric history, cognitive profiles and clinical features (Keller et al., 2007; Carragher et al., 2009). It has been estimated that 1 in 6 individuals with major depression also demonstrate psychotic features (psychotic major depression; PMD) (Johnson et al., 1991; Parker et al., 1992; Ohayon and Schatzberg, 2002). Nosological data have emerged since the early 1980s suggesting PMD and non-psychotic major depression (NPMD) are, indeed, separate subtypes of depression (Keller et al., 2007). PMD is associated with greater duration and severity of symptoms compared to NPMD (Nelson and Charney, 1981; Rothschild et al., 1989; Fleming et al., 2004; Keller et al., 2006; Maj et al., 2007). Additionally, individuals with PMD show greater cognitive deficits in verbal memory, attention and executive functioning compared to NPMD (Basso and Bornstein, 1999; Schatzberg et al., 2000; Fleming et al., 2004; Gomez et al., 2006). A recent functional brain imaging study (Garrett et al., 2011) identified aberrant working memory networks in PMD compared to NPMD and healthy control (HC) groups. Several studies have identified verbal memory deficits in PMD (Schatzberg et al., 2000; Fleming et al., 2004; Hill et al., 2004; Gomez et al., 2006; Zanelli et al., 2010). Two recent studies suggest that impaired encoding of verbal memory may be responsible for recognition memory deficits in PMD (Gomez et al., 2006; Zanelli et al., 2010). Similarly, a review of verbal declarative memory studies in schizophrenia concluded that deficits occur primarily during encoding, and are likely to involve prefrontal-hippocampal circuits (Cirillo and Seidman, 2003). It is possible that deficits in similar brain circuits during encoding underlie verbal memory deficits in PMD as well. The hippocampus is heavily resourced during verbal declara- tive memory encoding (Schacter and Wagner, 1999; Menon et al., 2002; Greicius et al., 2003; Parsons et al., 2006; Spaniol et al., 2009) and, to a lesser extent, during verbal declarative memory retrieval (Spaniol et al., 2009). Across the literature on hippocampus function during memory tasks in subjects with Contents lists available at SciVerse ScienceDirect journal homepage: www.elsevier.com/locate/psychresns Psychiatry Research: Neuroimaging 0925-4927/$ - see front matter & 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pscychresns.2012.06.008 n Corresponding author at: 401 Quarry Rd, Stanford, CA 94305-5795, USA. Tel.: þ1 650 736 1874; fax: þ1 650 724 4794. E-mail address: [email protected] (A. Garrett). Psychiatry Research: Neuroimaging 211 (2013) 119–126
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Altered brain function underlying verbal memory encoding and retrievalin psychotic major depression
Ryan Kelley a,b, Amy Garrett a,b,n, Jeremy Cohen a, Rowena Gomez b, Anna Lembke b, Jennifer Keller b,Allan L. Reiss a,b,c, Alan Schatzberg b
a Center for Interdisciplinary Brain Sciences Research, Stanford University School of Medicine, Stanford, CA 94305, USAb Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USAc Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA
Psychotic major depression (PMD) is associated with deficits in verbal memory as well as other
cognitive impairments. This study investigated brain function in individuals with PMD during a verbal
declarative memory task. Participants included 16 subjects with PMD, 15 subjects with non-psychotic
major depression (NPMD) and 16 healthy controls (HC). Functional magnetic resonance imaging (fMRI)
data were acquired while subjects performed verbal memory encoding and retrieval tasks. During the
explicit encoding task, subjects semantically categorized words as either ‘‘man-made’’ or ‘‘not man-
made.’’ For the retrieval task, subjects identified whether words had been presented during the
encoding task. Functional MRI data were processed using SPM5 and a group by condition ANOVA.
Clusters of activation showing either a significant main effect of group or an interaction of group by
condition were further examined using t-tests to identify group differences. During the encoding task,
the PMD group showed lower hippocampus, insula, and prefrontal activation compared to HC. During
the retrieval task, the PMD group showed lower recognition accuracy and higher prefrontal and parietal
cortex activation compared to both HC and NPMD groups. Verbal retrieval deficits in PMD may be
associated with deficient hippocampus function during encoding. Increased brain activation during
retrieval may reflect an attempt to compensate for encoding deficits.
& 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Depression can be regarded as a heterogeneous condition,likely consisting of various subtypes associated with familypsychiatric history, cognitive profiles and clinical features(Keller et al., 2007; Carragher et al., 2009). It has been estimatedthat 1 in 6 individuals with major depression also demonstratepsychotic features (psychotic major depression; PMD) (Johnsonet al., 1991; Parker et al., 1992; Ohayon and Schatzberg, 2002).Nosological data have emerged since the early 1980s suggestingPMD and non-psychotic major depression (NPMD) are, indeed,separate subtypes of depression (Keller et al., 2007). PMD isassociated with greater duration and severity of symptomscompared to NPMD (Nelson and Charney, 1981; Rothschildet al., 1989; Fleming et al., 2004; Keller et al., 2006; Maj et al.,2007). Additionally, individuals with PMD show greater cognitivedeficits in verbal memory, attention and executive functioning
d Ltd. All rights reserved.
d, CA 94305-5795,
).
compared to NPMD (Basso and Bornstein, 1999; Schatzberg et al.,2000; Fleming et al., 2004; Gomez et al., 2006). A recentfunctional brain imaging study (Garrett et al., 2011) identifiedaberrant working memory networks in PMD compared to NPMDand healthy control (HC) groups.
Several studies have identified verbal memory deficits in PMD(Schatzberg et al., 2000; Fleming et al., 2004; Hill et al., 2004;Gomez et al., 2006; Zanelli et al., 2010). Two recent studiessuggest that impaired encoding of verbal memory may beresponsible for recognition memory deficits in PMD (Gomezet al., 2006; Zanelli et al., 2010). Similarly, a review of verbaldeclarative memory studies in schizophrenia concluded thatdeficits occur primarily during encoding, and are likely to involveprefrontal-hippocampal circuits (Cirillo and Seidman, 2003). It ispossible that deficits in similar brain circuits during encodingunderlie verbal memory deficits in PMD as well.
The hippocampus is heavily resourced during verbal declara-tive memory encoding (Schacter and Wagner, 1999; Menon et al.,2002; Greicius et al., 2003; Parsons et al., 2006; Spaniol et al.,2009) and, to a lesser extent, during verbal declarative memoryretrieval (Spaniol et al., 2009). Across the literature onhippocampus function during memory tasks in subjects with
R. Kelley et al. / Psychiatry Research: Neuroimaging 211 (2013) 119–126120
depression, activation deficits have been observed during encoding(Bremner et al., 2004; Fairhall et al., 2010; Milne et al., 2011), exceptfor an associative learning paradigm that instead found increasedparahippocampal activation (Werner et al., 2009). While less com-mon, memory retrieval in depression has also been associated withlower hippocampus activation (Werner et al., 2009; Fairhall et al.,2010; Milne et al., 2011). Hippocampal dysfunction could also play arole in verbal memory deficits in PMD (Gomez et al., 2006).Although, gross hippocampal volume reductions have not beenobserved in PMD (Keller et al., 2008) hippocampal dysfunctioncould still exist (Czeh and Lucassen, 2007). Alternately, othercomponents of the verbal memory encoding network may beresponsible for deficits in recognition, such as the prefrontal cortex.Reviews of the memory encoding literature conclude that activationof the ventrolateral prefrontal cortex is associated with selecting andmaintaining incoming information while activation of the dorsolat-eral prefrontal cortex is associated with organizing and formingassociations between items during encoding (Blumenfeld andRanganath, 2007; Binder et al., 2009; Spaniol et al., 2009).
Using functional magnetic resonance imaging (fMRI), wehypothesized that individuals with PMD would demonstratealtered profiles of activation during encoding (but not retrieval)of verbal information, particularly within the hippocampus andprefrontal cortex. Such findings would suggest that verbal mem-ory retrieval deficits in PMD are primarily associated withencoding deficits.
2. Methods
2.1. Subjects
The initial sample comprised 24 subjects with PMD, 19 subjects with NPMD,
and 21 HC subjects. After screening for exclusionary criteria (see below), 16
subjects with PMD, 15 subjects with NPMD, and 16 HC subjects were included in
Hamilton Depression Rating Scale 29.06 (4.12) range¼21–37 24.53 (3.09) r
Brief Psychiatric Rating Scale—positive
symptom subscale score (�4)
8.06 (3.33) range¼3–14 0.13 (0.35) ra
Endogenomorphic scale 9.69 (1.88) 8.13 (1.40)
Age at onset 25.11 (12.86) range¼10–51
(N¼9)
31.77 (11.89)
(N¼9)
Gender distribution 8 F/8 M 8 F/7 M
Current medicationc 2 none; 4 anx; 7 AD; 9 AP;
1 MS (N¼12)
8 none; 1 anx
Comorbid diagnoses 6 none, 4 anxiety disorderd
(N¼10)
8 none, 7 anx
a Only significant post hoc t-test p-values presented.b Wechsler test of reading (WTAR) estimate of premorbid full scale IQ.c For medication; anx¼anxiolytics; AD¼antidepressant; AP¼antipsychotic, MS¼md Anxiety disorders in the PMD group included 1 subject with panic disorder, 2 with
1 with social phobia.e Anxiety disorders in the NPMD group included 1 subjects with OCD, 1 with agorn po0.001.
the final fMRI analysis. The Stanford University Institutional Review Board
approved the study and all subjects gave written consent before participation.
Subjects with PMD and NPMD were recruited through inpatient and outpatient
facilities at Stanford University Medical Center or self-referred from advertise-
ments. Healthy controls were recruited from the community through
advertisements.
Subjects with PMD and NPMD met the following inclusion criteria: (1) a
minimum score of 21 on the 21-item Hamilton Depression Rating Scale (HDRS)
(Hamilton, 1960), (2) a score of 7 or higher on 7 items of the core endogen-
omorphic scale (Thase et al., 1983), and (3) current unipolar major depressive
episode, with or without psychotic features, based on the DSM-IV criteria. More-
over, PMD was differentiated from NPMD by a minimum score of 5 on the positive
symptoms subscale of the Brief Psychiatric Rating Scale (BPRS) (Gorham and
Overall, 1961). When relevant, subjects were permitted to continue medications
for ethical and safety reasons; all medications were required to be stable for one-
week prior to study entry (Table 1). Healthy controls met the following inclusion
criteria: (1) score of less than 6 on the HDRS, (2) no psychotic symptoms as
measured by the BPRS, and (3) no past or present psychiatric disorders as
determined by the Structural Clinical Interview for DSM-IV-TR Axis I Disorders
(First MB et al., 1997).
Subjects were excluded from the study if they had a major medical illness,
a history of seizures, previous head trauma, unstable or untreated hypertension,
a history of substance abuse, were actively suicidal, met criteria for obsessive
compulsive disorder or bipolar I or II disorder, were pregnant or lactating, were less
than 18 years of age, or had electroconvulsive therapy within the last 6 months.
Subjects taking estrogen supplements or hormonal contraceptives were excluded
because of known interactions between cortisol and estrogen and potential con-
founding effects on brain function during semantic retrieval (Kuhlmann and Wolf,
2005; Konrad et al., 2008).
Subjects who were recruited into the study, were later excluded from the fMRI
analysis if performance was below chance (50% accuracy) on the recognition of
encoded words during the retrieval task. A subject’s functional MRI data were
excluded if more than 25% of the time points exceeded a 0.5 mm/TR motion
threshold or had global signal greater than 3% from the mean global signal of all
images as determined by ArtRepair (http://cibsr.stanford.edu/tools/ArtRepair/
ArtRepair.htm).
2.2. Verbal declarative memory tasks
The encoding task presented alternating blocks of encoding and control
epochs and had a duration of 5’56’’. The five encoding epochs each presented
c major
oup (NPMD)
Healthy control
group (HC) N¼16
ANOVA and post hoc T-testsa
range¼20–59 32.74 (13.55)
range¼18–57
F(2,43)¼0.283, p¼0.753
ange¼12–16 15.46 (2.40)
range¼12–20
(N¼13)
F(2,33)¼1.042, p¼0.364
1 cb(1,44)¼3.336, p¼0.189
) (N¼11) 110.94 (8.98)
(N¼16)
F(2,34)¼1.818, p¼0.178
ange¼21–31 0.47 (0.52)
range¼0–1
F(2,43)¼457.2, po0.001
PMD4NPMD,n PMD4HC,n
NPMD4HC,n
nge¼0–1 0 F(2,43)¼88.06, po0.001
PMD4NPMD,n PMD4HC,n
0 F(2,43)¼237.18, po0.001,
PMD4HC,n NPMD4HC,n
range¼17–51 N/A t(16)¼1.224, p¼0.285
7 F/9 M cb(1,47)¼0.296, p¼0.863
; 7 AD; 0 AP; 1 MS N/A AD use is similar but AP use in PMD
group only
iety disordere N/A Similar; however, limited data
available
ood stabilizer.
agoraphobia, 1 with GAD, 2 with PTSD, 1 with anxiety NOS, 1 with specific phobia,
aphobia, 1 with GAD, 2 with social phobia, 4 with specific phobia.
R. Kelley et al. / Psychiatry Research: Neuroimaging 211 (2013) 119–126122
To identify neuroanatomical locations, activation clusters were superimposed
on a single-subject high-resolution T1-weighted image. Additionally, activation
cluster coordinates were converted from MNI space into Talairach space (http://
imaging.mrc-cbu.cam.ac.uk/imaging/MniTalairach/) and input into a Talairach
daemon (http://www.nitrc.org/projects/tal-daemon/) to help identify neuroana-
tomical locations.
Fig. 1. Main effect of group: activation clusters. Main effect of group results of
2-way group by task analysis of variance: two clusters were significant, including
the sub-gyral right anterior cingulate and left parietal lobule. Extracted clusters
were adjusted for recognition accuracy using unstandardized residuals and means
plotted using bar graphs including 72 standard errors. Blue bars represent means
extracted from memory encoding task and green represent means extracted from
the memory retrieval task. Statistical results are presented for each cluster in
Table 3.
3. Results
3.1. Subjects
Five subjects with PMD, two with NPMD and two HC wereexcluded from the analysis due to retrieval task accuracy below50%. Three subjects with PMD, two with NPMD and three HC wereexcluded due to excessive motion during one of the functionalimaging verbal memory tasks. Included in the final analysis are 16PMD (8 females), 15 NPMD (8 females), and 16 HC (7 females)subjects. The groups were not significantly different in age,gender, handedness, or years of education. Additionally, thegroups had similar IQ (p¼0.60), as measured by the WechslerTest of Adult Reading (WTAR) (2001) full scale estimate ofpremorbid intellectual function.
3.2. Verbal declarative memory performance
Significant group differences were observed for correctedaccuracy of recognized words (F(1,47)¼4.80, p¼0.013). Two-group post hoc analyses indicated significantly lower correctedaccuracy for recognized words in the PMD group compared to theHC group (t(30)¼�2.91, p¼0.007) and the NPMD group(t(29)¼�2.15, p¼0.04) (Table 2). Therefore, fMRI analyses ofverbal encoding and retrieval were covaried for recognitionaccuracy. No other measures of task performance were signifi-cantly different between groups including false alarm rate and d’.
3.3. fMRI—main effect of group
The main effect of group across retrieval and encoding con-trasts identified 2 clusters of activation: right anterior cingulateand left parietal (Table 3, Fig. 1). Post-hoc t-tests found that sub-gyral right anterior cingulate differences was attributed to higheractivation in the HC group compared to both PMD (p¼0.001 andp¼0.009) and NPMD (p¼0.010 and p¼0.003) groups in bothencoding and retrieval tasks, respectively. No significant right
Table 3Significant clusters of activation from the main effect of group for encoding minus con
Neuroanatomy BA Cluster
size
Talairach
coordinates
F
value
Post-hoc T
ROI analysis: main effect of group
Left parietal lobule 40 24 �46, �33, 38 8.80 Encoding;
Left mid-cingulate gyrus 31 163 �18, �22, 34 10.22
Left mid-cingulate gyrus 24 71 �8, 6, 33 12.30
Right precentral gyrus 44 11 63, 8, 11 8.54
Right superior frontal gyrus 8 14 22, 18, 41 8.31
n Cluster significance within two 2-group t-tests; clusters from main effect of group
anterior cingulate activation differences were observed betweenPMD and NPMD groups. Group comparisons of left parietal lobuleactivation found the PMD group to have significantly higheractivation compared to both HC (po0.001) and NPMD (p¼0.013)groups exclusively in the retrieval task. No significant left parietallobule activation differences were observed between HC and NPMDgroups in either encoding or retrieval tasks.
3.4. fMRI—interaction of group by task
The interaction of group by task identified by the ANOVAresulted in 10 significant clusters of activation (Table 3, Fig. 2).
trol and retrieval minus control contrasts.
-test*
no significance, retrieval; PMD4HC, po0.001, PMD4NPMD, p¼0.013
Fig. 2. Interaction group by task: activation clusters. Interaction of group by task
results of 2-way group by task analysis of variance: 6 of 10 significant clusters
were analyzed, including the right and left insula and hippocampus, left middle
frontal gyrus, and right dorsolateral prefrontal cortex. Extracted clusters were
adjusted for recognition accuracy using unstandardized residuals and means
plotted using bar graphs including 72 standard errors. Blue bars represent means
extracted from memory encoding task and green represent means extracted from
the memory retrieval task. Statistical results are presented for each cluster in
Table 3.
R. Kelley et al. / Psychiatry Research: Neuroimaging 211 (2013) 119–126 123
Post-hoc t-tests were conducted on 6 clusters that were selectedbased on previous literature implicating aberrant hippocampus,prefrontal cortex and insular function in depression (Liotti et al.,2002; Werner et al., 2009; Fairhall et al., 2010; Sprengelmeyeret al., 2011; Garrett et al., 2011; Milne et al., 2011; Hamilton et al.,2012). During the encoding task the PMD group had significantlylower activation compared to HC in the right hippocampus(t¼3.15, p¼0.007), and left middle frontal gyrus (t¼3.80, p¼
0.001), while activation differences from left insula (p¼0.018),right insula (p¼0.016), left hippocampus (t¼2.18, p¼0.027)approached significance. Additionally, the PMD group had sig-nificantly lower activation in the right insula (t¼3.00, p¼0.003)compared to the NPMD group during encoding. Higher activationin HC group compared to NPMD group approached significance inthe left hippocampus, (t¼2.57, p¼0.009), left insula (p¼0.044),and left superior dorsolateral frontal gyrus (p¼0.038) duringencoding. The PMD group exhibited higher activation approach-ing significance during the retrieval task in the right dorsolateralprefrontal cortex compared to HC (p¼0.031) and in the leftmiddle frontal gyrus compared to NPMD (p¼0.032).
4. Discussion
In this study we investigated brain function related to encod-ing and retrieval of verbal information in carefully characterizedgroups of individuals with PMD compared to those with NPMDand HC. As expected, the PMD group had impaired memoryretrieval compared to the HC and NPMD groups. After adjustingfor recognition accuracy, fMRI results indicated hippocampus,insula and prefrontal cortical deficits in the PMD group duringencoding, possibly associated with inefficient organization andassociation of incoming information. The PMD group also showedrelatively greater prefrontal and parietal cortex activation duringretrieval, possibly reflecting a compensatory response in the faceof encoding deficits. These findings support the hypothesis thatverbal memory retrieval deficits in PMD stem from aberrant brainfunction during encoding.
The profile of activation within the HC group during theencoding task is largely compatible with previously describedmodels of verbal and semantic memory, including left hemi-sphere activation in the inferior frontal cortex, hippocampus,fusiform gyrus, and middle occipital gyrus (Wagner et al., 1998;Casasanto et al., 2002; Kraut et al., 2004; Davachi and Dobbins,2008; Spaniol et al., 2009) (Table S2, online supplemental mate-rial). Thus, we are confident that the task was valid for testing ourprimary hypothesis. The PMD and NPMD groups also showedactivation in these networks, including the left prefrontal cortexand visual areas. For the retrieval task, all three groups activatedthe bilateral inferior frontal gyri and the visual cortex, consistentwith previous literature on verbal memory retrieval (Raglandet al., 2000; Habib et al., 2003; Spaniol et al., 2009) (Table S3,online supplemental material). Several brain regions, includingthe left inferior frontal gyrus, are activated during both encodingand retrieval and may represent an overarching semantic mem-ory network (Nyberg et al., 2003; Binder et al., 2009).
Hippocampal activation during encoding was observed withinthe HC group, consistent with previous studies from our lab usingthe same task (Menon et al., 2002; Greicius et al., 2003). Our resultsof hippocampus dysfunction during memory encoding in PMD andNPMD support previous findings (Bremner et al., 2004; Fairhallet al., 2010). These activation deficits are located in the anteriorhippocampal head, which has been shown to be associated withsuccessful memory encoding in subjects with depression (Fairhallet al., 2010). Hippocampus activation deficits in depression have alsobeen observed during memory retrieval (Milne et al., 2011);
R. Kelley et al. / Psychiatry Research: Neuroimaging 211 (2013) 119–126124
however, our results support deficits only during encoding. Hyper-cortisolemia connected to PMD (Schatzberg et al., 1983; Rothschildet al., 1987; Nelson and Davis, 1997; Belanoff et al., 2001; Gomezet al., 2009) and NPMD (Lok et al., 2011) might have detrimentaleffects on hippocampus function (Sapolsky, 2000).
Group differences in activation suggest neural deficits in theprefrontal cortex in the PMD group during encoding, includingportions of the left prefrontal cortex. Previous studies of verbalmemory encoding in individuals with schizophrenia (Raglandet al., 2004) and those at risk for psychosis (Allen et al., 2011)have suggested that weak prefrontal cortex activations are attri-butable to inefficient organizational encoding strategies. Thisinterpretation is consistent with the idea that the prefrontalcortex is responsible for organizing and forming associationsbetween items during encoding (Blumenfeld and Ranganath,2007; Binder et al., 2009; Spaniol et al., 2009). Thus, verbalretrieval deficiencies in the PMD group may be related toinefficient organization of information during encoding.
Activation deficits near the anterior cingulate cortex duringmemory encoding and retrieval in the PMD and NPMD groupsmight represent shared pathophysiology. Our results also corro-borate previously reported anterior cingulate cortex activationdeficits in NPMD during encoding (Bremner et al., 2004).
Insular activation deficits in PMD might be associated withinadequate resources for controlled semantic processing involvedwith successful verbal memory encoding (Sperling et al., 2003;Kirwan et al., 2008). Right insula deficits in PMD compared toNPMD might be associated with dysfunction of verbal workingmemory networks (Schulze et al., 2011).
Group comparisons of activation during retrieval showed thatthe PMD group had higher dorsolateral prefrontal and parietalcortex activations. As verbal memory retrieval networks includeprefrontal and parietal regions (Spaniol et al., 2009), this findingmight be interpreted as neural compensation for inefficientencoding. Similar findings of stronger prefrontal and parietalactivation during retrieval in schizophrenia also have been inter-preted as compensation for encoding deficits (Ragland et al.,2004). However, despite increased neural effort during retrievalthe PMD group showed poor recognition accuracy. Despite sharedprefrontal deficits in the PMD and NPMD groups during encoding,the NPMD group did not demonstrate retrieval deficits or recruitcompensatory activation during retrieval.
Our results support the hypothesis that verbal memory deficitsin PMD are associated with aberrant hippocampus and prefrontalactivation during encoding. After accounting for poor recognitionaccuracy in PMD, higher activations associated with memoryretrieval networks appear to be recruited, in PMD only, as compen-sation for encoding deficits. This interpretation is preliminary,however, as our blocked task design does not allow accurateisolation of successful versus unsuccessful encoding trials or correctversus incorrect recognition trials (e.g., too few incorrect trials areavailable). Therefore, we cannot conclusively determine thatdecreased prefrontal activation is detrimental to effective encodingor that increased prefrontal and parietal activation aids recognitionaccuracy. It is possible, instead, that observed abnormalities repre-sent efficient encoding networks and ineffective retrieval mechan-isms, which contribute to retrieval deficits in PMD. However, thisexplanation appears unlikely as studies have shown that increaseddepth of semantic encoding and memory strength during retrievalhave corresponded to increased activation in the prefrontal cortex(Otten et al., 2001; Kahn et al., 2004; Vilberg and Rugg, 2007).
Our study included only those subjects who achieved retrievalscores greater than chance, as we could not be certain whetherextremely low scores could be attributed to noncompliance withtask demands, failure of the response device, or neuropsychologicaldeficits. Therefore, we may have excluded those PMD subjects who
could not adequately engage encoding or retrieval networks due totask difficulty. Additional limitations to this analysis include med-ication exposure in PMD and NPMD groups. Particularly, the use ofantipsychotic medication by most of the PMD subjects but none ofthe NPMD subjects confounds our comparisons of these groups andmay account for some of the group differences reported here.However, we have not observed an effect of medications oncognitive performance (Schatzberg et al., 2000; Gomez et al., 2006,2009) or fMRI activation (Greicius et al., 2007) in our subjects andthis is consistent with the observations of others on antipsychoticversus drug-free status on fMRI of related functions in schizophrenia(Barch et al., 2001; Snitz et al., 2005; Yoon et al., 2008) or bipolardisorder (Phillips et al., 2008). Still, our results should be consideredpreliminary, and future studies would benefit from imaging subjectsbefore they are placed on essential medications, or including largersamples that allow quantification of medication effects.
Financial disclosures
Dr. Schatzberg has served as a consultant to BrainCells, CeNeRx,CNS Response, Corcept, Eli Lilly, Forest Labs, GlaxoSmithKline,Jazz, Lundbeck, McKinsey, Merck, Neuronetics, NovaDel,PharmaNeuroBoost, Sanofi–Aventis, Takeda, Xytis and has equityin Amnestix, BrainCells, CeNeRx, Corcept (cofounder), Forest,Merck, Neurocrine, NovaDel, Pfizer, PharmaNeuroBoost, Somaxon,Synosia and is named inventor on pharmacogenetic use patents onprediction of antidepressant response and glucocorticoid antago-nists in psychiatry.
Dr. Reiss has served as a consultant for Novartis.All other authors report no financial relationships with com-
mercial interests.
Acknowledgments
This study was supported by: MH50604, MH47573, T32MH19938 (Schatzberg) and T32MH19908 (Reiss)
Appendix A. Supporting information
Supplementary data associated with this article can be foundin the online version at http://dx.doi.org/10.1016/j.pscychresns.2012.06.008.
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