Impaired Recruitment of the Dorsolateral Prefrontal Cortex and Hippocampus During Encoding in Bipolar Disorder

Impaired Recruitment of the Dorsolateral Prefrontal Cortex and Hippocampus During Encoding in Bipolar Disorder Thilo Deckersbach, Darin D. Dougherty, Cary Savage, Stephanie McMurrich, Alan J. Fischman, Andrew Nierenberg, Gary Sachs, and Scott L. Rauch Background: The aim of the present study was to examine the functional neuroanatomy of episodic memory impairment in euthymic subjects with bipolar I disorder. There is evidence that individuals with bipolar disorder have cognitive impairments not only during mood episodes but also when they are euthymic. The most consistently reported cognitive difficulty in euthymic subjects with bipolar disorder is impairment in verbal episodic memory (i.e., the ability to learn new verbal information). Methods: The current study examined verbal learning in eight euthymic, remitted subjects with bipolar I disorder (BP-I; seven nonmedicated) and eight control subjects matched for age, gender, education, and intelligence. Subjects underwent 15O-CO2 positron emission tomography scanning while completing a verbal learning paradigm that consisted of encoding (learning) several lists of words. Results: The BP-I subjects had more difficulties learning the lists of words compared with the control subjects. Compared with control subjects, BP-I subjects exhibited blunted regional cerebral blood flow (rCBF) increases in the left dorsolateral prefrontal cortex (Brodmann’s area 9/46) during encoding. Conclusions: Consistent with previous studies, subjects with BP-I were impaired in learning new verbal information. This was associated with rCBF abnormalities in brain regions involved in learning and episodic memory. Key Words: Bipolar disorder, episodic memory, working memory, PET

B

ipolar disorder is characterized by recurrent episodes of depression and/or hypomania/mania interspersed with periods of recovery or remission. Both depression and mania are associated with profound cognitive disturbances, such as impairments in attention, executive functions, and memory (Murphy et al 2001). Over the past decade, evidence has accumulated that these impairments are not restricted to mood episodes but are also found in individuals with bipolar disorder when they are euthymic (neither depressed nor manic) (e.g., Cavanagh et al 2002; Clark et al 2002; Deckersbach et al 2004a, 2004b; van Gorp et al 1998). One of the most consistently reported findings in euthymic individuals with bipolar disorder is impairment in episodic memory, the ability to explicitly recollect information encountered in a previous study episode (Graf and Schacter 1985). For an event to be remembered it must be encoded, stored, and consolidated over time, and later retrieved from storage (Kapur et al 1996). Encoding refers to the processes that convert a perceived event into a cognitive representation that is stored/ retained over time. Retrieval is the process that reactivates a stored representation, leading to the experience of explicit recollection of the past event (Kapur et al 1996). Different brain regions contribute to encoding, storage/retention, and retrieval. These include the medial temporal lobe (hippocampus and

From the Departments of Psychiatry (TD, DDD, SM, AN, GS, SLR) and Radiology (AJF), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and the University of Kansas Medical Center (CS), Kansas City, Kansas. Address reprint requests to Thilo Deckersbach, Ph.D., Massachusetts General Hospital-East, Department of Psychiatry, 149-2611, Psychiatric Neuroscience Program, Building 149, 13th Street, 2nd Floor, Charlestown, MA 02129; E-mail: [email protected]. Received February 3, 2005; revised May 26, 2005; accepted June 20, 2005.

0006-3223/05/$32.00 doi:10.1016/j.biopsych.2005.06.030

surrounding structures) and the prefrontal cortex. The prefrontal cortex, among other functions, mediates strategic aspects of episodic memory, such as active strategies for encoding and retrieving episodic information (Moscovitch 1992). For example, learning (encoding) a list of words that stem from different categories (e.g., fruits, tools) is facilitated if an individual groups these words into their categories during presentation of the word list (i.e., during encoding). This strategy is called semantic clustering. Individuals with lesions of the frontal lobes or with disorders affecting frontal–striatal system function (e.g., Parkinson’s disease, Huntington’s disease) have been shown to exhibit difficulties during encoding with efficient organization of the information to be remembered. This is associated with impairments in learning and subsequent free recall (e.g., Baldo et al 2002; Buytenhuijs et al 1994; Gershberg and Shimamura 1995; Pillon et al 1993). Functional neuroimaging studies (positron emission tomography [PET], functional magnetic resonance imaging [fMRI]) have consistently demonstrated increased activation of the prefrontal cortex (particularly the dorsolateral prefrontal cortex [DLPFC]) associated with the use of semantic clustering organizational strategies during encoding (Fletcher et al 1998; Savage et al 2001; Wagner et al 2001). In bipolar disorder, there is rapidly mounting evidence for DLPFC pathology. Postmortem studies indicate reduced density of neuronal and glial cells (Rajkowska et al 2001), reduced neuronal size (Cotter et al 2002), and reduced density of oligodendroglial cells (Orlovskaya et al 2000) in the DLPFC. Although evidence for prefrontal cortical volume reductions in individuals with bipolar disorder is mixed (Beyer and Krishnan 2002; Strakowski et al 2002), studies using magnetic resonance spectroscopy have reproducibly found reduced N-acetyl aspartate to creatine–phosphocreatine ratios in the DLPFC in euthymic individuals with bipolar disorder (Chang et al 2000; Winsberg et al 2000). Two recent neuropsychological studies conducted by our group suggest that impairment in organizational strategies during encoding (which rely on the integrity of the prefrontal cortex) underlie the observed episodic memory impairments in euthyBIOL PSYCHIATRY 2006;59:138 –146 © 2005 Society of Biological Psychiatry

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T. Deckersbach et al mic, remitted individuals with bipolar disorder (Deckersbach et al 2004a, 2004b). These studies used path-analytic modeling to demonstrate that episodic memory impairments in euthymic patients with bipolar disorder did not remain when effects of verbal and nonverbal organizational strategies during encoding were accounted for. This suggests that episodic memory impairments in bipolar disorder might be secondary to difficulties organizing information during encoding. The purpose of the present study was to investigate the functional neuroanatomy associated with impaired semantic clustering organizational encoding strategies in euthymic, remitted individuals with bipolar disorder. More specifically, we conducted a PET 15O-CO2 study that assessed regional cerebral blood flow (rCBF) during encoding of verbal information in euthymic, remitted patients with bipolar I disorder (BP-I) and control subjects. On the basis of our previous neuropsychological studies in bipolar disorder (Deckersbach et al 2004a, 2004b) and disorders affecting fronto–striatal function (Deckersbach et al 2000; Savage et al 2000), as well as the mounting evidence of DLPFC involvement in bipolar disorder, we hypothesized that the euthymic BP-I group would exhibit difficulties using semantic clustering organizational strategies during encoding and that this would be associated with decreased activation of the DLPFC.

Methods and Materials Subjects Study subjects were eight euthymic, remitted individuals who met DSM-IV criteria for BP-I (4 female) and eight healthy control subjects (4 female). The BP-I subjects were recruited through the Harvard Bipolar Research Program (HBRP) at the Massachusetts General Hospital. Healthy control subjects were recruited through bulletin board notices within the hospital. The PET data from this cohort of control subjects were reported in a previous publication (Savage et al 2001). None of the control subjects were related to the BP-I subjects. Diagnostic assessment of all subjects was performed with the Structured Clinical Interview for DSM-IV (SCID; First et al 1995). All subjects provided written informed consent before participation, in accordance with the guidelines of the Subcommittee on Human Studies of the Massachusetts General Hospital. All BP-I subjects were free of comorbid diagnoses. At the time of the PET scan, seven BP-I subjects were medication free and had been medication free for the previous 2 months. One BP-I participant was taking lithium. Nonmedicated BP-I subjects had discontinued all medication for bipolar disorder before contacting the HBRP for the study and had remained euthymic despite medication discontinuation. All patients met DSM-IV criteria for remission, as assessed by the SCID. After enrollment, each BP-I subject’s mood was prospectively monitored for 1 month with the Hamilton Depression Scale (HAM-D; Hamilton 1960) and the Young Mania Rating Scale (YMRS; Young et al 1978). Residual depression and mania symptoms in the BP-I group as assessed by the HAM-D and the YMRS were low (see Table 1 all BP-I HAM-D scores ⬍5; all YMRS scores ⬍3). All subjects were medically healthy and had no history of significant head injury, seizure, neurologic condition, or current major medical condition by report. Bipolar I patients who had endocrinological disorders were not included in the study. All subjects were right-handed (Oldfield 1971). Bipolar I and control subjects did not differ significantly with regard to age [t (14) ⫽ ⫺.97, p ⫽ .35; see Table 1], years of education [t (14) ⫽ .24, p ⫽ .81; see Table 1], or verbal intelligence quotient (IQ), as

Table 1. Demographic and Behavioral Characteristics of Bipolar I Disorder and Control Subjects Characteristic Demographic Age (y) Education (y) Verbal IQ HAM-D Score BDI Score YMRS Score Memory Measures Free recall Unrelated list Spontaneous list Directed list Recognition discriminability Semantic clustering Spontaneous list Directed list

Control Subjects

BP-I Subjects

28.00 (6.78) 15.75 (.70) 113.25 (13.76)

27.25 (5.60) 16.13 (.83) 112.5 (14.95) 1.88 (1.81) 2.38 (2.0) 1.00 (1.1)

1.75 (3.15)

14.00 (6.16) 16.31 (3.32) 17.81 (2.75) 16.32 (2.02)

14.13 (1.55) 13.34 (1.41) 13.25 (1.03) 16.26 (1.82)

.71 (.25) .87 (.16)

.46 (.19) .47 (.18)

Data are presented as mean (SD). BP-I, bipolar I disorder; IQ, intelligence quotient; HAM-D, Hamilton Rating Scale for Depression; BDI, Beck Depression Inventory; YMRS, Young Mania Rating Scale.

estimated by the Information, Vocabulary, and Similarities subtests of the Wechsler Memory Scale–Revised (Wechsler 1987) [t (14) ⫽ .10, p ⫽ .92]. Material Subjects completed a word-encoding paradigm that involved conditions with different levels of semantic clustering and a resting baseline condition. A detailed description of this paradigm has been previously published (Savage et al 2001). The paradigm consists of four conditions: a resting baseline condition and three different word list encoding conditions in which subjects listened to prerecorded lists of words presented through computer speakers. In the 90-sec resting baseline condition, subjects looked at a black fixation cross on a grey background in the center of a computer screen approximately 35 cm from their eyes and were instructed to relax and rest their minds. In the word list encoding conditions, subjects listened to (i.e., encoded) lists of either 24 categorized or uncategorized words presented through computer speakers positioned on either side of the computer screen. During each of the encoding conditions, subjects were also presented with the fixation cross. In the Spontaneous word-encoding condition, subjects were presented with 24 words taken from four different categories (e.g., fruits, herbs and spices, metals, furniture). There were six words per category, with one word presented every 3.3 sec. The words from each of four categories were presented such that a word from a given category was never followed by a word from the same category. During the Spontaneous condition, subjects were not informed about the categorized nature of the word list. In the Directed condition, subjects were presented with a different categorized word list (24 words, six words per category, one word presented every 3.3 sec). As in the Spontaneous encoding condition, a word from a given category was never followed by a word from the same category. In the Directed condition, subjects were explicitly instructed to group the words into their categories during encoding. Finally, in the Unrelated condition, subjects were presented with an uncategorized word list comprising 24 words taken from 24 different categories. Subjects were informed about the uncategorized nature of the list and www.sobp.org/journal

140 BIOL PSYCHIATRY 2005;59:138 –146 were instructed to encode the words in any order. This condition did not permit grouping the words into semantic categories. The paradigm was developed and tested extensively in pilot studies to develop word lists that promoted significant differences in semantic clustering between the spontaneous and directed conditions (Savage et al 2001). More specifically, the word lists for this paradigm were constructed by generating 32 categories for which normal subjects during pilot testing showed some clustering in the Spontaneous condition but significantly more in the Directed condition. In the present study, words were counterbalanced across subjects such that each word appeared once in each condition. Thus, differences among lists did not reflect differences in list difficulty level. PET Procedure Subjects underwent eight PET scans during a single session. Scanning occurred during the word list encoding conditions, while subjects listened to the word lists, and during the resting baseline fixation cross condition. Each condition was presented twice. The resting baseline condition was always presented first and last (scans 1 and 8). The Spontaneous condition (scans 2 and 3) always occurred after the first baseline to ensure that the strategies imposed by subjects were as “spontaneous” as possible—specifically, that subjects were not anticipating the presence of categorized structure in the word lists. The order of the Directed and Unrelated conditions was counterbalanced across subjects. That is, the two scans for the Directed condition were either presented before the two scans of the Unrelated condition (scans 4 and 5) or followed the two scans for the Unrelated condition (scans 6 and 7). In each word-encoding condition, subjects were asked to recall the words immediately after each scan, without intervening distraction. The experimenter kept a verbatim record of each subject’s recall. These data were used to calculate semantic clustering score as an estimation of each subject’s clustering during encoding. In addition, a recognition test was provided after the second scan of each encoding condition. In this recognition test, the 24 original items of each word list were intermixed with 24 distractor items. These items were read to the subject, and subjects were asked to answer “yes” if they thought an item was in the original list. Behavioral measures included (1) free recall score for each trial; (2) recognition discriminability score for each condition; and (3) semantic clustering score for each trial. The free recall score was the number of correctly recalled words in each trial. The ability to discriminate between the original words and distractors on the recognition test (recognition discriminability) was calculated with the following formula: [1 ⫺ (false positives ⫹ false negatives)/48] ⫻ 100 (Underwood 1974). The extent to which subjects grouped the words into their semantic categories during recall in the two categorized word lists (semantic clustering score) was calculated as follows: [cluster-points/(words recalled ⫺ number of categories recalled)] (Savage et al 2001). Subjects received a “cluster-point” whenever they recalled two words from the same category in succession in a given trial. Imaging Methods The reader is referred to Rauch et al (1995) for a detailed description of PET facilities and reconstruction procedures. Briefly, an individually molded thermoplastic face mask (True Scan, Annapolis, Maryland) was used to minimize head motion, and subjects were fitted with a nasal cannula and overlying face mask, which were attached to radiolabeled gas inflow and a vacuum, respectively. The PET data were acquired during 60-sec www.sobp.org/journal

T. Deckersbach et al scans while subjects performed the cognitive tasks and inhaled O-labeled CO2 gas. A Scanditronix PC4096 15-slice whole-body PET camera (General Electric, Milwaukee, Wisconsin) was used in the stationary mode. The slice geometry consists of contiguous slices with a center-to-center distance of 6.5 mm (axial field ⫽ 97.5 mm) and in-plane resolution of 6.0 mm full width half maximum (FWHM). The PET images were reconstructed with a conventional convolution– backprojection algorithm, correcting for photon absorption, scatter, and dead time effects. The Hanning-weighted reconstruction filter was set to yield 8.0-mm in-plane spatial resolution FWHM. Data were processed with SPM99 software (Wellcome Department of Cognitive Neurology, London, United Kingdom). The PET images were motion corrected, spatially normalized to the standardized normalized space established by the Montreal Neurological Institute (MNI; http://www.bic.mni.mcgill.ca), and smoothed with a two-dimensional Gaussian filter of 8 mm width (FWHM). At each voxel, the PET data were normalized to a global mean of 50 mL/min per 100 g to yield normalized images of rCBF.

15

PET Data Statistical Analysis Statistical analysis of PET data was conducted following the theory of statistical parametric mapping. More specifically, rCBF differences across encoding conditions (Unrelated vs. Spontaneous vs. Directed) were investigated with a linear contrast testing a linear (graded) increase in rCBF from the Unrelated condition to the Spontaneous condition to the Directed condition (unrelated ⬍ spontaneous ⬍ directed, shorthand U⬍S⬍D). The weights for the linear contrasts were chosen such that they reflected the increase in semantic clustering from the Unrelated condition (by definition, 0) to the Spontaneous condition to the Directed condition. For the linear contrast, regions of linear rCBF increases across encoding conditions were first investigated within each group (BP-I and normal control subjects) before group ⫻ condition interactions were investigated. Statistics (t tests, linear contrasts) were transformed to Z scores representing differences or linear increases in rCBF across conditions. We report regions containing foci of activation with Z scores ⱖ 3.09 (corresponding to a p ⱕ .001 [one tailed] uncorrected for multiple comparisons), with the added requirement that at least three contiguous voxels exceeded this statistical level (i.e., k ⱖ 3). The PET data of control subjects pertaining to the left prefrontal cortex rCBF have been previously published (Savage et al 2001). For this study, these data were reanalyzed with SPM99. Values for correlational analysis and graphs were extracted with MarsBaR software (Brett et al, unpublished data). Behavioral Data Statistical Analysis Free recall scores were evaluated by mixed-model analysis of variance (ANOVA), with trial (first and second) and condition (Unrelated, Spontaneous, Directed) as the within-group factors and group (control, BP-I) as the between-group factors. Semantic clustering scores were evaluated with mixed-model ANOVA, with trial (first and second) and condition (Spontaneous vs. Directed) as the within-group factors and group (control vs. BP-I) as the between-groups factor. Significant interactions were followed up by linear contrasts and/or paired and unpaired t tests. Recognition discriminability scores were evaluated by mixedmodel ANOVA, with condition (Unrelated, Spontaneous, Directed) as the within-group analysis and group (control vs. BP-I) as the between-groups factor. Correlations between semantic clustering, residual depressive or manic symptoms in the BP-I

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T. Deckersbach et al Table 2. Significant Increases in Regional Cerebral Blood Flow Across Encoding Conditions (Unrelated ⬍ Spontaneous ⬍ Directed) in Control Subjects

Region A Priori Dorsal prefrontal cortex

A Posteriori Anterior cingulate cortex Ventrolateral prefrontal cortex Premotor cortex Hippocampus Parahippocampal gyrus Superior temporal gyrus Inferior temporal gyrus Inferior parietal cortex

Occipital cortex Posterior cingulate cortex

Brodmann Area

MNI Coordinatesa y

z

⫺54 ⫺42 ⫺16

30 20 48

22 32 32

3.90 3.30 3.56

32

10

42

28

4.31

47 6

46 ⫺50 ⫺24 ⫺28 72 ⫺62 46 48 ⫺38 ⫺24 ⫺52 ⫺2 ⫺4

16 12 ⫺24 ⫺46 ⫺38 ⫺30 ⫺66 ⫺54 ⫺66 ⫺66 ⫺56 ⫺86 ⫺64

⫺14 48 ⫺6 ⫺2 10 ⫺20 42 50 38 60 46 ⫺12 16

3.60 3.68 3.70 3.69 3.35 3.27 3.83 3.83 4.78 3.51 3.47 3.32 3.15

9/46 9 8/9

37 22 20 40

7 40 18 31

x

Max Voxel Z Scoreb

subjects clustered less than control subjects in both the Spontaneous condition [t (14) ⫽ 2.12, p ⫽ .04] and the Directed condition [t (14) ⫽ 4.73, p ⬍ .001]. Control subjects clustered more in the Directed condition than in the Spontaneous condition [t (7) ⫽ 2.31, p ⫽ .05], whereas no significant difference between the two conditions was observed for BP-I subjects [t (7) ⫽ .72, p ⫽ .50].

PET Results Control Subjects. Regions of linear rCBF increases for the linear contrast (U⬍S⬍D) for control subjects are shown in Table 2 and Figure 1. Consistent with our hypothesis (and previously reported in Savage et al 2001), there was a significant increase in rCBF (mirroring the increase in semantic clustering) in the left DLPFC, with activation peaks in Brodmann areas 9 and 46 (see Table 2). Additional areas of significant rCBF increase (among others) included right anterior cingulate cortex (BA 32), right ventrolateral prefrontal cortex (BA 47), left hippocampus, and left parahippocampal gyrus (BA 37, see Table 2 and Figure 1). BP-I Subjects. Regions of linear rCBF increases for the linear contrast for BP-I subjects are shown in Table 3 and Figure 1. Notably, consistent with the lack of increase in semantic clustering across the encoding conditions and consistent with our hypothesis, BP-I subjects lacked any significant rCBF increases in

MNI, Montreal Neurological Institute. x indicates right (⫹) or left (⫺); y indicates anterior (⫹) or posterior (⫺); z indicates superior (⫹) or inferior (⫺) to the anterior commissure. b Z scores ⬎ 3.09 (p ⬍ .001) are shown. a

group, and rCBF were investigated by computing Spearman rank correlations.

Results Behavioral Data Memory. Free recall and recognition discriminability scores are shown in Table 1. For free recall scores, the mixed-model ANOVA indicated a main effect for trial [F(1,14) ⫽ 189.46, p ⬍ .0001], a trend toward a main effect of group [F(1,14) ⫽ 4.10, p ⫽ .06], and a significant group ⫻ condition interaction [F(1,28) ⫽ 3.44, p ⫽ .046]. There was no main effect of conditon [F(1,14) ⫽ 1.14, p ⫽ .34], no group ⫻ trial interaction [F(1,14) ⫽ 2.79, p ⫽ .12], no trial ⫻ condition interaction [F(1,14) ⫽ .07, p ⫽ .99], or group ⫻ trial ⫻ condition interaction [F (2,28) ⫽ .73, p ⫽ .41]. Follow-up t tests indicated no significant group differences in free recall between control and BP-I subjects in the Unrelated encoding condition [collapsed over trials 1 and 2 within each condition; t (14) ⫽ ⫺.06, p ⫽ .96], but BP-I subjects recalled fewer words than control subjects in the Spontaneous condition [collapsed over trials 1 and 2 within each condition; t (14) ⫽ 2.31, p ⫽ .04] and in the Directed condition [collapsed over trials 1 and 2; t (14) ⫽ 4.39, p ⫽ .001]. Although control subjects showed a trend toward a linear increase in free recall from the Unrelated to the Spontaneous to the Directed condition [F (1,7) ⫽ 3.2, p ⫽ .06], this was not true for BP-I subjects [F (1,7) ⫽ 1.6, p ⫽ .25]. Semantic Clustering. Semantic clustering scores are shown in Table 1. The mixed-model ANOVA indicated main effects for condition [F (1,14) ⫽ 5.68, p ⫽ .03] and group [F (1,14) ⫽ 12.25, p ⫽ .04], but no effect for trial [F (1,14) ⫽ 1.74, p ⫽ .21]. There was also a significant group ⫻ condition interaction [F (1,14) ⫽ 4.80, p ⫽ .046]. Follow-up unpaired t tests indicated that BP-I

Figure 1. Linear increases in regional cerebral blood flow across the three encoding conditions (Unrelated ⬍ Spontaneous ⬍ Directed) in the control and bipolar disorder groups as viewed by “glass brains.” (A) Coronal view; (B) sagittal view; (C) axial view. For Montreal Neurological Institute coordinates of max voxels, see Tables 2 (control subjects) and 3 (bipolar disorder subjects).

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142 BIOL PSYCHIATRY 2005;59:138 –146

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Table 3. Significant Increases in Regional Cerebral Blood Flow Across Encoding Conditions (Unrelated ⬍ Spontaneous ⬍ Directed) in Bipolar I Disorder Subjects

Region Ventrolateral prefrontal cortex Parahippocampal/fusiform gyrus Occipital cortex Thalamus Posterior cingulate cortex

Brodmann Area

47 10 36/37 19 31

z

Max Voxel Z Scoreb

38 60

6 ⫺10

3.46 3.79

⫺40 ⫺72 ⫺8 ⫺60

⫺16 8 14 12

3.71 3.60 4.15 3.25

MNI Coordinatesa x

y

50 16 ⫺34 ⫺20 4 ⫺2

MNI, Montreal Neurological Institute. x indicates right (⫹) or left (⫺); y indicates anterior (⫹) or posterior (⫺); z indicates superior (⫹) or inferior (⫺) to the anterior commissure. b Z scores ⬎ 3.09 (p ⬍ .001) are shown. a

the left prefrontal cortex. Post hoc findings (among others) included two regions of increased rCBF in the right ventrolateral prefrontal cortex, corresponding to Brodmann areas 10 and 47. In the medial temporal lobe, BP-I subjects lacked a significant rCBF increase in the left hippocampus but showed increased activation in an area at the junction of the left parahippocampal gyrus and left fusiform gyrus (BA 36/37; see Table 3 and Figure 1). Group ⴛ Condition Interaction. To determine areas that showed significantly greater rCBF increases with the linear contrast (U⬍S⬍D) in normal control subjects compared with BP-I subjects, we conducted a group ⫻ condition analysis (control subjects minus BP-I subjects for the contrast U⬍S⬍D). This yielded four areas in the prefrontal cortex and temporal lobe for which normal control subjects exhibited greater rCBF increases than BP-I subjects (see Table 4 and Figure 2). Consistent with our hypothesis, this included the area in the DLPFC (BA 9/46; see Figure 2) for which control subjects but not BP-I subjects had shown a linear rCBF increase in the within-group analysis (see Tables 2– 4). Control subjects also showed greater rCBF increases across the three encoding conditions in the left hippocampus (see Table 4 and Figure 2) for which the withingroup analysis had yielded significant rCBF increases in control but not BP-I subjects (see Tables 2 and 3). For BP-I subjects, rCBF in the left hippocampus did not change significantly across the three encoding conditions [see Figure 1; F (2,14) ⫽ 2.78, p ⫽ .10]. Finally, compared with BP-I subjects, control subjects showed greater rCBF increase in the left inferior prefrontal cortex (BA 44) and in the inferior temporal gyrus (BA 20). We also determined areas of rCBF group differences between BP-I and control subjects for the linear contrast U⬍S⬍D (BP-I subjects minus control subjects). This yielded two regions in the right anterior frontal–polar cortex (BA 10, see Table 4 and Figure 2) where control subjects, unlike BP-I subjects, showed a linear rCBF decrease from the Unrelated to the Spontaneous to the Directed encoding condition. In addition, BP-I subjects also exhibited greater increases in rCBF than control subjects at the border of parahippocampal gyrus and fusiform gyrus (BA 36/37, see Figure 2) and in the inferior temporal gyrus (BA 20). This area in BA 20 was slightly inferior to the area where control subjects showed more rCBF increases than BP-I subjects (see above, and Table 3). For rCBF changes obtained with the above-described linear contrast analyses, we also conducted a full 2 ⫻ 3 mixed-model ANOVA with group (control vs. BP-I) as the between-subjects www.sobp.org/journal

factor, condition (Unrelated vs. Spontaneous vs. Directed) as the within-subjects factor, and rCBF (max voxels) as the dependent variable. This was followed by pairwise group comparisons for each of the three encoding conditions. The results of these analyses are shown in Table 4. We also determined areas of rCBF group differences that were specific for (1) the Spontaneous encoding condition compared with the combined Unrelated and Directed encoding condition; as well as (2) for the combined Spontaneous and Directed condition compared with the Unrelated condition (see Table 5). Specifically, we computed group differences for a contrast comparing the Spontaneous encoding condition with the combined Unrelated and Directed condition (2S ⫺ [1U ⫹ 1D]; see Table 5). We also computed group differences for a contrast comparing the combined Spontaneous and Directed condition with the Unrelated encoding condition ([1S ⫹ 1D] ⫺ 2U; see Table 5). Most notably, for the Spontaneous encoding condition (2S ⫺ [1U ⫹ 1D]), compared with BP-I subjects, normal control Table 4. Group Differences in Regional Cerebral Blood Flow Increases Between Bipolar I Disorder and Control Subjects Across Encoding Conditions (Unrelated ⬍ Spontaneous ⬍ Directed)

y

z

Max Voxel Z Scoreb

⫺52

30

22

3.35c,f,i,k

20

⫺56 ⫺24 ⫺62

14 ⫺24 ⫺28

8 ⫺6 ⫺18

3.39f,k 3.34e,f,h,j 4.12d,f,i,k

10 10 36/37

36 16 ⫺32

48 58 ⫺42

4 ⫺8 ⫺16

4.22d,f,g,i 3.40d,f,g,i 3.42f,g,l

20 22 38 19 18

⫺60 50 ⫺46 50 24

⫺26 ⫺34 2 ⫺72 ⫺86

⫺24 20 ⫺16 22 ⫺10

3.09f,j,l 3.21f,l 3.17f,g 3.87f,l 3.12f,l

MNI Coordinatesa Comparison/Region Control Subjects Minus BP-I Subjects A Priori Dorsal prefrontal cortex A Posteriori Inferior prefrontal cortex Hippocampus Inferior temporal gyrus BP-I Subjects Minus Control Subjects Ventrolateral prefrontal cortex Parahippocampal/fusiform gyrus Inferior temporal gyrus Superior temporal gyrus Occipital cortex Occipital cortex

Brodmann Area

x

9/46 44

MNI, Montreal Neurological Institute; BPI, bipolar I disorder; NC, normal control subjects. a x indicates right (⫹) or left (⫺); y indicates anterior (⫹) or posterior (⫺); z indicates superior (⫹) or inferior (⫺) to the anterior commissure. b z-values ⱖ 3.09 (p ⱕ .001) are shown; BP-I ⫽ bipolar I disorder. We also computed a 2 by 3 mixed model analysis of variance for all max voxels shown in the table above. Group (controls vs. BP-I) was the between subjects’ factor. Condition (unrelated, spontaneous, directed) was the within subjects factor. Significant interactions were followed up with pairwise group comparisons for each of the three encoding conditions (Unrelated; Spontaneous; Directed) using F-tests: c main effect condition p ⬍ .05. d main effect group, NC ⬎ BP-I p ⬍ .05. e main effect group, BP-I ⬎ NC, p ⬍ .05. f group by condition interaction p ⬍ .05. g unrelated encoding condition NC ⬎ BP-I, p ⬍ .05. h unrelated encoding condition BP-I ⬎ NC, p ⬍ .05. i spontaneous encoding condition NC ⬎ BP-I, p ⬍ .05. j spontaneous encoding condition BP-I ⬎ NC, p ⬍ .05. k directed encoding condition, NC ⬎ BP-I, p ⬍ .05. l directed encoding condition, BP-I ⬎ NC, p ⬍ .05.

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r ⬍.19, all p ⬎ .65). Likewise, there were no significant correlations between semantic clustering in the directed condition and rCBF in the DLPFC and hippocampus, neither for BP-I subjects nor for control subjects (all r ⬍ .26, all p ⬎ .54). All above-described analyses were replicated while excluding the one medicated BP-I subject from the analyses. This did not change the pattern of results. All significant findings remained significant. All nonsignificant findings remained nonsignificant.

Discussion

Figure 2. Group differences in regional cerebral blood flow (p ⬍ .001) between subjects with bipolar I disorder and normal control subjects in the linear contrast Unrelated vs. Spontaneous vs. Directed in the (A) dorsolateral prefrontal cortex (DLPFC), (B) hippocampus, (C) frontal–polar cortex (Montreal Neurological Institute coordinates: x ⫽ 36, y ⫽ 48; z ⫽ 4), and (D) parahippocampus superimposed on averaged magnetic resonance images. rCBF, regional cerebral blood flow; Unrel, Unrelated condition; Spont, Spontaneous condition; Direct, Directed condition; BP, bipolar disorder I; NC, normal control subjects; BA, Brodmann’s area.

subjects showed higher rCBF in the dorsal anterior cingulate (BA 32), superior frontal gyrus (BA 10), and hippocampus (see Table 5). Compared with control subjects, BP-I subjects showed higher rCBF in the combined Spontaneous/Directed encoding condition (vs. Unrelated condition; [1S ⫹ 1D] ⫺ 2U; see Table 5) at the interface of the parahippocampal/fusiform gyrus (BA 36/37) as well as in the inferior parietal cortex (BA 40; see Table 5). Correlations. For the directed condition, there were no significant correlations between residual mood symptoms (HAM-D, YMRS) and rCBF in the DLPFC (MNI: x ⫽ ⫺54, y ⫽ 30, z ⫽ 22) or hippocampus (MNI: x ⫽ ⫺24, y ⫽ ⫺24, z ⫽ ⫺6; all

Compared with control subjects, BP-I subjects demonstrated a diminished ability to learn the categorical word lists presented in this study. This was associated with difficulties in using semantic clustering strategies that normally enhance memory performance. Memory and semantic clustering impairment in BP-I subjects cannot be attributed to differences in age, gender, education, or verbal IQ, because both groups were well matched with respect to these variables. It is also unlikely that medication or residual mood symptoms account for the observed findings. The pattern of results remained unchanged when only nonmedicated patients were considered, and correlations with depressive or elevated mood were small and nonsignificant. As a priori hypothesized, BP-I subjects exhibited blunted activation in the left DLPFC across the three encoding conditions (U⬍S⬍D) compared with control subjects, who showed a linear rCBF increase in the DLPFC parallel to their increased use of semantic clustering strategies. This finding is consistent with results of a recent fMRI study in euthymic patients with bipolar disorder, who exhibited blunted DLPFC activation in the context of a Sternberg working memory task compared with normal control subjects (Monks et al 2004). The DLPFC seems to be involved in cognitive tasks (e.g., episodic and working memory) that require subjects to monitor, manipulate, and/or update the contents of working memory (Owen et al 1996). These processes might support semantic organization because they allow subjects to monitor lists of study words and update or manipulate the representations in working memory as they mentally group related words (Savage et al 2001). Blunted DLPFC activation in the presence of patients’ performance impairments has been a widely discussed issue (see Ebmeier et al 1995; Manoach 2003). In schizophrenia, blunted prefrontal cortex activations in the context of working memory tasks have been challenged as a possible artifact of poor performance, possibly due to inattention, poor motivation, or high task difficulty (Ebmeier et al 1995; Manoach 2003). In the presence of both rCBF and performance differences, it is not possible to determine whether rCBF differences are due to impaired performance or vise versa. For the present study, patients showed preserved performance in the unrelated condition. This argues against a global performance impairment accounting for blunted DLPFC in BP-I patients. Yet, blunted activation in the DLPFC might reflect discrete structural neuropathology in BP-I patients (Cotter et al 2002; Lochhead et al 2004; Orlovskaya et al 2000; Rajkowska et al 2001). This might impair functional responsivity, thereby leading to blunted activation in the Spontaneous and Directed encoding condition. This might have “forced” BP-I participants to use an alternative encoding strategy (i.e., focusing on items themselves rather than on categories and inter-item relationships) associated with recruitment of alternative circuitry in the BP-I group (i.e., parahippocampal gyrus). Although caution is advised when discussing the meaning and implication of post hoc findings, some of the observed post www.sobp.org/journal

144 BIOL PSYCHIATRY 2005;59:138 –146

T. Deckersbach et al

Table 5. Group Differences in Regional Cerebral Blood Flow Between Bipolar I Disorder and Control Subjects for (1) the Spontaneous Encoding vs. the Combined Unrelated and Directed Encoding condition; and for (2) the Combined Spontaneous and Directed Encoding Condition vs. the Unrelated Encoding Condition

Comparison/Region

x

y

z

Max Voxel Z Scoreb

20 ⫺8 ⫺32 12

66 36 ⫺34 ⫺14

14 30 ⫺4 0

3.79 3.16 3.74 3.15

16 ⫺50 68 60

⫺32 8 ⫺24 ⫺44

2 ⫺16 28 20

3.26 3.51 4.03 3.30

⫺64

⫺28

⫺18

3.93

66 50 ⫺32 ⫺46 50 8

⫺24 ⫺36 ⫺42 4 ⫺76 ⫺96

28 28 ⫺16 ⫺16 24 24

3.92 3.23 3.44 3.79 3.93 3.92

MNI-Coordinatesa

Brodmann Area

1. Contrast: Spontaneous vs. Combined Unrelated and Directedc Control subjects minus BP-I subjects Frontal–polar cortex 10 Anterior cingulate 32 Hippocampus Thalamus BP-I subjects minus control subjects Parahippocampal gyrus 35 Superior temporal gyrus 38 Parietal cortex 40 2. Contrast: Combined Spontaneous and Directed vs. Unrelatedd Control subjects minus BP-I subjects Inferior Temporal Gyrus 20 BP-I subjects minus control subjects Parietal cortex 40 40 Parahippocampal/fusiform gyrus 36/37 Superior temporal gyrus 38 Occipital cortex 19 18

MNI, Montreal Neurological Institute; BP-I, bipolar I disorder. a x indicates right (⫹) or left (⫺); y indicates anterior (⫹) or posterior (⫺); z indicates superior (⫹) or inferior (⫺) to the anterior commissure. b Z values ⱖ 3.09 (p ⱕ .001) are shown. c Contrast: Spontaneous vs. combined Unrelated and Directed: 2S ⫺ (1U ⫹ 1D); S ⫽ Spontaneous condition, U ⫽ Unrelated condition, D ⫽ Directed condition, numbers indicate the weights for each condition in the contrast. d Contrast: Combined Spontaneous and Directed vs. Unrelated: (1S ⫹ 1D) ⫺ 2U; S ⫽ Spontaneous condition, D ⫽ Directed condition, U ⫽ Unrelated condition, numbers indicate the weights for each condition in the contrast.

hoc rCBF group differences might in fact support the view of an item-by-item encoding strategy used by BP-I subjects. For example, post hoc, we observed rCBF group differences in the hippocampus as well as at the interface of the fusiform/parahippocampal gyrus. Specifically, BP-I subjects exhibited higher hippocampal rCBF in all three encoding conditions (i.e., hyperactivity) coupled with lack of functional recruitment of the hippocampus in the spontaneous and directed condition. The hippocampus is well known to be involved in encoding and retention of new information (Lepage et al 1998; Schacter and Wagner 1999; Squire 1992). In particular, it seems to play a central role in relational learning that involves the establishment of relationship among items (Eichenbaum 2000), such as required in the memory task used in the present study. This suggests that in bipolar disorder in addition to impaired DLPFC function there are also problems within the actual medial temporal lobe memory system itself. The linear rCBF increase in the parahippocampal gyrus across the three encoding conditions in BP-I subjects but not control subjects might reflect increasing use of an item-by-item encoding strategy of BP-I subjects. In particular, a recent verbal learning fMRI study by Davachi and Wagner (2002) revealed increased left parahippocampal gyrus activation during encoding of isolated words compared with an encoding strategy that favored the encoding of relationship among items and activated the hippocampus. In this context, increased use of semantic clustering strategies in control subjects but not BP-I subjects in the Spontaneous and Directed condition might be www.sobp.org/journal

associated with more semantic and phonological processing (e.g., processing categories, subvocal rehearsal; Gabrieli et al 1998; Klein et al 1995; Poldrack et al 1999; Sergent et al 1992; Wagner 1999) leading to linear rCBF increases in the inferior prefrontal cortex in (BA 44). Likewise, the linear rCBF decrease in the frontal–polar cortex (BA 10; U⬎S⬎D) in control subjects might reflect that control subjects were increasingly using categorical cues and instructions. This might have facilitated navigating through environmental cues (words presented through the computer speaker) and representations (categories, category groups) constructed from memory (Koechlin et al 1999), thereby reducing rCBF across the three encoding conditions. Finally, encoding words on an item-by-item basis in BP-I subjects might also have resulted in a higher working memory load associated with higher parietal cortex activation (BA40; see Table 5) compared with control subjects who clustered items in their respective categories. It should be emphasized again, however, that this view of our findings is largely based on post hoc findings that might be spurious, need to be interpreted with caution, and warrant replication in a larger sample of BP-I patients. Abnormalities in frontal and medial temporal areas have been previously reported in several studies with depressed and manic patients but also with euthymic patients with bipolar disorder (e.g., Adler et al 2004; Benes et al 1998; Beyer and Krishnan 2002; Blumberg et al 1999, 2003; Heckers et al 2002; Lyoo et al 2004; Monk et al 2004; Rubinsztein et al 2001; Strakowski et al 2002). Our study suggests that abnormalities found during depression

T. Deckersbach et al or mania might not be fully resolved when patients are in remission. Our findings are also consistent with an evolving neuropsychological literature in bipolar disorder documenting persistent learning and memory impairments in euthymic patients with bipolar disorder (e.g., Cavanagh et al 2002; Clark et al 2002; Deckersbach et al 2004a, 2004b; van Gorp et al 1998). Specifically, a recent study by Martinez-Aran et al (2004) demonstrated memory impairments in depressed, hypomanic/manic, and euthymic patients with bipolar disorder compared with healthy control subjects. There were no differences across the bipolar groups in learning and free recall. This suggests that memory impairments represent a trait marker in bipolar disorder rather than a state marker of depressed or elevated mood. In addition, several neuropsychological studies show that episodic memory impairments worsen with the number of depressed and manic episodes, suggesting a “toxic” effect of mood episodes for memory functioning (Cavanagh et al 2002; Clark et al 2002; Deckersbach et al 2004a, 2004b). In summary, the present study confirmed our a priori hypothesis of blunted DLPFC activation associated with semantic clustering and memory impairment in bipolar disorder. In addition, post hoc analyses also identified additional frontal and medial temporal areas where rCBF differed between BP-I and control subjects across the three encoding conditions. Abnormalities during encoding in the DLPFC as found in our study are consistent with postmortem studies showing glial and/or neuronal pathology in this region (Cotter et al 2002; Orlovskaya et al 2000; Rajkowska et al 2001) in bipolar disorder. Our study complements these findings, in that BP-I subjects in our study failed to recruit these regions for successful completion of a memory encoding task, suggesting DLPFC as a potential substrate for observed episodic memory impairments in individuals with BP-I. This work was supported by a Young Investigator Award from the National Alliance for Research in Schizophrenia and Depression (TD) and the Clinical Research Training Program at Harvard Medical School (TD). Part of this research was presented at the annual meeting of the Society for Biological Psychiatry, April 29 –May 1, 2004, New York, New York. Adler CM, Holland SK, Schmithorst V, Tuchfarber MJ, Strakowski SM (2004): Changes in neuronal activation in patients with bipolar disorder during performance of a working memory task. Bipolar Disord 6:540 –549. Baldo JV, Delis D, Kramer J, Shimamura AP (2002): Memory performance on the California Verbal Learning Test–II: Findings from patients with focal frontal lesions. J Int Neuropsychol Soc 8:539 –546. Benes FM, Kwok EW, Vincent SL, Todtenkopf MS (1998): A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol Psychiatry 44:88 –97. Beyer JL, Krishnan KRR (2002): Volumetric brain imaging findings in mood disorders. Bipolar Disord 4:89 –104. Blumberg HP, Leung HC, Skudlarski P, Lacadie CM, Fredericks CA, Harris BC, et al (2003): A functional magnetic resonance imaging study of bipolar disorder: State- and trait-related dysfunction in ventral prefrontal cortices. Arch Gen Psychiatry 60:601– 609. Blumberg HP, Stern E, Ricketts S, Martinez D, de Asis J, White T, et al (1999): Rostral and orbital prefrontal cortex dysfunction in the manic state of bipolar disorder. Am J Psychiatry 156:1986 –1988. Buytenhuijs EL, Berger HJC, Van Spaendonck KPM, Horstink MWIM, Borm GE, Cools AR (1994): Memory and learning strategies in patients with Parkinson’s disease. Neuropsychologia 32:335–342. Cavanagh JTO, Van Beck M, Muir W, Blackwood DHR (2002): Case-control study of neurocognitive function in euthymic patients with bipolar disorder: An association with mania. Br J Psychiatry 180:320 –326.

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