ANPA Abstracts

P1. Chronic fatigue syndrome: quantitative single-voxel ¹H MR spectroscopy of the basal ganglia Gordon Andrews, Kenna Sleigh, Bruce Forster, Grant Stiver, Anthony Chow, Burkhart Maedler, Alex MacKay, Saul Isserow (Department of Radiology, University of British Columbia, Vancouver, BC, Canada). [email protected]

Background: Chronic fatigue syndrome (CFS) is a poorly understood disorder of uncertain etiology. A recent study (Haley et al, Radiology 2000; 215:807–817) has utilized MR spectroscopy (MRS) in identifying biochemical abnormalities within the basal ganglia in individuals with Gulf War syndrome, a disorder that shares many clinical features with CFS. With this in mind, we have undertaken a pilot study to assess for similar abnormalities within the basal ganglia of CFS patients. Methods: 5 patients meeting the strict clinical criteria for CFS were matched with 5 otherwise healthy volunteers. Each individual was physically stressed with treadmill exercise. Spectroscopy was performed on three separate occasions: immediately pre-exercise, 1 hour post exercise, and 24 hours post exercise. Statistical analysis of the quantitative neurometabolite measurements was undertaken by using repeated measures. Results: Although CFS patients experienced a temporary worsening of symptoms following exercise, MRS did not demonstrate a statistical difference in neurometabolite concentration. Conclusions: There is no MRS evidence of basal ganglia neuronal cell loss or membrane breakdown in individuals with CFS. As this is a pilot study, there are limitations related to the small sample size, and continued investigation is required to confirm the findings.

P2. Creation of teaching materials to promote transfer of neuroanatomical knowledge from classroom to bedside Robin A. Hurley, L. Anne Hayman, Katherine H. Taber (Baylor College of Medicine, Houston VAMC, Houston, TX). [email protected]

Background: It is difficult to apply classroom-derived knowledge of functional anatomy to clinical practice. Educational research strongly supports the use of guided experiences in which an expert explicitly draws the learner's attention to key connections to promote the creation of active (useable) knowledge. A search indicates that few appropriate teaching tools are presently available. Methods: Clinical literature relevant to functional neuroanatomy was reviewed, synthesized, and summarized into graphic, rich teaching materials (diagrams, charts, 3D models) in which color carries a significant portion of the information. This approach allows large volumes of information to be presented without overwhelming the learner. Illustrative teaching examples combining these new materials with clinical cases were created. Results: These tools were used both in preparing learners prior to patient examination and in discussion afterwards. Resident evaluations have been very positive. This approach helped them establish connections between functional neuroanatomy and clinical practice, deepened their interest in the individual aspects of each patient, and enhanced their appreciation of pathology and prognosis. Conclusions: These new tools support guiding learners through the intricacies of this complicated field. Use of guided experiences strongly promotes the development of the active, integrated knowledge of functional anatomy required for the practice of neuropsychiatry.

P3. The neural connectivity of the retrosplenial cingulate cortex Josef Parvizi, Gary Van Hoesen, Joseph V. Buckwalter, Eduardo Vianna (Mayo Clinic, Rochester, MN, and Department of Neurology, University of Iowa, Iowa City, IA). [email protected]

Background: We believe understanding the neural connectivity of the retrosplenial cingulate cortex (RSC) might help us gain insight into its possible functional involvement in affective processing, a role that has been subject to recent controversy (Maddock, Trends Neurosci 1999, 22:310–316; Vogt et al, Trends Neurosci 2000, 23:195–197). Methods: Superior colliculi were injected in four cynomolgus monkeys with the retrograde tracers Fast Blue and Dyanudino Yellow and the anterograde tracers biotinylated dextran amine (BDA) and FluoroRuby. Results: The RSC is reciprocally interconnected with anterior cingulate (Brodmann area 24), prefrontal (BA8, 9, 46, 9/46), lateral and mesial parietal (areas PG, PE, PGm) and temporal cortices (entorhinal and area TPO) as well as the claustrum and the dorsal thalamus. The RSC projects to the caudate nucleus, the periaqueductal gray matter (PAG), and the pontine nuclei. It receives projections from the orbitofrontal cortex, the amygdala, and the frontal pole. Conclusions: The RSC has strong connections with brain regions involved in cognitive processing. It also has a special connectivity pattern with structures involved in emotional processing and is reciprocally interconnected with the anterior cingulate gyrus. It receives projections from, but does not project to, the amygdala and orbitofrontal cortex, and sends projections to, but does not receive projections from, the PAG. Support from NINDS Program Project Grant 5P01 NS 19632-20.

P4. Ethanol-induced reduction of CREB activity and BDNF production in human neuroblastoma SH-SY5Y cells Toshikazu Saito, Rie Sakai, Hitoshi Sohma, Hiroshi Ikeda, Megumi Yamamoto, Yoshio Kuroki (Departments of Neuropsychiatry and Biochemistry, Sapporo Medical University School of Medicine, Sapporo, Japan). [email protected]

Background: Many recent studies have reported that alteration in brain adenosine 3′,5′-cyclic monophosphate (cAMP) is involved in pathogenesis of alcoholism. It has also been demonstrated that cyclic AMP–responsive element binding protein (CREB) helps to modulate neural plasticity. It is plausible that ethanol affects the CREB-induced gene transcriptions in alcoholic brain. Methods and Results: In this study, we investigated ethanol-induced toxicity and CREB activity by using SH-SY5Y cells. Retinoic acid induces the neuronal differentiation of SH-SY5Y cells and is accompanied by expression of TrkB, the receptor for neurotrophins brain-derived neurotrophic factor (BDNF). It was shown that 200 mM of ethanol treatment for 24 hours reduced cell viability to 70%, whereas it was 55% with undifferentiated cells. The undifferentiated cells were more susceptible to ethanol than the differentiated cells. Electrophoretic mobility shift assay showed a decrease in the bands with the ³²P-labeled CRE oligonucleotide probe in both the differentiated and undifferentiated cells by ethanol treatment. Conclusions: These results demonstrated that ethanol downregulates CREB activity and reduces BDNF production, suggesting that these processes might be involved in the pathophysiology of alcoholic dependence. Support from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.

P7. Detecting adverse drug events in neuropsychiatric care John J. Campbell, C.E. Coffey, Michael Boyle, Carol Ludwicki, Rosemary Gafka (Kingswood Hospital, Ferndale, MI). [email protected]

Safety is an essential attribute of ideal neuropsychiatric care. Persons with neuropsychiatric disorders seeking treatment often receive medications, placing them at risk for adverse drug events (ADEs). Although newer-generation drugs are much safer and better tolerated than earlier medications, their use may nonetheless be associated with adverse effects. Little has been published about the detection and measurement of ADEs in patients with neuropsychiatric disorders. Our goal at Henry Ford Behavioral Health is to eliminate preventable ADEs. To achieve this goal, we revised and implemented a tool to detect ADEs based on the model developed by the Idealized Design of the Medication System (IDMS) Design Group in May 2000. This tool is efficient and is accurate and without bias (especially undercounts) in patients with neuropsychiatric disorders. We monitor 12 triggers as they appear in the medical record and ascertain the presence of ADEs. Each ADE is assigned a Harm Rating Score, and these data are analyzed for patterns to identify opportunities for perfecting our medication system. We will present our screening tool and provide data documenting its usefulness for identifying ADEs in patients with neuropsychiatric disorders.

P8. A controlled study of the association of older age with depression and anxiety in HIV-1 infection Karl Goodkin, Imad Khamis, Diana Lee, Robert Lecusay, Paola Suarez, Frances L. Wilkie, Mauricio Concha, Stephen Symes (University of Miami, Miami, FL). [email protected]

Background: Older individuals with HIV-1 infection (HIV+) may experience stigma, isolation, and psychological distress. Methods: Depression and anxiety were rated in a 2×2 study design: older (>50) HIV+; younger (18–39) HIV+; older HIV−; and younger HIV− individuals. All HIV+ individuals were in symptomatic stages. Depression was measured by the 17-item Ham-D and anxiety by the 14-item Ham-A. Prior psychopathology (by the SCID) and CD4 cell count were controlled. Results: Participant data (n=128) were analyzed by a generalized linear model. HIV-1 serostatus, age, and a serostatus by age interaction were the predictors. On the Ham-D and Ham-A (including and excluding somatic items), older HIV− individuals showed higher adjusted mean depression than younger HIV− individuals. Older HIV+ individuals showed a lower adjusted mean depression than younger HIV+ individuals. Conclusions: Controlled evidence suggests lower depression and anxiety with aging in HIV+ individuals and higher levels with aging in HIV− individuals. This may relate to greater confrontation of mortality among older HIV+ than among older HIV− individuals. Support from NIMH and NIA Grants R01 MH58532, MH/AG61628, and MH/AG61629.

P9. Effects of nicotine on eye movement during visual attentional performance Hiroshi Ikeda, Yoshihisa Hatakeyama, Hidetoshi Tominaga, Hirotaka Miura, Ryuji Sasaki, Toshikazu Saito (Sapporo Medical University School of Medicine, Sapporo, Japan). [email protected]

Background: Nicotine is known to improve performance on a range of cognitive tasks, notably attention; this could contribute to smoking maintenance by improving concentration. In nicotine-dependent individuals, tobacco deprivation can impair attentional abilities within 12 hours of smoking cessation, and nicotine administration or cigarette smoking can reverse such deficits to predeprivation performance levels. Whether improved performance associated with relief from withdrawal should be considered attentional enhancement has been questioned. The purpose of this study was to examine the influence of past smoking history and acute nicotine administration on attentional performance. Methods: We compared the effects of nicotine on a visual attention task in 12-hours-abstinent smokers, ex-smokers, and never-smokers. Smokers reported a smoking history of at least 2 years and currently smoked more than 20 cigarettes per day. Ex-smokers reported a history of past exposure to nicotine (more than 5 cigarettes in their lifetime) but no current smoking. Never-smokers smoked fewer than 5 cigarettes in their lifetime. After a testing session, the task was performed after the administration of polacrilex gum containing 4 mg of nicotine. Smokers had to be abstinent from smoking for the previous 12 hours. Participants performed a computerized visual attention task, and then eye movement and gazing during the session were analyzed quantitatively. Support from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.

P10. Impairment in social cognition following lesions of ventromedial and dorsolateral prefrontal cortex Linda W.Y. Mah, Miriam Courtney Arnold, Jordan Grafman (National Institutes of Health, Bethesda, MD). [email protected]

Background: We previously reported dissociable social cognitive deficits on the Interpersonal Perception Task in patients with lesions of ventromedial (VMPFC) and dorsolateral prefrontal cortex (DLPFC), suggesting a role for both prefrontal sectors in social cognition. Here we report results from another standardized task of social cognition, the Tests of Social Intelligence (TSI). The TSI consists of a series of drawings and cartoons requiring subjects to use nonverbal cues to interpret social and emotional situations. Methods: Patients included those with left VMPFC (n=6), right VMPFC (n=5), left DLPFC (n=3), or right DLPFC lesions (n=5). We examined the relationship between performance on the TSI, WAIS Picture Arrangement subtest, and the Neurobehavioural Rating Scale. Results: Patients with VMPFC, but not DLPFC, lesions were impaired on the TSI, relative to healthy control subjects. Deficits on the TSI were correlated with greater neuropsychiatric pathology, but not with picture-arranging ability. Conclusions: Disturbances in social behavior following lesions of VMPFC may result from deficits in interpreting nonverbal cues of emotion and social interaction. The role of DLPFC in social cognition is unclear. It is hypothesized that DLPFC may be involved in more complex aspects of social cognition, such as the ability to make inferences about interpersonal situations.

P11. Anxiety, sensitivity, cognition, and coping strategies in panic disorder patients with and without agoraphobia N. Minamikawa, T. Iketani, K. Nagao, A. Shidao, H. Fukuhara, M. Katagami, N. Kiriike (Department of Neuropsychiatry, Osaka City University Medical School, Osaka, Japan). [email protected]

Background: Ever since a cognitive model of panic attacks was proposed, the importance of cognitive factors or coping strategies on the course of panic disorder and agoraphobia has been addressed. Methods: Anxiety sensitivity, anticipatory and catastrophic thoughts, and coping strategies, as measured by responses to the Anxiety Sensitivity Index (ASI), the Agoraphobic Cognitions Questionnaire (ACQ), and the Coping Inventory for Stressful Situations (CISS), were compared in patients with the subtypes of panic disorder. Results: Panic disorder patients with agoraphobia showed significantly more use of maladaptive coping strategies and dysfunctional cognition about anxiety-related symptoms than did those without agoraphobia. Correlative analyses demonstrated that the patients' self-rated cognition significantly positively correlated with emotion-oriented coping in CISS. Conclusions: These results suggest that agoraphobic avoidance may be related to dysfunctional catastrophic cognition and maladaptive coping. Considering the strong association of the emotion-oriented coping scale of CISS with various measures of psychological pathology, agoraphobic avoidance may be derived not from specific psychological features related to panic disorder, but from general psychopathology. With these findings taken into account, identification of relationships between cognitive factors and coping strategies may assist clinicians in designing therapeutic strategies and in monitoring therapeutic change in patients. Further prospective study will be needed to confirm our results.

P12. Motor and cognitive symptoms are associated with depression in preclinical Huntington's disease Carissa Nehl, Karin Ferneybough, Bradley McDowell, Jane Paulsen* (University of Iowa, Iowa City, IA). [email protected]

Background: Our own past research indicated that individuals with mildly abnormal motor exams (not severe enough to warrant a diagnosis of Huntington's disease) experience the highest rates of depression. The current study is to further examine depression in presymptomatic HD. Methods: 71 individuals at risk for HD were assessed with the BDI and the Unified Huntington's Disease Rating Scale (UHDRS). A neurologist administered standardized motor evaluations as part of the UHDRS. No participant was rated as having diagnosed HD. Results: 32 individuals (45%) exhibited abnormal motor symptoms on the UHDRS. Motor severity ratings were strongly associated with BDI total score (r=0.51; P<0.01). Importantly, depressive symptoms were also associated with decreased cognitive performance (Symbol Digit Modalities Test, r=−0.368, P<0.01; Verbal Fluency, r=−0.35, P<0.01; Stroop Word Reading, r=−0.34, P<0.01; and Stroop Color Reading, r=−0.29, P<0.05. Conclusions: Depression in individuals at risk for HD but not yet meeting criteria for the disease is associated with increased motor symptoms and decreased cognitive performance. Findings suggest that depressed mood may be due, in part, to an awareness of increased cognitive and motor abnormalities and impending HD diagnosis. Further research is needed to examine the biological and reactive components of depression in HD. Support from NINDS PREDICT Grant NS40068.

P14. Cognitive and somatic symptoms of depression in at-risk individuals and symptomatic Huntington's disease patients Karin Ferneybough, Carissa Nehl, Bradley McDowell, Jane S. Paulsen* (University of Iowa, Iowa City, IA). [email protected]

Background: Depression is common in Huntington's disease. Previous research has suggested that depression may be particularly prevalent during the period when motor symptoms of HD first appear; however, relatively little research has characterized depression in different stages of the disease. Methods: We assessed depressive symptoms in 103 individuals at risk for and diagnosed with HD. Participants were grouped according to ratings on a standardized neurological exam (normal, possible/probable HD, and unequivocal HD). Depression was measured with the BDI. The cognitive and somatic items on the BDI were selected and all summary scores (total score, cognitive items, and somatic items) were compared across groups. Results: The total BDI score was highest for the at-risk group manifesting abnormal motor findings. The BDI cognitive score was significantly greater in the at-risk group with abnormal neurological findings than in individuals with a normal exam. In contrast, the BDI somatic score was greatest in the group diagnosed with HD. Conclusions: Findings confirm that depressive symptoms are elevated in individuals at risk for HD with abnormal neurological exams. Depression in presymptomatic HD is characterized by nonsomatic symptoms of depression (e.g., sadness, guilt), whereas somatic symptoms (e.g., sleep disturbance, decreased appetite) are predominant after diagnosis. Support from NINDS PREDICT Grant NS40068 and the Huntington's Disease Society of America.

P15. The effect of early versus late antidepressant treatment on physical impairment associated with poststroke depression: a time-related therapeutic window Kenji Narushima, Robert G. Robinson (Department of Psychiatry, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA). [email protected]

Background: Impairments in activities of daily living (ADL) are common after stroke and have been shown in numerous studies to correlate with severity of depression. In addition, time since stroke has been an important factor in the relationship between poststroke depression and clinical correlates such as lesion location and severity of impairment. The current study was therefore designed to examine the effects of early versus late antidepressant treatment of poststroke patients on recovery in ADL. Methods: Among 62 patients with stroke, early therapeutic intervention (i.e., fluoxetine or nortriptyline administered double blind for 3 months and started within 1 month after stroke; mean=19.7 days, SD=1.5) was compared with late therapeutic intervention (i.e., same treatment but started more than 1 month following stroke; mean=140.2 days, SD=41.8), using the Functional Independence Measure (FIM) as the outcome variable over 2 years. Results: Although both early and late treatment groups showed improvements in FIM scores over the first 3 months, the early treatment group (n=34) improved more significantly than the late treatment group (n=28). After the 3-month treatment terminated, the early treatment group maintained the initial improvement over 2 years, whereas the late treatment group deteriorated significantly over time. These phenomena were not related to depression status, recurrence of cerebrovascular disease, or physical complications during the follow-up period. Conclusions: Recovery in ADL impairment following stroke appeared to be enhanced by the use of antidepressant medication if the treatment was started within one month following stroke. There might be a time-related therapeutic window in the treatment of physical impairment associated with poststroke depression. Support from NIMH Grants MH40355, MH52879, MNH53592, MH63405, and Research Scientist Award MH00163 (R.G.R.).

P16. Slow-frequency rTMS reduces fibromyalgia pain Shirlene M. Sampson, Jeffrey D. Rome, Teresa A. Rummans (Mayo Clinic, Rochester, MN). [email protected]

Background: Fibromyalgia (FM) is a generalized chronic pain disorder of unknown etiology. FM is characterized by widespread pain and muscle tenderness and is typically accompanied by sleep disturbance, fatigue, depressive symptoms, and cognitive complaints. Although FM is characterized by musculoskeletal pain, there is evidence suggesting it is a centrally mediated pain disorder. Antidepressants (mostly tricyclics) have been shown to provide some symptomatic relief in FM, and ECT has been effective in refractory pain states. Central brain stimulation with repetitive transcranial magnetic stimulation (rTMS) has been shown to be effective in treatment-resistant depression and may be of benefit in chronic pain. Methods: 4 women with depression, FM, and borderline personality disorder received 20 rTMS treatments applied to the right dorsolateral prefrontal cortex using a 1-Hz frequency, 110% motor threshold intensity, and a total of 1,600 stimuli per session. Depression was evaluated with Ham-D and the Montgomery-Åsberg Depression Rating Scale. Subjects rated pain on an 11-point Likert-type scale. Results: Pretreatment pain averaged 8.2 points (range 7–9.5), and reduced to 1.5 (0–3.5) after treatment (P<0.009). All had improvement in pain, and 2 had complete resolution of pain. Only 1 of the 4 subjects had an antidepressant response. Conclusions: These preliminary findings suggest a possible role for rTMS in treating FM. Support from the O'Shaughnessy Foundation.

P17. Improvement of cognitive function associated with olanzapine in the treatment of acute mania Lizheng Shi, Leslie M. Schuh, Linda X. Huang, Michael G. Wilson, Madhav A. Namioshil, Robert W. Baker, Paula T. Trzepacz, Mauricio Tolien (Lilly Research Laboratories, Indianapolis, IN). [email protected]

Background: Cognitive impairment exists in patients with bipolar disorder even after prolonged remission. Our objective was to determine olanzapine's effects on cognitive function and examine the relationship between cognitive and symptom improvement in patients with acute mania. Methods: Study sample (N=254) was pooled from two placebo-controlled clinical trials (n=139, 3 weeks of olanzapine treatment, and n=115, 4 weeks of olanzapine treatment, respectively). Cognitive function was measured by using the cognitive component subscale of the Positive and Negative Syndrome Scale (PANSS-Cognitive score). Clinical symptom severity measures were the Young-Mania Rating Scale (Y-MRS), Ham-D, and Clinical Global Impressions-Bipolar (CGI-BP). To facilitate data interpretation, last observation carried forward analyses considered only results through 3 weeks. Results: Olanzapine significantly improved PANSS-Cognitive scores after 1 week (olanzapine: −3.26, placebo: −1.83; P<0.05), and over 3 weeks of treatment (olanzapine: −4.25, placebo: −1.69; P<0.001). Significant improvement occurred regardless of mania subtype or presence of psychotic features. Olanzapine-treated patients experienced significantly greater improvement than placebo takers on four of seven PANSS-cognitive items: abstract thinking, stereotypic thinking, tension, and attention. Cognitive improvement was more strongly correlated with mania than with depression improvement, particularly as measured by the CGI-BP. Conclusions: Olanzapine improved cognitive outcomes in patients with acute mania. Support from Eli Lilly and Company.

P18. Spanish-English issues in the psychiatric assessment of Axis I disorders in HIV-1 seropositive individuals Paola Suarez, Karl Goodkin, Alfredo Ardila, Frances L. Wilkie, Mauricio Concha, Diana Lee, Robert Lecusay, Sandra O'Mellan (University of Miami, Miami, FL). [email protected]

Background: To our knowledge, a Spanish translation of the Structured Clinical Interview for the DSM-IV (SCID for DSM-IV) has not been explicitly validated for use with the HIV-1 infected. Methods: The SCID-I/P (Inpatient Version 2.0) for DSM-IV was translated and modified to include the somatization, eating, adjustment, and “optional” disorder modules, to use with 1) nonpsychiatric patients and 2) the HIV-1 infected, per parallel changes in English. Results: The English interview format required a longer time to administer in Spanish. Use of the word “cuénteme” raised concerns that the interviewee perceived being asked to expand on responses, rather than to answer in a clear, concise fashion. Definitions of symptoms that include idioms, e.g., alcoholic “blackouts,” were special concerns. Hispanic culture-specific patterns of behavior needed to be accounted for in defining symptom presence—particularly for symptoms requiring judgment of excessive or reduced behavior from a “normal range.” Conclusions: Differences between what is translated to Spanish as the equivalent of a specific symptom defined in English and the interviewee's response to that item should be verified against target symptoms/behaviors to minimize culturally introduced heterogeneity in psychiatric diagnoses between Spanish and English versions of the SCID.

P19. Psychiatric manifestations of Creutzfeldt-Jakob disease: a 25-year analysis Christopher A. Wall, Teresa A. Rummans, Allen J. Aksamit, V. Shane Pankratz (Mayo Clinic, Rochester, MN). [email protected]

Background: Creutzfeldt-Jakob disease (CJD) is a rapid, fatal illness in which psychiatric manifestations have been reported (Yen et al, Kaohsiung Journal of Medical Sciences 1997; 13:263–267) Methods: Retrospective hospital and clinic chart review was conducted for all 219 patients diagnosed and treated for CJD during 1976–2001 at the Mayo Clinic in Rochester, MN, to characterize neuropsychiatric presentation and treatment. These cases were reviewed for presence and timing of depression, anxiety, psychosis, behavior dyscontrol, sleep disturbances, and neurologic signs during the course of the disease. Results: 219 cases were reviewed and 126 met criteria for either definite or probable CJD. Of these 126 cases, 87.3% demonstrated psychiatric manifestations during the course of illness. Specifically, 42.9% had symptoms of depression, 32.5% had symptoms of anxiety, 31.8% showed evidence of psychosis, 23.8% had behavior dyscontrol, and 40.5% had sleep disturbances. Mood and sleep disturbances were more prominent in the early portion of illness. A wide range of pharmacologic treatments was offered to alleviate neurologic and psychiatric suffering. Anxiolytic administration followed by antipsychotic-class medications appear to be the most beneficial. Conclusions: Psychiatric manifestations are a prominent feature of Creutzfeldt-Jakob disease. Sleep abnormalities and depressive symptoms were most commonly reported. Anxiolytic and antipsychotic agents appear to be the most favorable interventions in improving behavior and mood symptoms in CJD.

P20. Divalproex decreases impulsivity in compulsive gamblers James A. Wilcox (El Paso, TX). [email protected]

Methods: The progress of 40 individuals with gambling problems was examined over a period of one year. These people were screened to rule out other psychiatric diagnoses, using the SCID. The existence of a gambling problem was confirmed by operational criteria and by a history that had to include social impairment, indebtedness, or arrest due to gambling. Each subject was treated with either divalproex at doses of 20 mg/kg or oxcarbazepine at doses of 600 mg/day (20 persons in each group). Subjects were given the Barratt and the Karolinska impulsivity scales before treatment and at the conclusion of the one-year follow-up. We also kept track of social impairment, indebtedness, and arrests for subjects during the year. Results and Conclusions: At the conclusion of the study there was a significant decrease in the scores for both impulsivity scales in subjects on divalproex (t=7.29, P<0.001), but no change in the oxcarbazepine group. The divalproex group also had fewer arrests than the other group (t=5.29, P<0.01). We conclude that divalproex reduces impulsivity in subjects with compulsive gambling.

P21. Aggression induced by interferon alfa-2b during long-term therapy for chronic hepatitis Nancy W. Withers (VA San Diego Healthcare System, San Diego, CA). [email protected]

Background: The hepatitis C virus (HCV) is the leading cause of chronic liver disease in the U.S. At the San Diego VA Healthcare System, 40% of patients requesting drug and alcohol treatment are HCV-antibody positive. Treatment, which is available for chronic infection, includes interferon alfa-2b with ribavirin and is lengthy with significant side effects. The major side effects reported to date are neuropsychiatric; they include depression, anxiety, irritability, and fatigue and have been severe enough for patients to leave treatment. This report documents severe aggression in patients during interferon-based therapy. The current report was triggered by observations that a number of patients during interferon therapy were experiencing anger, reported as episodes of domestic violence, “road rage,” and other significant interpersonal conflicts that were intolerable and required psychiatric intervention and/or reduction or cessation of interferon. Methods: 25 patients were assessed with the Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and Aggression Questionnaire (AQ) preceding therapy and again at intervals during their 24- or 48-week course. Patients with severe depression, anxiety, or aggressive symptoms were excluded, as well as patients using substances of abuse within 6 months prior to treatment. Results: Of 25 patients, 4 reported severe aggressive symptoms during treatment but not at pretreatment assessment. For these 4 patients, there were no significant changes in anxiety (BAI) or depression (BDI-II) or in sleep patterns. All had been abstinent from drugs or alcohol and did not relapse. The 4 patients were all white males ages 38 to 64. The individual AQ (total aggression) scores for the 4 patients increased in T score from 44 to 65, 55 to 68, 54 to 64, and 46 to 65, respectively. The pretreatment percentile for total aggression was 26%–70% of age/sex-matched control subjects; during treatment, this increased to 92%–96% for all 4 patients. All patients reported an increase in subscale anger (from T 54–56 [67%–73%] to T 69–73 [97%–99%]). Severe anger symptoms (T 72) were reported in 2 patients; severe indirect aggression in 2 patients; and severe hostility in 1 patient. All patients required psychiatric intervention but were able to complete treatment. Conclusion: Severe apparent interferon alfa-2b—induced aggressive symptoms distinct from depression or anxiety were found in 4/25 patients treated for chronic HCV.

P22. Right lenticular lacunar infarction and delusion: a case report Kenji Yoshiyama, Takashi Nishikawa, Yoshitaka Ikejiri, Hiroaki Kazui, Hiromasa Tokunaga, Seigo Tamenaga, Masatoshi Takeda (Tamenaga-Onsen Hospital, Osaka, Japan). [email protected]

Background: The lenticular nucleus is a part of the basal ganglia that is concerned with motor activity. Lesions in this area sometimes cause motor disturbance. Few clinical reports suggest that lesions in the basal ganglia can cause psychotic symptoms. We report the case of a patient with a lesion in this area who shows psychotic symptoms. Case Report: A 72-year-old right-handed man manifested a delusional state; delusion of theft and persecution. He gradually showed various types of disorientation and excessively violent behavior toward his family. He could tell the date and his age exactly but could not recognize where he was. He did not show any motor symptoms. When he was admitted to our hospital at age 75, there was no clear atrophic change in his cerebral cortex except for a low-density area in the right lenticular nucleus on CT scan, indicating lacunar infarction. Conclusions: The basal ganglia, particularly the lenticular nucleus, is related not only to motor activity but also to psychotic functions.

P23. A group-averaged structural MRI study of Tourette syndrome Charissa F. Black, Johanna M. Hartlein, Tamara Hershey, Joel S. Perlmutter, Kevin J. Black* (Washington University School of Medicine, St. Louis, MO). [email protected]

Background: Abnormal function of basal ganglia—influenced neuronal pathways has been hypothesized in Tourette syndrome (TS). A large volumetric MRI study has been reported in TS based on a priori-defined brain regions. However, we are unaware of any published whole-brain voxelwise study of brain structure in TS. We hypothesized that subtle but consistent change in brain structure, not necessarily visible on individual T₁-weighted MR images of patients and not necessarily corresponding to a priori-defined regions, might be found by using a matched group comparison in a common atlas space. Methods: A board-certified psychiatrist and movement disorders specialist examined every subject. We compared 3D MP-RAGE images of 15 neuroleptic-naive adults with TS or chronic motor tic disorder by Tourette Syndrome Study Group criteria (ages 19–56 yr; mean=33, SD=11), and 15 matched control subjects (ages 19–55 yr; mean=33, SD=12). Images were smoothed with a 3D gaussian filter with half-frequency 1.0 cm/s, normalized linearly to the Talairach and Tournoux stereotactic atlas by using a validated automated method, and analyzed by using SPM99 to correct for multiple comparisons. Results: By conservative statistical criteria, there were no significant group differences in MR signal intensity. Conclusions: This negative study does not preclude possible group differences in T₂-weighted MR signal or subtle volumetric differences, or a type II error given the limited number of subjects. Support from the Tourette Syndrome Association, NARSAD, NINDS, the Dana Foundation, the McDonnell Center for Higher Brain Function, and the Mallinckrodt Institute of Radiology.

P24. Abnormal dopamine-mediated brain function in Tourette syndrome revealed by cognitive-pharmacologic fMRI Tamara Hershey, Kevin J. Black*, Johanna M. Hartlein, Deanna M. Barch, Todd S. Braver, Juanita L. Carl, Joel S. Perlmutter (Washington University School of Medicine, St. Louis, MO). [email protected]

Background: Abnormal dopamine modulation of brain function has been suspected but not convincingly demonstrated in Tourette syndrome (TS). We hypothesized that abnormal function might be more sensitively detected by combining cognitive and pharmacologic probes of dopaminergic function and noninvasive brain imaging. Methods: A board-certified psychiatrist and movement disorders specialist examined every subject. We studied 8 neuroleptic-naive adults with TS or chronic motor tic disorder by Tourette Syndrome Study Group criteria and 10 matched control subjects. Mean age was 35.5 years and mean education level 14.1 years in each group. After 200 mg carbidopa po, we infused iv levodopa at individualized rates based on age and body mass. A 35-year-old 70-kg subject would receive a total dose bioequivalent to 150 mg oral levodopa. Before and again 35–60 min after the levodopa loading dose, subjects performed a 2-back working memory (WM) task alternating with visual fixation. fMRI data were analyzed with a conservative multistep approach to find WM task-related regions. The activity in these regions varied based on diagnosis or drug condition (baseline or levodopa). Results: In adults with or without TS, levodopa improved or worsened WM performance in proportion to the plasma concentration achieved. In TS subjects, despite normal task performance, the WM task induced excessive activity in left parietal cortex, supplementary motor area, and left thalamus. Levodopa normalized the excess activity, and in left parietal cortex the degree of normalization correlated with plasma concentrations. Conclusions: These findings demonstrate a dopamine-influenced brain abnormality in Tourette syndrome. Support from the Tourette Syndrome Association, NARSAD, NINDS, Dana Foundation, McDonnell Center for Higher Brain Function, and Mallinckrodt Institute of Radiology.

P25. The relationship between multiple sclerosis and major depression clarified: an MRI brain segmentation study Laury Chamellan, Anthony Feinstein*, Peter Roy, Nancy Lobaugh, Karen Feinstein, Paul O'Connor, Sandra Black (University of Toronto, Toronto, ON, Canada). [email protected]

Background: Depression is common in multiple sclerosis, yet MRI studies exploring pathogenesis linked to brain pathology have yielded inconsistent results. This study aimed to demonstrate an association between depression and anatomical abnormalities in frontal-subcortical limbic pathways in MS patients. Methods: 21 patients with clinically definite MS and DSM-IV-defined major depression were matched on demographic, disease, and cognitive parameters to 19 subjects without depression. All subjects underwent brain MRI. Tissue segmentation and regional brain masking were applied to the MRI data. Results: Compared with the euthymic subjects, those with major depression had a greater T₂-weighted lesion volume in the left medial inferior prefrontal cortex (P=0.003), more extensive T₁-weighted lesion in the left medial inferior prefrontal cortex (P=0.01), less gray matter volume in the left anterior temporal region (P=0.01), and more CSF volume in the left anterior temporal region (P=0.005). A logistic regression analysis identified two independent predictors of depression, namely left medial inferior prefrontal cortex T₂ lesion volume and left anterior temporal CSF volume. These variables accounted for 42% of the depression variance score. Conclusions: These results extend and clarify previous MRI-depression studies in MS. While our data demonstrate that both lesion burden and atrophy are important in the pathogenesis of depression in MS, psychological influences must also be considered. Support from the Canadian Institute of Health Research (CIHR).

P26. Reduced superior temporal gyrus volumes in bipolar disorder Glen E. Getz, David E. Fleck, Molly E. Zimmerman, Michael Schwiers, Melissa P. DelBello, Stephen M. Strakowski (University of Cincinnati, Cincinnati, OH). [email protected]

Background: Several studies have reported that patients with schizophrenia have a reduction in volume of the superior temporal gyrus (STG). Because this important brain region is connected with the anterior limbic system, it is possible that the STG may also exhibit abnormalities in other major mental illnesses, specifically bipolar disorder (BPD). However, whether volumetric reductions exist in BPD in the STG as reported in schizophrenia is not known. The goal of this study, then, was to examine the MRI-derived volume of the STG in BPD as compared with healthy subjects. Methods: 40 BPD patients and 40 healthy comparison subjects (HC), matched for sex, age, and handedness, were assessed by using the SCID-P. Contiguous 1-mm axial T₁-weighted MRI slices were obtained by using a 1.5-T MRI scanner. Raters, who were blind to subject identity and diagnosis, measured left and right STG volumes along with whole-brain volumes. The STG was traced anteriorly as far as the joining of the insular cortex and the temporal gyrus; the posterior boundary extended to the most anterior portion of the splenium. Results: Analysis of covariance adjusting for whole-brain volume revealed that compared with HC, BPD patients demonstrated smaller overall STG volumes (F=12.2, df=1,77, P=0.001) on both the left side (t=−3.3 1, df=78, P=0.002) and the right (t=−3.27, df=78, P=0.002). Discussion: Our results suggest that patients with BPD have volume reductions in the STG, as has been reported in studies of schizophrenia. Other temporal subregions should be examined in this population. Support from the Theodore and Vada Stanley Foundation.

P27. Right frontal white and gray matter volumes correlate with depressive symptoms in MS Brian A. Greenlee, Heather A. Wishart, Brenna C. McDonald, John J. Randolph, Carmlo E. Fadul, Lloyd H. Kasper, Kathleen A. Ryan, Thomas W. McAllister, Andrew J. Saykin (Section of Neuropsychiatry and Brain Imaging Lab, Dartmouth Medical School, Lebanon, NH). [email protected]

Background: Individuals with multiple sclerosis have higher rates of depression than the general population. Depression in MS patients correlates with overall lesion burden, and lesions in various regions including right frontotemporal white matter (WM), arcuate fasciculus, and right temporal WM. This study used voxel-based morphometry (VBM), a novel automated technique for assessing regional and local differences in gray (GM) and WM volume in an unbiased fashion. We used VBM to explore the relationship between regional changes in GM and WM and depressive symptoms. Methods: 16 patients with mild to moderate relapsing-remitting MS (median on Expanded Disability Status Scale=2.0) were studied with structural MRI scans acquired on a GE 1.5-T LX scanner, including a T₁ SPGR 1.5-mm coronal volume, and axial T₂ and FLAIR series for lesion identification. VBM procedures were conducted with minor modifications (Ashburner, Neurolmage 2000, 11:805–821; Good et al, Neurolmage 2001, 14:21–36). SPGR volumes were spatially normalized, segmented, smoothed (full width half maximum=10), modulated, and contrasted by using SPM99. The Profile of Mood States depression subscale was used to quantify depressive symptoms. Results: Depression scores were negatively correlated with regional WM volume in the corpus callosum and right orbital-frontal region, and with regional GM volume in the right frontal cortex (all P<0.01). Conclusions: The correlation between depressive symptoms and measures of both WM and GM volume in the right frontal region suggests that pathology in this region plays an important role in the modulation of mood in MS patients. Support from the National Multiple Sclerosis Society, the Hitchcock Foundation, and the Ira W. DeCamp Foundation.

P28. Neural substrates of emotional habituation: a PET study Naoki Hatta, Yoshihiro Masaki, Doronbekov Talant, Atsushi Ogino, Noriko Miyoshi, Hiromasa Tokunaga, Hiroaki Kazui, Yoshitaka Ikejiri, Takeshi Uema, Takashi Nishikawa, Naohiko Oku, Masatoshi Takeda (Department of Psychiatry and Behavioral Science, Osaka University Graduate School of Medicine, Osaka, Japan). [email protected]

Background: As external stimuli are given repeatedly, the level of emotional response decreases. This is called habituation. The aim of this study was to reveal the neural substrates of emotional habituation. Methods: 15 healthy male volunteers were examined by using [¹⁵O]H₂O PET. The subject was required to watch two film clips, a horror scene (emotional task) and a calm scene (nonemotional task). Each film clip was repeatedly presented six times during the total 12 PET scans. The regional cerebral blood flow in the first two presentations of each task was compared with that in the last two presentations. Results: On the emotional task, the right retrosplenial cortex (Brodmann areas 30 and 23) was activated during the former scans, and the bilateral occipital cortices (BA 13A, 19, and 37) were activated during the latter scans. On the nonemotional task, the bilateral occipital cortices (BA 19 and 37) were activated during the former scans, and the bilateral prefrontal cortices (BA 10) were activated during the latter scans. Conclusions: The cerebral activation by emotional experience reciprocally transferred from the paralimbic region (retrosplenial cortex) to the neocortical region (bilateral occipital cortices) as the experience was repeated. This result is consistent with the theory that the process of emotional habituation is promoted by the process of conceptualization. Support from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.

P29. Acquired brain injury: amount of tissue loss, not etiology, alters cognitive and emotional function Ramona O. Hopkins, David Tate, Erin D. Bigler (Psychology Department and Neuroscience Center, Brigham Young University, Provo, UT). [email protected]

Background: Current thought in neuropsychology and neuropsychiatry is that the etiology of a particular neurological injury will determine the neuropsychological profile that occurs following an injury. The purpose of this study was to compare neuropsychological outcome in subjects with traumatic brain injury (TBI) and anoxia due to carbon monoxide poisoning. Methods: 10 subjects with accidental carbon monoxide (CO) poisoning with concomitant anoxia were matched to 10 subjects with TBI from our archival data base. Subjects were matched for age, gender, and ventricle-to-brain ratio (VBR), a measure of diffuse atrophic change. All 20 subjects underwent a comprehensive neuropsychological testing and quantitative brain MRI analysis. Results: There were no significant differences between the TBI and anoxic groups for any morphologic or neuropsychological outcome measure. Both groups' intellectual function was essentially within normal limits, but the two groups showed similar deficits in memory, attention, executive function, and mental processing speed. Measures of intelligence were correlated with whole-brain volume and measures of memory were correlated with hippocampal atrophy in both the CO and TBI subjects. Conclusions: These results indicate that the amount of neural tissue loss, not the etiology of the brain injury, may be the critical factor in predicting neuropsychological outcome.

P30. A case with a transient lesion in the splenium of the corpus callosum caused by antiepileptic drug Hiroyuki Narita, Toshinari Odawara, Chiaki Kawanishi, Ikuko Kishida, Eizo Iseki, Kenji Kosaka (Department of Psychiatry, Yokohama City University, Yokohama, Japan). [email protected]

Background: A few cases with a transient lesion in the splenium of the corpus callosum (SCC) have been reported. The lesion was considered to be caused by antiepileptic drugs (AEDs). However, such cases have never been presented in Japan. This is a first report of a case with a transient lesion in the SCC that was considered to be caused by AEDs in Japan. Case Report: A 24-year-old female was diagnosed as having obsessive-compulsive disorder, migraine, and analgesic abuse. She did not exhibit abnormal neurological findings or interhemispheric symptoms. On her admission, the head MRI showed no abnormal finding. The EEG showed spike waves in the bilateral temporal regions. Carbamazepine was administered because her headache was thought to be caused by epilepsy. Three weeks later, carbamazepine was withdrawn because of leukocytopenia. The head MRI was performed again and showed an obvious lesion in the SCC. A week later, the head MRI showed a decrease of the lesion in size. Then the lesion completely disappeared and the EEG showed no epileptic discharge. Although the mechanism of the appearance and disappearance of this lesion is still unclear, carbamazepine was considered to be responsible for the transient lesion in the SCC.

P31. An fMRI study of brain activation during implicit learning in obsessive-compulsive disorder Robert M. Roth, Andrew J. Saykin, Heather A. Wishart, Laura A. Flashman, Julianna Ward, Alexander C. Mamourian (Brain Imaging Laboratory, Department of Psychiatry, Dartmouth Medical School and New Hampshire Hospital, Lebanon, NH). [email protected]

Background: Neuroimaging studies have shown frontal-striatal-thalamic-cortical circuitry (FSTC) abnormality in obsessive-compulsive disorder at rest and during symptom provocation. It has been proposed that OCD is due to abnormal implicit learning, mediated by FSTC circuitry. We used fMRI to evaluate whether brain activation differed in patients with OCD compared with healthy control subjects during implicit learning. Methods: Participants included 5 medicated adults with OCD and 6 healthy matched control subjects. Participants completed a probabilistic classification (weather prediction) task (Poldrack et al, Neuropsychology 1999; 13:564–574) in which sets of one to four different abstract patterns were presented and subjects were required to determine whether each set predicted sunshine or rain. A baseline condition was included to control for response-related motor activity and basic decision making. After each trial, participants were informed of the correct response. Data were analyzed by using a random effects model in SPM99. Results: Groups were equivalent for performance accuracy. Compared with control subjects, patients with OCD showed less activation in thalamus and basal ganglia. Furthermore, patients showed more widespread activation in the frontal lobes, as well as additional areas of activation not seen in control subjects, including hippocampus and anterior temporal lobe. Conclusions: Findings indicate a differential pattern of FSTC circuitry activity in OCD, with recruitment of frontotemporal circuitry suggesting engagement of the episodic memory system, consistent with findings of Rauch et al (J Neuropsychiatry Clin Neurosci 1997; 9:568–573). Support from the Obsessive-Compulsive Foundation.

P32. Functional neuroanatomy of obsessive-compulsive hoarding Sanjaya Saxena, Karron Maidment, Erlyn C. Smith, Narineh Zohrabi, Matthew L. Ho, Arthur L. Brody, Lewis R. Baxter, Jr. (UCLA Neuropsychiatric Institute, Los Angeles, CA). [email protected]

Background: Compulsive hoarding and saving symptoms, found in many patients with obsessive-compulsive disorder, are part of a discrete clinical syndrome that also includes indecisiveness, impaired organizational abilities, perfectionism, procrastination, and behavioral avoidance, and has been associated with poor response to medications and cognitive-behavioral therapy. Using PET, we sought to identify cerebral metabolic patterns specifically associated with the compulsive hoarding syndrome. Methods: Regional cerebral glucose metabolism was measured with FDG PET in 45 adult subjects meeting DSM-IV criteria for OCD (12 of whom had the compulsive hoarding syndrome as their most prominent OCD symptom factor) and 17 normal control subjects. All subjects were free of psychotropic medication for at least 4 weeks. Results: Patients with the compulsive hoarding syndrome had significantly lower glucose metabolism than controls in posterior cingulate cortex (P=0.001). Compared with nonhoarding OCD patients, compulsive hoarders had significantly lower metabolism in the anterior and dorsal cingulate cortex (P<0.001). Across all OCD patients, hoarding severity was strongly correlated with lower metabolism throughout the cingulate cortex (P<0.001). Conclusions: The compulsive hoarding syndrome may be mediated by lower activity in the cingulate gyrus and may represent an etiologically or neurobiologically distinct subgroup or variant of OCD. Support from NIMH Grant K23 01654 and an Obsessive-Compulsive Foundation research award.

P33. Relationship of decreased gray matter volume to verbal learning and subjective memory complaints in healthy older adults and patients with mild cognitive impairment Andrew J. Saykin, Heather A. Wishart, Robert Santulli, Laura A. Flashman, Laura A. Rabin, Tara L. McHugh, Jennifer S. Ramirez, Alex C. Mamourian (Brain Imaging Laboratory, Dartmouth Medical School, Lebanon, NH). [email protected]

Background: Loss of gray matter (GM) is associated with aging, dementia, and prodromal conditions including mild cognitive impairment (MCI). We recently reported reduction of medial temporal lobe (MTL) GM in patients with MCI and in a group with cognitive complaints (CC) but no deficits on psychometric assessment. Here, we directly examined the relationship between GM volume, verbal learning performance, and subjective cognitive complaints. Methods: Participants included patients with MCI (n=12), a nondepressed CC group (n=12), and matched healthy elders (n=19). Structural MRI scans, including a T₁ SPGR 1.5-mm coronal volume and an axial T₂ series (to rule out structural lesions), were acquired on a GE 1.5-T LX scanner. We assessed GM density using voxel-based morphometry (Ashburner et al, Neuroimage 2000, 11:805–882; Good et al, Neuroimage 2001, 14:21–36). SPGR volumes were spatially normalized, segmented, smoothed (FWHM=10) and analyzed by using SPM99. Covariance models were used to map, on a voxel-by-voxel basis, the relationship between GM volume, CVLT performance (total recall) and a composite subjective cognitive complaints score. Results: Both the MCI and CC groups showed reduced GM volume relative to control subjects (P<0.01), especially in the MTL region. Covariance maps for the combined sample indicated a striking pattern of correlation between left hippocampal GM reduction and both verbal learning deficits and subjective memory complaints. Conclusions: These findings indicate that there are early structural changes in the MTL memory circuitry associated with impaired learning and subjective memory decline in MCI and also in healthy, nondemented, nondepressed elders. These groups are being followed longitudinally to assess the prognostic significance for risk of conversion to Alzheimer's disease. Support from NIA Grant R01 AG19771, the Alzheimer's Association, the Ira W. DeCamp Foundation, and New Hampshire Hospital.

P34. Gray matter volume predicts age-related alterations in brain fMRI activation pattern during working memory Heather A. Wishart, Andrew J. Saykin, Brenna C. McDonald, Laura A. Flashman, Robert Santulli, Tara L. McHugh, Kim R. Schuschu, Laura A. Rabin, Alex C. Mamourian (Dartmouth Medical School, Lebanon, NH). [email protected]

Background: Age-related declines in working memory are associated with changes in brain activation patterns on fMRI. Structural brain changes also occur with age, but the relationship between changes in brain activity and brain structure in aging is not well understood. We hypothesized that age-associated changes in regional gray matter (GM) volume would predict working memory task-related brain activity. Methods: Auditory n-back fMRI data and T₁-weighted SPGR volumes were obtained for healthy older adults (mean age=70 yr, SD=4.3; n=8) and matched young control subjects (mean age=30 yr, SD=3.5; n=8). Voxel-based morphology procedures were slightly modified from Good et al (Neuroimage 2001; 14:21–36). Statistical analyses were completed by using SPM99 and Matlab. A map of GM regions showing age-related decline was extracted. Then a covariance model with GM volume in this region was used to predict working memory-related fMRI activation. Results: Older adults showed a diffuse decline in GM volume in frontal, parietal, and cerebellar regions (P<0.01), as well as reduced working memory-related activity in left dorsolateral prefrontal cortex and increased activity in posterior prefrontal, inferior temporal, and cerebellar regions (P<0.01). Across the sample, reduced GM volume was related to decreased anterior prefrontal and parietotemporal activity and to increased activation in posterior prefrontal regions (P<0.01). Conclusions: These results provide evidence of a direct relationship between local age-related changes in gray matter and alterations in brain activation during working memory. Improved understanding of normal age-related structural and functional changes has direct relevance for early diagnosis of neurodegenerative conditions. Support from NIA Grant R01 AG19771, the National Multiple Sclerosis Society, the Hitchcock Foundation, the Ira W. DeCamp Foundation, and the Alzheimer's Association.

P35. PET images of emotionally valenced episodic memory Masaki Yoshihiro, Naoki Hatta, Doronbekov Talant, Atsushi Ogino, Noriko Miyoshi, Hiromasa Tokunaga, Hiroaki Kazui, Yoshitaka lkejiri, Takeshi Uema, Takashi Nishikawa, Naohiko Oku, Masatoshi Takeda (Department of Psychiatry and Behavioral Science, Osaka University Graduate School of Medicine, Osaka, Japan). [email protected]

Background: We investigated the neural substrates of the model of emotionally valenced episodic memory (fear) in healthy volunteers. The subjects did not watch a previously viewed terrifying scene directly, but by exposure to a trigger, they reexperienced fear. By comparing the rCBF during the resulting state with that during control tasks, we would capture the neural substrates of episodic memory associated with fear. Methods: 10 right-handed healthy volunteers underwent [¹⁵O]H₂O PET. Each subject had been required to watch a horror film the previous day. During the PET scan, the subject was presented a part of the film for 60 seconds immediately before the terrible climax scene and was told to recall the following scene. The rCBF in this task was compared with those in control tasks by analysis with SPM99. Subjective and objective emotional state of the subject in each task was evaluated with the State—Trait Anxiety Inventory and an analog scale. Results and Conclusions: The main cerebral areas where rCBF significantly correlated with the task of emotionally valenced episodic memory included the retrosplenial cortex, which has been suggested to play an important role in processing episodic memory and emotion by other studies. This result may contribute to explication of the reexperience symptoms in posttraumatic stress disorder. Support from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.

P36. Longitudinal association between Clinical Dementia Rating and Geriatric Depression Scale scores in mildly cognitively impaired elderly subjects Chaim E. Bromberg, Karen L. Dahlman, William Hirst, James Schmeldler, Deborah B. Marin (Mt. Sinai Medical Center, New York, NY). [email protected]

Background: Depression and dementia are prevalent comorbid disorders in elderly persons. This study explores the relationship over time of Clinical Dementia Rating (CDR) and Geriatric Depression Scale (GDS) scores in mildly cognitively impaired subjects. Methods: Subjects were 34 nursing home or assisted-living residents, ages 80 to 99, selected from 263 participants in a longitudinal study. Inclusion required initial CDR ratings indicating nondemented or questionably demented status, at least one CDR change, and no primary Axis I disorders. Subjects were measured two to seven times over 6 to 90 months. Compared with the previous visit, 29 CDR scores remained the same, 27 increased, and 16 decreased. Within-subjects longitudinal associations were pooled by using partial correlation, controlling for dummy-coded subject identifiers. Both the CDR-staged dementia rating (“total score”), emphasizing memory, and the raw total score (“sum of boxes”) were analyzed. Results: CDR and GDS scores were significantly correlated across visits for “sum of boxes” (r=0.25, df=71, P=0.033) but not for “total score” (r=0.22, df=71, P=0.064). Conclusions: The results suggest a positive relationship between changes over time in cognitive impairment and depressive symptoms in mildly cognitively impaired elderly persons. Support from NIH Grant AG02219.

P37. Alternate-form reliability of five alternate forms for five neuropsychological tests Philip S. Fastenau (Indiana University, Purdue University, Indianapolis, Indianapolis, IN). [email protected]

Background: Five alternate forms were designed for WAIS-III Digit Span, Digit Symbol, and Letter-Number Sequencing; the Trail Making Test; the Paced Auditory Serial Addition Test (PASAT); and the Rey Auditory-Verbal Learning Test (RAVLT). Content validity and criterion-related validity have been described previously. Relationships to demographic variables were examined here. Methods: Participants were 102 nonclinical adults (79% female, 88% right-handed; 78% Caucasian, 14% African-American, 8% Other/ Multiracial) diverse in age (18–60 yr, mean=36.9, SD=12.5), education (10–21 yr; mean=15.3, SD=2.7), and estimated IQ (WRAT-3 Reading SS range 53–123; mean=104.5, SD=12.0). Participants completed two test sessions separated by a brief break at week 1 (T1 and T2) and two more test sessions at week 2 (T3 and T4). Results: Correlations between the original test and demographic variables (age, education, estimated IQ) were nearly identical to the correlations between the alternate forms and the same demographic variables. Conclusions: The parallel relationships to relevant demographic variables lend further support to the construct validity of the five new alternate forms for all tests. These alternate forms should prove very useful in neuropsychiatric studies requiring assessments across multiple trials (e.g., drug studies). Support from Eli Lilly and Company.

P38. Is the cognitive impairment in isolated subtentorial stroke primarily state dependent? Michael Hoffmann, Frederick Schmitt, Timothy Carnaby, Michelle Mattingly (Stroke Program, University of South Florida, Tampa, FL). [email protected]

Background: The neurobiology of cognitive impairment in isolated subtentorial stroke is unknown. Is it channel or state dependent? Methods: A dedicated cognitive stroke registry comprising a cognitive screening battery and neuropsychological tests (frontal network syndromes, emotional, memory, language, sensory, motor, and perceptual domains). Neurological deficit, disability, and handicap were quantified. Of the isolated subtentorial stroke patients (brainstem and cerebellum), those that had no or minimal neurological deficit and had returned to their former employment were neuropsychologically tested. Results: Within the cognitive stroke registry (n=158), 37 patients (23.4%) had brainstem or cerebellar stroke, including 16 with infarcts isolated to the brainstem or cerebellum. Among these, 5 patients had made a complete neurological recovery enabling resumption of former employment: 3 with an isolated brainstem stroke (IBSS; midbrain n=2, pons n=1) and 2 with an isolated cerebellar infarct (ICI; SCA territory n=1, PICA territory n=1). In these 5 patients, frontal network syndromes (FNS; n=5) predominated, with memory disturbance (n=3) and dysphasia (n=2). The NIHSS scores were normal (score=0, n=4; score=1, n=1), and Rankin scores were 1 (n=3) or 2 (n=2). Conclusions: In IBSS and ICI patients devoid of significant neurological impairment, FNS appear to be the most significant deficit. The mismatch of long-tract and frontal syndromes supports a view of cognitive impairment in IBSS/ICI as a state-dependent or neurotransmitter perturbation.

P39. High scores on the cognitive difficulties scale reflect neuropsychological performance in HIV-1 infection Diana Lee, Paola Suarez, Frances L. Wilkie, Mauricio Concha, Stephen Symes, Rebeca Molina, Karl Goodkin (University of Miami, Miami, FL). [email protected]

Background: Screening method choices for cognitive-motor impairment have been at issue for HIV-1—infected (HIV+) adults because prior studies showed that self-report was not associated with standardized neuropsychological test performance. Methods: A sample of 131 HIV+ adults were administered the Cognitive Difficulties Scale (CDS). Neuropsychological test performance was measured in the following seven domains: information processing speed, verbal memory, attention, visuospatial skills, executive function, motor, and language. Results: High scores on the CDS were associated with poor performance on measures of attention (Digit Span) and memory (CVLT [recognition] and Logical Memory [verbal]). There were significant correlations associating higher CDS scores with longer reaction times (go/no-go paradigm) and decreased information processing speed (Figural Visual Scanning Task). Higher CDS scores were associated with lower levels of executive functioning (Stroop interference measure) and complex psychomotor skills (Trail Making Test Part B). Conclusions: In HIV-1-infected patients, self-reported cognitive difficulties are significantly associated with performance on standardized neuropsychological tests. Support from NIMH and NIA Grants R01 MH58532, MH/AG61629, and MH/AG61629.

P40. Huntington's disease and comorbid cocaine abuse: a case study Susan Mascoop (private practice, Boston, MA). [email protected]

Background: Huntington's disease is a neurodegenerative disorder of the basal ganglia (caudate and putamen) characterized by movement disorder, psychiatric symptoms, and cognitive impairment. Mood and cognitive changes may develop years prior to formal diagnosis, suggesting that the neuronal loss in the medial caudate and resultant neurotransmitter changes may begin much earlier than previously thought (Rosenblatt et al, Psychosomatics 2000; 41:24–30). Given that disturbing symptoms may develop years before diagnosis, and given the prevalence of substance abuse in our society, surprisingly little research has addressed the effects of substance abuse in patients with HD. Case Report: The subject is a 31-year-old right-handed white woman with a strong maternal familial history of HD and a 10-year history of cocaine abuse. Diagnosis of HD was confirmed by genetic testing. Neuropsychological evaluation (19 months after diagnosis) revealed significant depression and impairments in frontal-executive functions, memory (encoding and storage), visual organization, speech, and fine motor control. Notably, the subject was specific in stating that while she was under the influence of cocaine, her balance, coordination, speech and attention span all improved. Conclusions: In HD, there is a reduction in inhibitory and an increase in excitatory neurotransmitters. Cocaine, which blocks the reuptake of dopamine, may, with chronic use, lead to dopamine depletion and in turn affect functionally interrelated neurotransmitter systems. In the cocaine abuser with HD, multiple neurotransmitter systems are simultaneously affected in unknown ways. One explanation for the patient's report in this case may be that the cocaine use led to decreased fatigue and increased energy level, which may have allowed the subject to apply greater effort leading to improved functioning.

P41. Double dissociation of reading routes in focal dementing syndromes Mario F. Mendez (University of California at Los Angeles, Los Angeles, CA). [email protected]

Background: Neuropsychological models of reading indicate two main routes for reading, a lexical semantic route and a sublexical phonological route. One is based on direct lexical access and the other on hearing the read words. We investigated the dissociation of these routes in focal dementing syndromes. Methods: 12 patients with semantic dementia and anterior temporal pathology were compared with 12 patients with posterior cortical atrophy and occipitotemporal pathology. The patients were asked to read aloud 232 words, comprising 56 regular words, 56 words with irregular grapheme-phoneme correspondence (exception words), and 120 nonsense words. Results: The groups differed on the reading tests. The semantic dementia patients could read most of the regular and nonsense words, were impaired on the exception words, and made regularization errors. The posterior cortical atrophy patients could read most of the regular and exception words, were impaired on the nonsense words, and made lexicalization errors. Group differences reached statistical significance on all three types of words. Conclusions: These findings suggest a double dissociation between the two reading routes, with the semantic dementia patients having surface dyslexia and the posterior cortical atrophy patients tending to phonological dyslexia. These findings have implications for the anatomy of these reading routes. Support from the California Alzheimer's Disease Centers Consortium on Frontotemporal Dementia.

P42. Anomia in nonfluent primary progressive aphasia Mario F. Mendez, David G. Clark (University of California at Los Angeles, Los Angeles, CA). [email protected]

Background: Primary progressive aphasia (PPA) is a slowly progressive language deterioration that remains relatively isolated from other cognitive or behavioral deficits for at least two years. PPA is a frontotemporal lobar degeneration that later evolves into a dementia. PPA is characterized by anomia as well as difficulty in verbal expression and shortened phrase length in the presence of relative preservation of comprehension. This investigation aimed to characterize the nature of the presenting anomia in patients with PPA. Methods: We administered an anomia battery to 16 patients initially presenting with PPA by established clinical criteria (Neary et al, Neurology 1998; 51:1546–1554). The battery included the Boston Naming Test, the Pyramids and Palm Trees Test, and a naming battery consisting of tests of phonemic cuing, word comprehension, and an assessment of paraphasic errors. Results: The majority of patients (n=12) had a predominant word-production anomia facilitated by phonemic cues and without word comprehension problem. These patients manifested pronounced phonemic or literal paraphasic errors and attempted to self-correct by approximations. There were few verbal or whole-word paraphasias. Conclusions: Patients with nonfluent PPA often present with a word-production anomia characterized by phonemic disintegration due to lexical-phonetic dissociation or phonemic substitution of paraphasias. Support from the California Alzheimer's Disease Centers Consortium on Frontotemporal Dementia.

P43. Semantic dementia in two multilingual patients Mario F. Mendez, Samira Saghafi, David G. Clark (University of California at Los Angeles, Los Angeles, CA). [email protected]

Background: Semantic dementia (SD) is frontotemporal lobar degeneration due to atrophy of the anterior temporal neocortex. In SD there is fluent and grammatical speech output but impairments in naming and in word comprehension. In two multilingual patients, we investigated whether the word comprehension deficits occurred at the language or the semantic level. Methods: The first patient was a 66-year-old man who spoke English, Polish, and Spanish (Spanish was L1, his first language), and the other was a 71-year-old man who spoke English, German, and Spanish (English was L1). They were given an aphasia battery translated into the different languages, a naming battery, and tests for translational equivalents across the languages. Results: L1 was better preserved in both patients, but both were severely anomic in all of their languages. The patients had nearly a 100% correspondence between their ability to comprehend a word and its meaning in L1 if they could retrieve it in L2 or L3. The production of a word in L2 and L3 often spontaneously elicited the word in L1. Conclusions: These observations suggest that SD results in word comprehension deficits from a problem in semantic access rather than from a problem in language comprehension itself. Support from the California Alzheimer's Disease Centers Consortium on Frontotemporal Dementia.

P44. Directed forgetting effect in obsessive-compulsive disorder Mika Hayashi, Masaru Mimura*, Kurie Shishikura, Kunitoshi Kamijima (Showa University, Tokyo, Japan). [email protected]

Background: Recent neuropsychological studies demonstrated that patients with obsessive-compulsive disorder (OCD) present with strategic impairment in episodic remembering. We introduced a directed forgetting paradigm to further investigate characteristics of specific memory problems in OCD. Methods: 27 patients with OCD (mean age=32.7 yr) and 15 age-matched normal subjects were given two lists of 24 nouns (12 remember-cued words and 12 forget-cued words). The remember or forget cue was given in a blocked condition for one list and in a scrambled condition for the other list. Results: Patients with OCD recalled significantly fewer remember-cued words than normal control subjects, both in blocked and scrambled conditions. In contrast, OCD patients and control subjects recalled equivalent numbers of forget-cued words. Consequently, directed forgetting effect (remember-forget) was significantly smaller in OCD than control both for blocked (OCD 1.9 vs. control 3.7, P<0.05) and scrambled conditions (OCD 2.6 vs. control 5.9, P<0.01). Conclusions: OCD patients appeared to have impairment in both selective encoding and retrieval inhibition. Inappropriate and intruding stimuli that should be forgotten interfered with OCD patients' encoding and retrieval processes. Ineffective memory activities may partially account for their unique clinical symptoms.

P45. Measurement of attention in children by use of the NEPSY Judith R. O'Jile, Claude E. Davis, Catherine Simpson, David Elkin, Jamie Rhudy (University of Mississippi Medical Center, Jackson, MS). [email protected]

Background: The NEPSY is a neuropsychological test battery designed for children. It assesses attention within one of its five domains of abilities, Attention/Executive Functioning. One of the measures within this domain is the Auditory Attention and Response Set (AARS), which is divided into two tasks. Task 1 involves vigilance and simple attention to verbal stimuli. Task 2 has more complex rules (such as using yellow tokens in response to the word red). We examined the relationship of the AARS to other measures of attention. Methods: Subjects were 34 children referred for neuropsychological assessment with various psychiatric diagnoses. The following measures of attention were given: the Connors CPT Trail Making A and B, WISC-III Coding and Digit Span, NEPSY Knock and Tap, and AARS. Data analyses included Pearson correlation analyses and regression. Results: Task 1 correlated significantly with WISC-III Symbol Search (r=0.37) and CPT-II Commissions (r=0.35). Task 2 correlated significantly with WISC-III Symbol Search (r=0.54) and WISC-III Coding (r=0.49). Regression for both tasks showed little contribution from other attentional variables (Task 1: R²=0.114; Task 2: R²=0.209). This result suggests that the AARS assesses attentional abilities beyond those measured by other tests. Implications will be discussed.

P46. Mixed handedness and cognitive abilities in boys P.S.B. Sarma (Department of Psychiatry and Psychology, FUHS/The Chicago Medical School, North Chicago, IL). [email protected]

Background: RWLT (right writer, left thrower) males manifest impaired spelling skills more frequently than LWRT males (Sarma, J Neuropsychiatry Clin Neurosci 2001; 13:146). However, there are some high-achieving RWLT males. Is there some other mediating variable? Crow et al (Neuropsychologia 1998; 36:1275–1282) found that a lack of superiority of one hand (in a square-checking task) was associated with a drop in verbal and nonverbal abilities (greater drop in verbal abilities in males). Methods: This is an ongoing study of RWLT males in college preparatory school in India. The relative hand skill is tested by “coding” (WISC-R) and the nonverbal IQ by the Test of Nonverbal Intelligence (TONI). Results: So far, those who obtained a relative hand skill ratio (R/L) of 1.5 or higher (n=4) scored above the 40th percentile on TONI (range 42–99). Others (n=4) got TONI scores below the 40th percentile (range 23–38). Conclusions: The findings support the use of “coding” as a measure of relative hand skill. The relationships between RWLT status, cognitive abilities, and relative hand skills deserve further examination.

P47. Neuropsychological functioning in breast cancer patients prior to systemic therapy in comparison to published norms Angela Stewart, Barbara Collins, Catherine Bielajew, Eva Tomiak (University of Ottawa, Ottawa, ON, Canada). [email protected]

Background: Retrospective studies in breast cancer patients indicate that women exposed to chemotherapy have poorer neuropsychological function than similar patients who did not receive chemotherapy (Ahles et al, J Clin Oncol 2002; 20:485–493). This has been construed as evidence of a neurotoxic effect of chemotherapeutic agents. However, prospective studies with cancer patients suggest that these cognitive differences predate systemic oncologic treatment (Myers et al, Lung Cancer 1995; 12:231–235). Methods: 19 post-menopausal women with stage I and II breast cancer, after surgery but before adjuvant systemic therapy, underwent neuropsychological and mood assessment. Results: A series of t-tests was conducted comparing neuropsychological test scores of the cancer patients with published peer norms. Of 30 such comparisons, only 3 were significant, and these indicated higher scores on the part of the cancer patients than the normative sample. The cancer patients did not show signs of mood disturbance. In fact, they actually scored lower than the normative sample on several dimensions of psychological distress. Among the cancer patients, several significant correlations were obtained between cognitive measures and mood ratings (particularly between anxiety and working memory), with greater psychological distress associated with poorer neuropsychological test performance. Conclusions: Although psychological distress did seem to adversely affect cognitive function in our sample, these women, as a group, did not indicate heightened psychological distress, nor did they display abnormal cognitive functioning. These results suggest that the cognitive deficits observed following chemotherapy in breast cancer patients do not predate treatment and thus may be attributable to systemic cancer drugs. Support from an Ontario Women's Health Scholars' Award.

P49. Neural basis for writing familiar and novel letters: a PET study Hiromasa Tokunaga, Takashi Nishikawa, Yoshitaka Ikejiri, Hiroaki Kazui, Naohiko Oku, Masatoshi Takeda (Psychiatry and Behavioral Science, Osaka University Graduate School of Medicine, Osaka, Japan). [email protected]

Background: The left superior parietal lobule (SPL) is assumed to be involved in writing, and damage is critical for apraxic agraphia. But it is unclear whether this area participates in writing novel letters. Methods: 10 normal right-handed Japanese males, ages 19–27, participated in this study. They underwent 12 [¹⁵O]H₂O PET scans accompanied by two types of tasks: Copy and Control. In each task, three types of stimuli were presented visually: Familiar (Kanji: Japanese morphogram), Unfamiliar (Hangul: Korean phonogram), and Novel (Thai, Arabic, Devanagari, etc.: very novel for Japanese). In the Copy task, they were required to copy the visual stimulant letters mentally. In the Control task, they were only to look at the stimuli and not to copy mentally. Results: Expectedly, the SPL was activated in the three Copy tasks relative to the corresponding Control tasks. The left SPL was activated in the Familiar-Copy task, the right SPL in the Novel-Copy task. Interestingly, the Unfamiliar-Copy task activated the left SPL, although all subjects knew no linguistic properties of Hangul, e.g., how to read it. Conclusions: Hangul seems to be partly similar to Kanji in terms of graphemic pattern. It is suggested that the left SPL might be involved in the graphemic process even in writing unfamiliar letters, while the right SPL may be involved in “drawing” novel letters as non-letters.

P50. Relationship of cognitive functioning to antiretroviral medication adherence in HIV-1 infection Frances L. Wilkie, Karl Goodkin, Mauricio Concha, Stephen Symes, Diana Lee, Paola Suarez, Rebeca Molina (University of Miami, Miami, FL). [email protected]

Background: HIV-1 infection is associated with cognitive impairment in varying severity. Strict adherence to antiretroviral regimens is required to maximally suppress viral load and avert resistance. Cognitive impairment may decrease adherence. Methods: A sample of 111 HIV-1-seropostive (HIV+) symptomatic-stage individuals was assessed. Neuropsychological test performance was measured in the following seven domains: information processing speed, verbal memory, attention, visuospatial skills, executive function, motor, and language. Adherence was assessed with four measures: pill count; physician rating; and two pharmacy record measures (number of months missed of medication and average deviation in days from on-time renewal). Results: Pill count is associated with three measures of memory: CVLT (learning trials 1–5, delayed recall, semantic clustering, and recognition), WMS-R Logical Memory, and Visual Reproduction (immediate and delayed recall). Number of missed months is related to visual memory performance, to slowing on information processing speed measures (simple and choice reaction times), and to executive functioning (Stroop interference measure). Conclusions: Impairment in these cognitive functions may cause decreased adherence and may be responsive to intervention. Support from NIMH and NIA Grants R01 MH58532, MH/AG61629, and MH/AG61629.

P51. Severe, refractory depression and the development of a buccofacial movement disorder in a patient with vascular dementia secondary to polycythemia vera: a case study Catherine L. Bishop, Holly J. Westervelt, Robert A. Stern (Brown Medical School/Rhode Island Hospital, Providence, RI). [email protected]

Background: Polycythemia vera (PV) is a myeloproliferative blood disorder that is associated with cerebrovascular ischemia, transient ischemic attacks, stroke, and, rarely, hyperviscosity-induced dementia. Although data on cognitive and psychiatric changes in PV are scarce, a small number of reports in the PV literature report severe, refractory anhedonia, suicidal ideation (SI), cognitive decline, and the development of unusual movement disorders following a diagnosis of PV. We present an 80-year-old man with PV who developed profound anhedonia and chronic SI that have been refractory to medication and ECT. Imaging studies showed atrophy, ischemic white matter changes, and multiple lacunes. Case Report: The patient received four serial neuropsychological evaluations over the course of 6 years. The patient's first two neuropsychological evaluations (3 years apart) revealed mostly mild memory and spatial deficits, with no functional decline. A third evaluation 1 year later showed additional deficits in executive and naming skills, with severe depression and suicidal ideation. On his fourth, most recent evaluation, the patient demonstrated significant functional and global cognitive decline, confusion, disorientation, continued anhedonia and SI, behavioral disinhibition, and a new-onset buccofacial movement disorder, with no associated change in neuroimaging findings. Conclusions: This case study serves as another example of PV and similar proliferative blood disorders causing treatment-resistant depression, vascular dementia, and movement disorder.

P52. A case of apparent progressive cognitive decline in an older woman with multiple treated endocrinopathies: importance of considering endocrine status in diagnosing dementia Jennifer Duncan Davis, Robert A. Stern (Brown Medical School/Rhode Island Hospital, RI). [email protected]

Background: The relationship between endocrine disorders and neuropsychiatric symptoms has long been recognized (Whybrow & Hurwitz, Horm Behav 1976; 7:125–143), and it is generally well accepted that neuropsychiatric symptoms resolve with treatment of acute endocrine dysfunction (for review, see Erlanger et al, Neuropsychol Rev 1999; 9:175–207). We present serial neuropsychological assessments of a 73-year-old woman with treated hypothyroidism, Addison's disease, type II diabetes mellitus, and depression. Methods: The patient underwent three neuropsychological evaluations over a 3-year period due to complaints of progressive cognitive and functional decline. ACTH, thyroid hormone, and glucose levels were measured at regular intervals. Endocrine measures were relatively stable at each time point, although ACTH was chronically low. Initial MRI scan revealed mild periventricular white matter disease and mild atrophy with no progression over one year. Results: Initial neuropsychological evaluation revealed deficits in executive functioning, visuospatial skills, and learning efficiency. Neuropsychological testing 1 year later indicated a decline in most areas of cognition and functional status, and the patient met criteria for an early dementia. The pattern of her neuropsychological test results and MRI findings was suggestive of a vascular etiology. 13 months later, neuropsychological testing revealed a complete reversal of all of her cognitive deficits. Mood remained moderately depressed over the 3 years. Conclusions: Results suggest that despite treatment, multiple treated endocrinopathies can mimic a primary progressive brain disorder. This argues for repeat neuropsychological evaluations for the accurate diagnosis of dementia and highlights the complex interrelationship between endocrine stability and cognition in treated patients.

P53. The determinants of subjective quality of life in patients with Huntington's disease James D. Duffy, Erin Doherty, Sarah Bullard, Mary Jane Fitzpatrick, Bonnie Hennig, A Wallace Deckel, Steven Spencer (Hartford Hospital/Institute of Living/University of Connecticut School of Medicine, Hartford, CT). [email protected]

Background: Very few data are available on the psychosocial consequences of Huntington's disease. Better understanding of the major contributors to quality of life in HD should provide important insights into more effective treatment strategies for HD patients. Methods: 29 patients with early (stage 1–2) and mid-stage (stage 3) HD completed the SF-36 as well as other psychometric instruments including the BDI, BAI, Apathy Evaluation Scale, Neuropsychiatric Inventory, Quality of Social Support Scale, and demographic variables. Results: In early-stage HD patients, a significant correlation was found between the patients' subjective emotional limitations and the presence of irritability, physical pain, and depression (P<0.01). Physical pain contributed significantly to subjective poor quality of life and was correlated with the presence of anxiety (P< 0.01) and depression (P<0.05). In mid-stage RD, subjective limitations secondary to emotional problems correlated most strongly with poor social supports (P< 0.01) and less strongly with irritability (P<0.05 ). Unlike early-stage patients, mid-stage HD patients experienced significant problems in social functioning, correlated with limitations in emotional and physical functioning and with physical pain (P< 0.01). Conclusions: These results suggest that targeted treatment interventions for depression, irritability, anxiety, and pain are likely to significantly improve the quality of life for patients with HD. Support from a State of Connecticut grant.

P54. The neurobehavioral characteristics of patients with early and mid-stage Huntington's disease Steven Spencer, James D. Duffy*, Sarah Bullard, Erin Doherty, Mary Jane Fitzpatrick, Bonnie Hennig, A. Wallace Deckel (Hartford Hospital/Institute of Living, Hartford, CT). [email protected]

Background: The Neuropsychiatric Inventory (NPI) has proven validity and reliability in patients with dementia. Previous studies using the NPI have reported distinct “behavioral phenotypes” associated with each dementia type. Methods: 44 Huntington's disease patients, staged by functional capacity, completed the NPI. Statistical significance between stages on the NPI was identified only in the domain of agitation, although trends were evident for delusions, hallucinations, and depression. Each of these behavioral domains was found to be greater in the early stage (stages 1–2) versus the mid-stage (stage 3) of the disease. Scores on the NPI were also compared between sexes. Results: Males had significantly higher rates of delusions, agitation, irritability, elation, disinhibition, aberrant behavior, and disturbed sleep and a trend toward more frequent depression. These differences were not attributable to any difference in gender distribution between stages. Conclusions: These results suggest that 1) diminished functional capacity in HD may be related to symptoms of agitation, psychosis, and/or depression; 2) compared with female patients, male patients are more likely to have functional impairment because of neuropsychiatric symptoms of the illness; and 3) HD results in a neuropsychiatric profile distinct from those of other dementing illnesses. These symptoms should be specifically assessed and treated. Support from a State of Connecticut grant.

P55. Prevalence of depression and anxiety in early and mid-stage Huntington's disease Sarah Bullard, Erin Doherty, James D. Duffy*, Bonnie Hennig, Mary Jane Fitzpatrick, A. Wallace Deckle (Hartford Hospital/Institute of Living, Hartford, CT). [email protected]

Background: Although the prevalence of depression in Huntington's disease is reported to be high, research characterizing mood disorders in HD is very limited. As both disorders have implications for the management of HD, as well as quality of life, it is essential to gain a better understanding of their prevalence within the early and mid-stages of HD. Methods: 44 patients diagnosed with early (stages 1–2) or mid-stage HD (stage 3) were administered the Neuropsychiatric Inventory (NPI). A subset of this group of patients was also administered the BDI (n=18) and BAI (n=11). Results: Depression as measured by the NPI was elevated in both early and mid-stage HD. In contrast, only minimal depression-related symptomatology was reported on the BDI. Anxiety, as measured by both the NPI and BAI, was elevated in both early and mid-stage HD. Gender effects were found for the BAI, with females endorsing a significantly higher degree of anxiety-related symptomatology than males. Conclusions: Both depression and anxiety are common in early and mid-stage HD. ln addition, females presented with significantly higher reported anxiety than males. When taken together, these results suggest that anxiety needs to be addressed independently of depression. Support from a State of Connecticut grant.

P56. Relationship between cerebral atrophy and informant-based ratings of dementia participants in the Cache County study Michael A. Fearing, E.D. Bigler, K.D. Garrett, J. Tschanz, K.A. Welsh-Bohmer (Brigham Young University, Provo, UT). [email protected]

Background: The 26-item Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) is administered to individuals close to a patient with suspected dementia to assess the degree of perceived change in various daily activities. This method of evaluating function has considerable merit for purposes of tracking changes over time, particularly in instances of advanced dementia where cognitive testing is not feasible. However, quantitative neuroimaging findings associated with the IQCODE have not been systematically investigated. We examined the relationships between IQCODE ratings and degree of generalized atrophy, based on the whole-brain ventricle-to-brain ratio (VBR) and total temporal lobe (TL), mesial temporal lobe (MTL), and hippocampal volumes, as an anatomical means of tracking dementia severity. Methods: The IQCODE was administered to informants of those participants who scored in the moderate to severe impairment range on the Modified Mini-Mental State Examination (3MS), suggestive of dementia symptoms of at least moderate severity. Participants included 60 individuals who scored below 60 on the 3MS. Results: Total IQCODE score was correlated to generalized atrophy as measured by the VBR (r=0.39, P<0.05). Correlations were found between total IQCODE and TL volume (r=−0.41, P<0.02), and a trend towards MTL volume (r=−0.25, P<0.06). There was no relationship between Total IQCODE and hippocampal volume. Conclusions: These findings suggest that informant reports relate to MRI structural imaging changes in a way that parallels the disease course, generally supporting the utility of MRI structural measures and informant reports as objective means for tracking dementia progression. Support from NIH Grant AG1380 and the Ira Fulton Foundation.

P57. Reduction by olanzapine of occupational disruptiveness among caregivers of patients with Alzheimer's dementia Peter D. Feldman, John S. Kennedy, Carrie A. Young, Deborah L. Kadam, Willie R. Earley, Alan Breier (Lilly Research Laboratories, Indianapolis, IN). [email protected]

Background: Neuropsychiatric disturbances in patients with dementia can affect caregivers and overall patient management. This a priori-defined analysis investigates changes in caregiver distress, as measured by Occupational Disruptiveness scores associated with each individual dimension of the Neuropsychiatric Inventory-Nursing Home version (NPI/NH) rating scale. Methods: Elderly nursing home patients with Alzheimer's dementia were randomized to either placebo or fixed-dose olanzapine (Olz: 5, 10, or 15 mg/day) for 6 weeks of double-blind therapy. Successful completers entered an 18-week open-label extension, during which they received flexible-dose Olz (5–15 mg/day). Results: After the acute phase, reductions were seen in distress ratings reported by caregivers of patients receiving low-dose (5 mg) Olz. Significant reductions occurred relative to placebo in the NPI/NH Occupational Disruptiveness Psychosis Total (sum of Hallucinations and Delusions scores) and Core Total (sum of Hallucinations, Delusions, and Agitation scores), and in the Delusions and Irritability dimensions. Results with higher doses (10 mg, 15 mg) were largely nonsignificant compared with placebo. However, patients entering the extension improved significantly further on the Occupational Disruptiveness total, Psychosis Total, and Core Total, and in the Agitation, Delusions, Disinhibition, and Irritability dimensions. Conclusions: These results indicate that olanzapine may significantly reduce occupational disruptiveness for caregivers of dementia patients with neuropsychiatric disturbances. Support from Eli Lilly and Company.

P58. Behavioral and psychological symptoms of dementia and ECD-SPECT findings in patients with vascular dementia Hiroshi Hashimoto, Joji Kawabe, Toshihiro Kai, Shigeaki Higashiyama, Hiroshi Mori, Susumu Shiomi, Nobuo Kiriike (Osaka City University, Osaka, Japan). [email protected]

Background: Frontal hypoperfusion is common in patients with vascular dementia (VD). But some patients with VD show different imaging patterns, and the relationships between SPECT findings and behavioral and psychological symptoms of dementia (BPSD) remain unclear. Our object was to study the relationship between frontal hypoperfusion and BPSD in patients with VD. Methods: 18 patients with VD were divided into frontal (F: n=12) and nonfrontal (NF: n=6) hypoperfusion groups by using ^99mTc-ethyl cysteinate dimmer ([^99mTc]ECD) SPECT. Each patient was assessed for BPSD with the Neuropsychiatric Inventory (NPI). We compared the NPI score between F and NF groups. Results: The mean NPI irritability, depression, and anxiety scores were significantly higher for the F than for the NF group (P<0.05, P<0.01, and P<0.05, respectively). Conclusions: These results suggest that ECD-SPECT is useful for classification of the subtypes of VD.

P59. Performance of Spanish- and English-speaking normal control subjects on the Mattis Dementia Rating Scale Isis Hernandez, Scott A. Lyness, Evelyn L. Teng, Helena C. Chui (University of Southern California, Los Angeles, CA). [email protected]

Presenter: Sonia Padilla

Background: The Mattis Dementia Rating Scale (MDRS; Mattis, DRS Professional Manual, 1988) is a brief neuropsychological test that has been used to screen for and track dementia. Although a large amount of data has been collected from English-speaking subjects, only limited data have been collected from Spanish-speaking subjects to date. The present study was conducted to examine whether data based on English-speaking subjects can be applied to Spanish-speaking subjects after controlling for age and education. Methods: MDRS performance of 35 Spanish-speaking normal controls was compared with that of 35 age- and education-matched English-speaking normal control subjects. Results: Even though subjects were matched on age and education, Spanish-speaking normal control subjects performed significantly worse on the MDRS Total and all subscales. Furthermore, the intercorrelations among the MDRS subscales as well as their association with age, education, and gender were different between the two language groups. Conclusions: Findings suggest the need to develop separate Spanish-speaking norms for the MDRS. Support from Alzheimer's Disease and Research Center of Los Angeles County.

P60. Alteration of regional cerebral glucose metabolism with delusional misidentification syndrome in Alzheimer's disease Yoshitaka Ikejiri, Mamoru Hashimoto, Etsuro Mori, Kazunari Ishii, Nobutsugu Hirono, Takashi Nishikawa, Masatoshi Takeda (Psychiatry and Behavioral Science, Osaka University Graduate School of Medicine, Osaka, Japan). [email protected]

Background: The underlying brain dysfunction for delusional misidentification syndrome (DMS) in Alzheimer's disease is still unclear. Methods: We examined regional cerebral glucose metabolism using FDG PET for 10 AD patients with DMS, 10 without DMS, and 10 normal control subjects (NC). The two groups of patients were matched in age, sex, duration of education and illness, and dementia severity. In anatomic standardization and statistical comparisons of the PET data, we used a part of a program set that generates standardized three-dimensional stereotactic surface projection data sets (Minoshima et al, J Nucl Med 1992; 33:1579–1585) and the SPM96, respectively. Results: The patients had significantly greater hypometabolism of glucose in the bilateral temporal and temporoparietal lobes and the cingulate gyrus than NC (P< 0.005). The patients with DMS had significantly greater hypermetabolism of glucose in the bilateral parietal lobes and the posterior cingulate gyrus and in the right temporooccipital region (P<0.005) and hypometabolism in the bilateral orbitofrontal lobes, the left anterior cingulate gyrus, and the insular cortex (P<0.05) than those without DMS. Conclusions: DMS in AD might be attributable to a dysfunction in specific brain areas that are involved in perception of environment and retrieval of old episodic memory. Support from a grant by the Japan Foundation for Neuroscience and Mental Health.

P61. The concentrations of serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and cortisol in Japanese sporadic Alzheimer's disease Takuyu Ishizuka, Shinji Higashi, Hajime Baba, Ko Eto, Heii Arai (Department of Psychiatry, Juntendo University School of Medicine, Tokyo, Japan). [email protected]

Background: Dehydroepiandrosterone sulfate (DHEA-S) is formed in vivo from dehydroepiandrosterone (DHEA) in the presence of DHEA sulfotransferase. These hormones are also called adrenal androgens, and they are found in higher concentrations in the blood than any other steroid hormone. The blood levels of DHEA-S and DHEA (DHEAs) are likely to be increased sharply during puberty, reach a peak during the third decade of life, and thereafter decrease with age. Thus, the secretion of these hormones shows a specific age-related pattern (Sulcova J et al, Endocrinol 1997; 154:57–62). It is known that DHEA exerts weak androgenic actions. It is noteworthy that DHEA, which has been considered to possess antiatherosclerotic, antidiabetic, antiosteoporotic, and immunopotentiating actions (Baulieu EE et al, Psychoneuroendocrinology 1998; 23:963–987) has been implicated in aging and the development of aging-related pathologic conditions. DHEA is also synthesized and degraded in the central nervous system, and its effects on CNS have been studied. DHEAs were reported to stimulate neuronal differentiation in fetal mouse brain cell cultures (Cardounel A et al, Proc Soc Exp Biol Med 1999; 22:145–149), suggesting that adrenal androgens may play an important role in nerve cell functions and that they can prevent the loss or damage of nerve cells. Methods: We examined serum concentrations of DHEA, DHEA-S, and cortisol (CRT) in 30 patients with Alzheimer's disease (AD) and 30 age- and gender-matched healthy control subjects. All blood samples were collected between 10:00 a.m. and noon. Serum concentrations of DHEA, DHEA-S, and CRT were measured, and statistical analysis of the results was performed by using the two-tailed Mann-Whitney U-test. Results: Levels of DHEA and DHEA-S in the AD group were significantly lower in AD patients than in healthy control subjects. CRT levels did not differ significantly between the two groups. The CRT/DHEA and CRT/DHEA-S ratios were significantly higher in AD patients than in healthy control subjects. Conclusions: These changes in AD suggest that the homeostatic secretion of adrenal androgens may be disturbed in AD.

P62. Clinicopathological and neurochemical study of two subtypes of Pick's disease in Japan Toshiari Odawara, Eizo Iseki, Kazurnasa Shiozaki, Tetsuaki Aral, Kenji Kosaka (Department of Psychiatry, Yokohama City University School of Medicine, Yokohama, Japan). [email protected]

Background: The Pick type of frontotemporal dementia includes two subtypes: Pick's disease with Pick bodies (PiD) and atypical Pick's disease without Pick bodies (aPiD) (Iseki et al, J Neurol Sci 1998; 159:194–201). We compared the clinicopathological findings in two subtypes. In addition, we examined amount of muscarinic acetylcholine receptor (mAchR) because neurochemical analyses in aPiD are very few. Methods: 3 cases of PiD and 7 cases of aPiD were compared. Diagnoses were made according to neuropathological and biochemical examination. The amounts of mAchR in aPiD were estimated as the binding sites of [³H]-QNB. Results: PiD and aPiD cases corresponded clinically to frontotemporal dementia and semantic dementia, respectively, according to the criteria of frontotemporal lobar degeneration. Both subtypes revealed degeneration with neuronal loss with gliosis in the affected cortex and subcortical nuclei, but only aPiD cases had pyramidal tract degeneration. Immunohistochemical analyses demonstrated tauopathy with phosphorylated tau accumulation in Pick bodies in PiD, whereas aPiD showed ubiquitinopathy with ubiquitin accumulation in the intraneuronal and dendritic inclusions. [³H]QNB binding sites of aPiD were significantly lower in the temporal cortex than in control and Alzheimer's disease subjects. Conclusions: Two subtypes of Pick's disease in Japan can be distinguished not only neuropathologically but also clinically on the basis of differences in pathogenesis (Odawara et al, Dement Geriatr Cogn Disord, in press). Support from grants-in-aid for scientific research by the Japanese Ministry of Education.

P63. Donepezil provides significant benefits in patients with vascular dementia Carlos A. Perdomo, Raymond D. Pratt, and the donepezil 307 and 308 VaD Study groups (Eisai Inc., Teaneck, NJ). [email protected]

Background: There is evidence that patients with vascular dementia (VaD) benefit from treatment with cholinesterase inhibitors such as donepezil. Methods: We performed a combined analysis of two randomized, double-blind, placebo-controlled, parallel-group, 24-week clinical trials. A diagnosis of probable or possible VaD (according to NINDS-AIREN criteria) was required. Patients received placebo, donepezil 5 mg/day, or donepezil 10 mg/day. Results are reported for intent-to-treat observed cases. Results: Of 1,219 enrolled patients (392 placebo, 406 donepezil 5 mg/day, 421 donepezil 10 mg/day), 73% had probable VaD and 27% had possible VaD. Both donepezil-treated groups showed significant improvements in cognitive function compared with placebo (ADAS-cog mean change from baseline score at week 24: placebo, −0.10, donepezil 5 mg/day, −1.89, P<0.001; donepezil 10 mg/day, −2.38; P<0.001). Greater improvements in global function were observed with both donepezil groups than with the placebo group (CIBIC-plus, % patients showing minimal, moderate, or marked improvement at Week 24: placebo, 29%; donepezil 5 mg/day, 41%, P<0.001; donepezil 10 mg/day, 33%, P=0.07; overall treatment, P<0.001). Donepezil was well tolerated, with low withdrawal rates due to adverse events (placebo, 10%; donepezil 5 mg/day, 11%; donepezil 10 mg/day, 19%). Conclusions: Significant benefits of donepezil compared with placebo treatment were observed on measures of cognition and global function. The results indicate that donepezil may have an important role in the management of patients with VaD. Support from Eisai Inc.

P64. A double-blind study of thyroxine in the treatment of Alzheimer's dementia Robert A. Stern, Jennifer Duncan Davis, Brooke L. Rogers, Kristin M. Smith, Colin J. Harrington, Brian R. Ott, Arthur J. Prange, Jr. (Brown Medical School/Rhode Island Hospital, Providence, RI). [email protected]

Background: Converging evidence suggests a possible link between thyroid state and Alzheimer's disease, including a higher probability of dementia in subjects with elevated TSH concentrations (Ganguli et al, Biol Psychiatry 1996; 40:714–725), a twofold increased risk of AD in hypothyroid patients (Breteler et al, Int J Epidemiol 1991; 20:S36–S42), and lower serum triiodothyronine (T₃) concentrations in AD patients than control subjects (Thomas et al, Acta Psychiatr Scand 1987; 76:158–163). This study is the first to examine the efficacy of thyroxine (T₄) in the treatment of cognitive and neuropsychiatric dysfunction in AD. Methods: 28 patients with AD, already on stable doses of donepezil, were randomized to placebo (n=18) or 0.050 mg T₄ (n=10) for a 4-month double-blind trial. Cognition and neuropsychiatric symptoms were assessed at baseline and at the conclusion of the trial with the Alzheimer's Disease Assessment Scale (ADAS-cog), Neuropsychiatric Inventory (NPI), and Visual Analog Mood Scales (VAMS). Results: We found no significant differences between placebo and T₄ on the ADAS-cog, NPI, or VAMS. Conclusions: These preliminary results suggest that cognitive and neuropsychiatric dysfunction in AD is not responsive to treatment with T₄. Although a parsimonious explanation for these negative findings may be the relatively small sample size (and low statistical power), the lack of efficacy of T₄ is supported by recent preliminary findings from our group indicating lower T₃, but not T₄, levels in postmortem brains of advanced AD patients relative to controls. Conversion of T₄ to T₃ may be reduced in AD and may be associated with some of the clinical features of AD. Support from the Alzheimer's Disease Association.

P65. Thyroid hormone concentrations in prefrontal cortex of postmortem brains of Alzheimer's disease patients and control subjects Anna Podolanczuk, Jennifer Duncan Davis, Edward Stopa, James V. Hennessey, Lu-Guang Luo, Yow-Pin Lim, Robert A. Stern (Brown Medical School/Rhode Island Hospital, Providence, RI). [email protected]

Background: Converging evidence suggests a possible link between thyroid hormone (TH) and Alzheimer's disease, including a higher probability of dementia in subjects with higher thyroid-stimulating hormone levels (Ganguli et al, Biol Psychiatry 1996; 40:714–725) and a two-fold risk of AD in individuals with hypothyroidism (Breteler et al, Int J Epidemiol 1991; 20:S36–S42). TH modulates choline acetyl transferase activity (Hayashi & Patel, Dev Brain Res 1987; 36:109–120) and amyloid precursor protein expression in the brain (Latasa et al, Endocrinol 1998; 139:2692–2698). These proteins are affected in AD, suggesting a possible role for TH in AD pathology. The present study is the first to directly evaluate brain TH levels in AD. Methods: Triiodothyronine (T₃) and thyroxine (T₄) levels were measured with radio immunoassay in postmortem samples of prefrontal cortex of patients with early AD (n=8), advanced AD (n=8), and of a group of healthy control subjects (n=8). Results: T₄ levels did not differ between groups. T₃ levels were significantly lower in advanced AD brains relative to control subjects, but there was no difference between T₃ levels in early AD versus control subjects. Conclusions: Results suggest that the conversion of T₄ to T₃ may be affected in AD, perhaps due to alterations of type II deiodinase. T₃ is the bioactive form of TH, and reduced conversion of T₄ to T₃ in AD may be associated with both AD pathology and the clinical presentation of dementia.

P66. A meta-analysis of neuropsychologic, neuroanatomic, and APOE genotype changes in preclinical Alzheimer's disease Konstantine K. Zakzanis, Mark I. Boulos (Division of Life Sciences, University of Toronto, Cognitive Neurology, Sunnybrook and Women's College Health Science Centre, Toronto, ON, Canada). [email protected]

Background: Dementia of the Alzheimer's type (DAT) is the most common of the dementias, affecting up to 47% of the population over the age of 85. As the age of distribution shifts over the next quarter century, the increasing prevalence of DAT poses a burgeoning health crisis and intensifies the need for efforts toward detection, treatment, and cure. Initiatives to develop biological tests for DAT are under way, but to date, neuropsychological and neuroanatomic changes (as visualized in vivo) remain the earliest, most reliable evidence of disease. Combined neuropsychological and neuroanatomic changes in persons at genetic risk (e.g., by virtue of the APOE E4 genotype) have also been identified as potential preclinical markers for the disease. Methods: The contribution of neuropsychological and neuroimaging measures in the preclinical detection of DAT was quantitatively reviewed in terms of their sensitivities. We also examined the contribution of APOE-related genetic susceptibility in terms of its effect on neuropsychological test performance and volumetric measurement of specific neuroanatomic variables. To do so, we employed meta-analytic methods where we determined the magnitude of effect for neuropsychological and neuroanatomic changes in persons with APOE E4 positive versus E4 negative genotype. The results of this effect size analysis were derived to evaluate the following research questions: 1) What are the most sensitive and predictive neuropsychological test measures in the preclinical detection of DAT? 2) What structures are most implicated when using brain-imaging instrumentation in the preclinical stage of DAT? 3) What neuropsychological tests and neuroanatomic structures best discriminate between those individuals carrying the APOE E4 genotype and those not carrying it? Results and Conclusions: The primary finding reported is that verbal memory performance and hippocampal size best differentiate DAT and non-DAT individuals preclinically. In accordance with the belief that patients carrying the APOE E4 genotype may present with a different neuroanatomic test signature from patients who do not carry the genotype, an odor identification test best differentiates APOE E4 positive and negative individuals.

P67. Cognitive and MRI findings in an autopsy-confirmed case of Pick's disease nine years prior to death Ronald F. Zec, Mona Ghobrial, Zeng Wang, Tom Ala, Geun Yeong Pyo, Rodger Elble (Southern Illinois University School of Medicine, Springfield, IL). [email protected]

Background: A 67-year-old man with autopsy-confirmed Pick's disease received a comprehensive neuropsychological assessment in 1992 nine years prior to death. In 1992, MRI revealed mild age-related bilateral atrophy and in 1997 moderately severe atrophy. The autopsy in 2001 revealed severe atrophy of the frontal/temporal lobes and moderate atrophy of the parietal/occipital lobes, and stained sections revealed changes diagnostic of Pick's disease. The patient displayed progressive dementia, speech disturbance, personality changes, and indifference, but the behavioral/personality changes were subtle at the time of the first assessment. Methods: The patient was administered the Alzheimer's Disease Assessment Scale (ADAS) and SIU Comprehensive Cognitive Battery for Dementia. Results: The patient was intact on most measures, including the MMSE and ADAS, but he displayed mild to severe impairments in learning and memory (including many false-positive errors on delayed recognition), moderate impairments on similarities and visuointegration ability, slow reading and color naming speeds, mildly slow simple timed psychomotor performance, and mildly impaired phonemic word fluency, Block Design, and Picture Completion. Conclusions: The early presentation of this Pick's disease case mimicked that of mild dementia of the Alzheimer's type, but there were a few subtle atypical cognitive findings and some subtle personality/behavior changes that suggested greater-than-expected frontal lobe involvement.

P68. Practice effects of serial neuropsychological testing in patients with schizophrenia and healthy volunteers Saeeduddin Ahmed, Leigh Beglinger, Oranee Tangphao-Daniels, Michael Derby, Eric Siemers, David A. Kareken (Eli Lilly and Company and Indiana University School of Medicine, Indianapolis, IN). [email protected]

Background: Practice effects of multiple neuropsychological assessments over short durations have not been well studied in healthy volunteers (HV) or schizophrenic (SCZ) patients. Methods: 19 HV and 6 SCZ patients were tested weekly in a fixed order for 6 sessions. Tests comprised finger tapping (FT), letter fluency, AVLT, Digit Symbol, Trail Making Test, Letter-Number Sequencing, Stroop, and the PASAT. SCZ patients completed a longer battery; cognition composite scores were derived from tests common to both batteries. To minimize variability, examiner, time of day, and caffeine and tobacco use were held constant. Prescription medications did not change during testing, with one exception that did not appear to affect results. Three or six alternate forms were used for each test except FT and Stroop. Results: For HV, most learning occurred in the first 3 to 4 sessions (P-values 0.001–0.046) then plateaued, in part from ceiling effects on some tests. PASAT (P<0.001) and Stroop interference (P=0.001) showed the greatest learning. However, composite scores from summing all tests revealed learning across all six sessions with minimal reductions in variance. For SCZ patients, both intersession and intrasubject variability were high. Conclusions: Intervention studies in SCZ patients involving repeated assessments should include sufficient numbers of subjects to overcome the test-retest variability. Learning effects in patients were difficult to interpret due to this variability. Support from Eli Lilly and Company.

P69. Quantitative analysis of nitric oxide synthase and guanilate cyclase in schizophrenia brain Hajime Baba, Heii Arai (Department of Psychiatry, Juntendo University School of Medicine, Tokyo, Japan). [email protected]

Background: Nitric oxide (NO) has been functionally linked to both dopaminergic and glutamatergic systems, both of which are strongly implicated in the biochemical pathology of schizophrenia. Soluble guanylyl cyclase (sGC) is activated by NO and catalyzes the conversion of GTP to cGTP. We investigated the quantity of nitric oxide synthase (NOS), sGC alpha 1, alpha 2, and beta 1 subunits, in frontal cortex in schizophrenia brains. Methods: Fresh-frozen prefrontal cortex tissue from 20 schizophrenia patients and 15 controls were obtained. Total RNA was extracted and reverse transcribed with AMV reverse transcriptase by using random hexamers. Real-time PCR was performed by using an ABI Prism 7700 sequence detection system. Reactions were performed with the SYBR Green I Mastermix (Mimmack et al, Proc Natl Acad Sci USA 2002). Results: NOS expression was significantly higher in schizophrenia. No significant changes were found in expression levels of sGC alpha 1, sGC alpha 2, and sGC beta 1 in schizophrenia compared with control. Discussion: In the frontal cortex, a decreased density of NOS neurons has been reported (Akbar et al, Arch Gen Psychiatry 1993). This suggests that NOS neurons are decreased in frontal cortex in schizophrenia; however, NOS production is increased by improving the turnover.

P70. Late postnatal sprouting of amygdalocortical projections targeting the GABAergic interneuron Miles G. Cunningham, Sujoy Bhattacharyya, Francine M. Benes (Program in Neuroscience, Department of Psychiatry, Harvard Medical School, Belmont, MA). [email protected]

Background: We have shown that between birth and adulthood, amygdalar projections from the basolateral amygdaloid nucleus (BLA) progressively infiltrate rat medial prefrontal cortex (mPFC) and form functional synaptic interactions with dendritic spines and shafts. We further hypothesize that a key amygdalar target in this corticolimbic relay is the GABAergic interneuron, which plays a critical modulatory role in mPFC/cingulate functioning. Methods: BLA fibers were visualized with the anterograde tracer biocytin and were co-localized with GABAergic interneurons. The numerical density of biocytin-IR fibers forming axodendritic or axosomatic contacts with GABAergic neurons was determined with confocal microscopy. These interactions were also evaluated using electron microscopy (EM). Results: The numerical density of GABAergic cells was highest at birth and showed an exponential decrease within 2 weeks. Through development, axosomatic contacts showed a 3-fold increase in layer II, and axodendritic contacts showed an 8-fold increase in both layer II and layer V. These data were corroborated with EM. Conclusions: Our data suggest that BLA fibers are forming synapses with GABA cells during the late postweanling period. Given the postulated role of the amygdala, cingulate cortex, and GABAergic interneurons in schizophrenia, these late postnatal changes may contribute to the onset of this illness during late adolescence. Support from NIMH Grants MH00423 and MH42261.

P71. Apathy and neuropsychological functioning in schizophrenia Laura A. Flashman, Robert M. Roth, Andrew J. Saykin, Thomas McAllister, Robert Vidaver (Neuropsychology Program, Department of Psychiatry, Dartmouth Medical School & New Hampshire Hospital, Lebanon, NH). [email protected]

Background: Apathy is a common negative symptom in schizophrenia, associated with poor treatment response. We evaluated whether apathy is associated with executive and/or right hemisphere dysfunction, as seen in some other patient groups (e.g., stroke, Alzheimer's disease). Methods: Participants included 38 patients with schizophrenia (DSM-IV criteria) and 12 healthy control subjects. They were assessed with the SCID and Scale for the Assessment of Negative Symptoms/Scale for the Assessment of Positive Symptoms (SANS/SAPS) and completed a comprehensive neuropsychological battery. Using the Apathy subscale of the SANS, patients were divided into two groups; 18 with absent or mild apathy (LA; low apathy, scores 0–2) and 20 with moderate to severe apathy (HA; high apathy, scores 3–5). Results: Patient groups were equivalent in terms of overall psychiatric symptom severity, including depression (BPRS). Group differences in apathy severity were unrelated to overall negative symptom severity. The HA group, but not the LA group, scored lower than control subjects on measures of rapid visuomotor sequencing and verbal memory. The HA group also obtained a lower performance IQ score than both the LA group and the control group. HA and LA groups did not differ in psychomotor speed, Wisconsin Card Sorting Test performance, verbal learning, naming, or verbal or full-scale IQ. Conclusions: Findings suggest that apathy in schizophrenia is related to right hemisphere and possibly frontal-subcortical circuitry dysfunction. Future research using neuroimaging may clarify the structural and functional substrate of apathy in schizophrenia. Support from NARSAD and the Ira W. DeCamp Foundation.

P72. Neurocognition and long-term prediction of quality of life in schizophrenia Daryl E. Fujii, A.M. Wylie, J. Nathan (Hawaii State Hospital, Honolulu, HI). [email protected]

Background: Quality of life is an important issue in schizophrenia. The present study examines the long-term predictive ability of cognitive functioning to quality of life in a sample of schizophrenic patients. Methods: 36 subjects were procured from merging two community mental health data bases: inpatient neuropsychology services and results from a Substance Abuse and Mental Health Services Administration study. The mean age at time of testing was 28.6 years, and mean age at time of SAMHSA data collection was 42.7, with a mean interval of 14.06 years. Neuropsychological measures of intelligence, working memory, short-term memory, executive functioning, and motor skills were used as predictor variables in a stepwise regression analysis with the scales from the Brief Quality of Life Inventory (Lehman, Eval Prog Plan 1988; 11:51–62) as dependent variables. Results: Memory was predictive of income and satisfaction with daily activities and general health. Intelligence was predictive of satisfaction with social contacts. Executive functioning was predictive of contact with family and financial support. Motor skills were predictive of satisfaction with family contact. Working memory was predictive of victimization. Conclusions: Neurocognition is a significant long-term predictor of quality of life in schizophrenia.

P73. Diminished flexibility of central nervous system in never-medicated schizophrenia: EEG analysis during intermittent photic stimulation Mitsuru Kikuchi, Yoshifumi Koshino (Kanazawa University, Kanazawa, Japan). [email protected]

Background: EEG studies of photic driving response (PDR) have shown attenuated PDRs in schizophrenic patients. However, few studies have focused on sequential EEG change during intermittent photic stimulation. Methods: Quantitative EEG analysis for 9–11 Hz band (which corresponds to the stimulus frequency) was performed to investigate the sequential EEG change during intermittent photic stimulation (PS) in 17 drug-naive schizophrenia patients and 17 sex- and age-matched control subjects. The PS consisted of white flickers at 10 flashes per second, which were given for the duration of 10 s and repeated six times after intervals of 10 s. Results: Under the stimulus condition, absolute 9–11 Hz band power at the posterior areas was higher than at the anterior areas all through the periods in the patient group. However, these trends could not be seen in the first period in the control group. During the nonstimulus interval condition, in the patient group, posterior dominance of 9–11 Hz band power was maintained all through the periods. In the control group, however, this trend was weak in the latter half of the periods. Conclusions: The continuous posterior dominance of alpha band power in schizophrenic patients may reflect diminished flexibility of central nervous system under various conditions.

P74. Global CAG repeat profiles in psychiatric patients with and without tardive dyskinesia: a pilot study Patricia Lowrimore, Yuh-Hwa Wang, Andrew Epstein, David Mulvehill, Michael McCormack (University of Medicine and Dentistry of New Jersey, Piscataway, NJ). [email protected]

Background: Tardive dyskinesia (TD) is a drug-induced syndrome of involuntary movements that has a similar phenotypic presentation to Huntington's disease. HD and other neurological conditions are known to be related to CAG repeat expansions on specific genes. We hypothesize that TD may be related to CAG repeat expansions. Methods: Subjects were persons with schizophrenia or schizoaffective disorders with (n=10) and without (n=9) TD according to the Abnormal Involuntary Movement Scale (AIMS). The repeat expansion determination (RED) method was used to characterize global CAG in whole blood. A simple analysis of the mean number of CAG repeats between groups was performed by using Student's two-tailed t-test for comparison of the means. Results: CAG nucleotide profiles in subjects with TD (mean=57.00, SD=19.35) and without (mean=56.90, SD=23.34) were not measurably different (P=0.99). A subgroup of patients had triplet profiles (n=10; mean=45.00, SD=0.00) that were smaller than those of a second subgroup (n=9; mean=70.22, SD=24.83; P<0.005), but this was not related to TD. Conclusions: Results suggest triplet expansions in the study, but not in TD populations. Results are encouraging that a larger population and more structured subject selection process may yield meaningful information about the relationship between trinucleotide repeat phenomena and TD.

P75. A comparative profile analysis of neuropsychological functioning in schizotypal personality disorder and schizophrenia Mié Matsui, Tomiki Sumiyoshi, Kanade Kato, Eiichi Yoneyama, Masayoshi Kurachi (Toyama Medical & Pharmaceutical University, Toyama, Japan). [email protected]

Background: Neuropsychological impairments have been consistently reported in patients with schizophrenia (SCZ). Little is known about whether subjects with schizotypal personality disorder (SPD) exhibit neurocognitive dysfunction similar to that in SCZ. Therefore, we assessed neuropsychological profile in SPD subjects and compared it with that in patients with SCZ. Methods: Participants were 15 SPD patients and 15 patients with SCZ who fulfilled the ICD-10 diagnostic criteria. All participants were administered a standard neuropsychological battery assessing language ability, spatial ability, visuomotor function, verbal memory, visual memory, auditory attention, visual attention, and executive function. Results: Performance in most of the cognitive domains was impaired in SPD subjects, but to a lesser degree compared with SCZ patients. Specifically, the degree of impairment in verbal memory in SPD subjects was comparable to that in patients with SCZ, whereas SCZ patients performed worse on the test of visual attention than did subjects with SPD. Conclusions: As a whole, the pattern of deficits in SPD patients was qualitatively similar to but milder than that seen in patients with SCZ. The results of this study also suggest that cognitive abilities related to temporal lobe function are disturbed across these schizophrenia spectrum disorders. Support from a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.

P76. Reduced EEG coherence during photic stimulation in paranoid schizophrenia with acute exacerbation: longitudinal stability and relationship to symptom change Tatsuya Nagasawa, Mitsuru Kikuchi, Tsutomu Takeda, Takashi Oka, Maki Kitamura, Naohisa Hirao, Msato Higashima, Yoshifumi Koshino (Department of Neuropsychiatry, Kanazawa University School of Medicine, Kanazawa, Japan). [email protected]

Background: We previously reported that drug-naive schizophrenia patients had significantly higher EEG coherence during photic stimulation over the left posterior regions than control subjects, and they showed diminished coherence reactivity from rest to stimulus condition (Wada et al, Neuropsychobiology 1998; 38:63–69). The purpose of the present study was to investigate the longitudinal EEG coherence changes during photic stimulation in the course of treatment. Methods: Subjects were 13 patients with paranoid schizophrenia with acute exacerbation (DSM-IV). Subjects were assessed at baseline and again an average of 34 days later. The BPRS was used to assess the severity of symptoms. EEG coherence to 10-Hz photic stimulation was calculated for frontal-central, central-occipital, and frontal-temporal pairs. Results: There was a significant inverse correlation between changes in the total symptom scores and left central-occipital coherence in the 9.5–10.5 Hz frequency range. Furthermore, 9.5–10.5 Hz coherence between left central and occipital pairs was smaller than right pairs at the first record, whereas such laterality disappeared at the second record in conjunction with the improvement of symptoms. Conclusions: These results suggest that impairment in functional connectivity within the left hemisphere may contribute to acute symptoms in paranoid schizophrenia.

P78. Cholinesterase inhibition after discrete basal forebrain injury John C. Adair (University of New Mexico, Albuquerque, NM). [email protected]

Background: In contrast to Alzheimer's disease, patients with focal basal forebrain (BF) lesions provide an opportunity to examine the influence of cholinesterase inhibition (CI) for restricted presynaptic cholinergic deficits. Methods (case report): A patient noted profound amnesia after recovery from resection of an orbitofrontal meningioma. Testing over 2 years after surgery confirmed profound disturbance of recall and recognition for both verbal and nonverbal material with relative preservation of other cognitive functions. Brain MRI showed encephalomalacia affecting the frontopolar cortex and gyrus rectus bilaterally, as well as the BF rostral to the anterior commissure. Results: Cognitive testing repeated after 8 weeks of donepezil treatment (10 mg/day) showed declines on 7 of 9 measures not already at floor values, a result not consistent with random variability (P=0.002, binomial). Repeat assessment 4 weeks after discontinuing the CI resulted in return of test scores to pretreatment values. Conclusions: Given the “inverted U” relationship between acetylcholine levels and cognitive performance, we speculate that deterioration may have resulted from excess cholinergic transmission, possibly due to upregulation of postsynaptic receptors combined with CI. Experience with other patients in whom BF lesions mediate behavioral disorders (e.g. trauma, aneurysm) may substantiate this speculation.

P79. Apolipoprotein E4 in association with persistent neurophysiologic impairment after mild traumatic brain injury David B. Arciniegas, Jeannie L. Topkoff, Christopher M. Filley, Lawrence E. Adler, C. Alan Anderson, Kimberly A. Ricketts, Elaine B. Spector (University of Colorado School of Medicine, Denver, CO). [email protected]

Background: We reported comparable structural and functional hippocampal abnormalities among persons with chronic symptoms of impaired sensory gating, attention, and memory following TBI at all levels of initial severity (Arciniegas et al, Brain Inj 1999, 13:1–13; Arciniegas et al, J Neuropsychiatry Clin Neurosci 2000, 12:77–85; Arciniegas et al, J Neuropsychiatry Clin Neurosci 2001, 13:213–221). We interpreted the similarity of neurobiological findings despite disparate initial injury severity as a product of our subject selection methods, which recruited based on symptoms and outcome severity rather than initial injury severity. To explore further this interpretation, we investigated the frequency of the APOE E4 genotype in these subjects. We hypothesized that the frequency of the APOE E4 genotype would be highest in the mild TBI subjects given their relatively poor recovery from their injuries and their symptomatic, neurophysiologic, and structural similarity to the more severely injured subjects included in our studies. Methods: APOE genotype was determined in 26 subjects with mild or moderate/severe TBI and P50 nonsuppression included in our previous studies. Results: 11 of the 26 TBI subjects (42%) are heterozygous APOE E4 carriers. Among those with mild TBI, 9/18 (50%) are APOE E4 carriers, whereas only 2/8 (25%) with moderate/severe TBI are APOE E4 carriers. Binomial statistical comparison of the frequency of APOE E4 status in the mild TBI group differs significantly (P=0.03) from the APOE E4 expected population frequency (28%). Conclusions: These preliminary results suggest that the APOE E4 genotype may play a role in the development of persistent neurophysiologic abnormalities and suboptimal outcome following mild TBI. Prospective studies are needed to understand more fully the role of APOE genotype in outcome after an ostensibly “mild” TBI.

P80. Clinical rating of cortical atrophy and cognitive correlates following traumatic brain injury A.G. Bergeson, R. Lundin, R.B. Parkinson, D.F. Tate, J. Victoroff, R.O. Hopkins, Erin D. Bigler* (Departments of Psychology and Neuroscience, Brigham Young University, Provo, UT). [email protected]

Background: We report on the utility of using a rapid, visually based semiquantitative neuroimage rating scale in the study of brain/behavior relationships in cases of traumatic brain injury (TBI). Methods: Magnetic resonance (MR) scans from 75 subjects who were participants in an ongoing TBI investigation (50 males, 25 females), were rated for atrophy in frontal, temporal, and parietal areas by using a four-point semiquantitative scale. Results were compared with those of 75 age- and gender-matched control subjects. Lobar atrophy ratings were compared with the quantitatively determined ventricular-brain ratio (VBR). Lobar atrophy ratings of TBI subjects were also compared with the subjects' performance on a battery of standard neuropsychological tests. Results: TBI patients had significantly higher atrophy ratings in frontal and temporal lobe areas compared with control subjects. All clinical atrophy ratings correlated significantly with the quantitatively determined VBR. Frontal and temporal atrophy also correlated well with deficits in memory and executive function. Conclusions: This method of clinically rating lobar atrophy represents a valid and reliable method for the assessment of atrophic changes in TBI and can be easily used by clinicians. Atrophy determined by this method found in frontal and temporal regions correlated with neuropsychological deficits in memory and executive function. Support from the Ira Fulton Foundation.

P81. Neuropsychological, psychiatric, and demographic factors relate to postconcussion symptom reporting after traumatic brain injury Kara S. Comins, Laurie M. Ryan, Molly B. Sparling, Deborah L. Warden (Defense and Veterans Brain Injury Center; Department of Neurology, Walter Reed Army Medical Center; and Department of Neurology, Uniformed Services University of Health Sciences, Bethesda, MD; and Henry M. Jackson Foundation for the Advancement of Military Medicine). [email protected]

Background: Individuals sustaining traumatic brain injury may complain of a number of physical, cognitive, and behavioral symptoms referred to as postconcussion symptoms (PCS). PCS can persist from months to years following injury and may even cause persistent disability. Identifying factors that relate to PCS reporting is important for identifying persons at risk after TBI and developing preventative and palliative intervention strategies for these individuals. Methods: 69 patients evaluated at Walter Reed Army Medical Center completed the Post Concussion Symptom Checklist (PCSC; Gouvier et al, 1992) as well as a neuropsychological test battery and psychiatric scales. PCSC scores were divided into thirds. Demographic, neuropsychological, and psychiatric variables were analyzed in high-symptom and low-symptom reporting groups. Results: Significant differences between high- and low-symptom reporting groups were found in complex attentional tasks including Trigrams, Stroop Color, and Color-Word (P<0.05). With the exception of Psychopathic Deviate and Hypomania, all MMPI clinical scores were significantly higher in the high-PCS reporting group. A greater time postinjury was associated with the high-PCS group. Conclusions: Persistent PCS was associated with complex attentional difficulties and high levels of psychiatric symptom reporting in this patient sample. Patients with this profile may benefit from targeted education and treatment strategies.

P82. The combination of dopamine agonists and mood stabilizers in traumatic brain injury Zeina Chemali (Neuropsychiatry/BBNG, Boston, MA). [email protected]

We will present our clinical data pertaining to the treatment of a cohort of patients with TBI who received a dopamine agonist such as bupropion to enhance cognition after achieving good mood stabilization and therapeutic levels on antiepileptic drugs (AED) such as divalproex, oxcarbazepine, or lamotrigine. Our patients benefited from this treatment modality on different levels. Symptoms targeted were mood lability, impulsivity, inattention, and apathy. In addition, our patients had better pain management in regard to their headache on this regimen. The concern for seizures while on bupropion was counteracted by the concomitant use of AED. Follow-up after a year of treatment will also be presented.

P83. Characteristics of a group of military traumatic brain injury patients with somatoform symptoms Louis M. French, Laurie M. Ryan, Deborah Warden (Defense and Veterans Brain Injury Center, Walter Reed Army Medical Center; Bethesda, MD). [email protected]

Background: The idea that unconscious psychological factors can manifest themselves in somatic distress has a long history in psychiatry. Charcot, Breuer, and Freud in the late 19th and early 20th centuries described the concept of hysteria, in which neurological symptoms occurred but could not be explained by a known neurological or medical disorder. In a military setting, a number of authors have described increased somatic distress in soldiers exposed to psychologically traumatic events. Methods: Subjects were 31 active-duty military who received serial neuropsychological evaluations as part of a comprehensive evaluation following a traumatic brain injury and demonstrated symptoms consistent with the somatoform spectrum of disorders. These subjects were compared with the larger group of soldiers (n=222) assessed during that same period. Results: The two groups showed no differences in basic demographic variables. Significant differences were found in greater levels of psychopathology (depression, scales 0, 1, 2, 3 on the MMPI-2) in the somatic group. They also showed weaker effort and poorer cognitive performance, especially on measures of attention and memory. Conclusions: These results suggest that a subgroup of patients classified as part of a somatoform spectrum show distinct personality and cognitive performance characteristics.

P84. A comparison of neuropsychological functioning in psychotic disorder following traumatic brain injury, traumatic brain injury without psychosis, and schizophrenia Daryl E. Fujii, Iqbal Ahmed (University of Hawaii, Honolulu, HI). [email protected]

Background: This study examines the neuropsychological functioning of TBI patients with and without psychosis. It was predicted that the psychotic TBI (PTBI) group would be similar to the schizophrenic group in pattern of deficits, but milder in severity, whereas the profile of the nonpsychotic TBI (NPTBI) group would be more similar to that of normal subjects. Methods: The neuropsychological functioning of 24 PTBI patients, 21 NPTBI patients, and 24 patients with schizophrenia were compared with means for normal subjects as well as against each other. Data were procured from the archives of a state hospital-based neuropsychological service. Results: After Bonferroni correction, the PTBI group demonstrated significantly lower scores in intelligence, vocabulary, verbal memory, and executive functioning than means for the normal sample. The schizophrenic group demonstrated lower scores than the normal sample in intelligence, working memory, verbal memory, visual spatial abilities, and executive functioning. No differences were found between normal subjects and the NPTBI group. Conclusions: The neuropsychological profile of the PTBI group was more similar to the schizophrenia than to the NPTBI group. Implications of our findings for the conceptualization of psychotic disorders are discussed.

P85. MMSE scores among traumatic brain injury patients admitted for acute rehabilitation Barry D. Jordan, Karina Ortega-Verdejo (Burke Rehabilitation Hospital, White Plains, NY). [email protected]

Background: The Mini-Mental State Examination (MMSE) has been used as a screen for dementia in elderly individuals. Methods: The MMSE was administered to a cohort of 180 patients with the diagnosis of traumatic brain injury at the time of admission to the Brain Injury Rehabilitation Program at Burke Rehabilitation Hospital. Results: The average age of the cohort was 45 years (SD=22.9) and the average length of stay (LOS) in acute rehabilitation was 28.3 days (SD=21). The mean score on the MMSE at the time of admission was 16.7 (SD=9.7). The mean total admission Functional Independence Measure (FIM) score was 61.6 (SD=25.3) and the mean admission cognitive FIM score was 18.5 (SD=8). The mean discharge total and cognitive FIM scores were 100.4 (SD=22) and 25.5 (SD=6.3), respectively. The MMSE inversely correlated with LOS (r=−0.464; P<0.001). There was a good correlation with admission cognitive FIM score (r=0.791; P<0.001) and admission total FIM score (r=0.699; P<0.001); however, there was no correlation with age. Patients with MMSE<24 had significantly longer LOS and lower cognitive and total FIM scores at admission and discharge. Conclusions: The MMSE can serve as a useful adjunct to the evaluation of TBI patients admitted to acute rehabilitation.

P86. Differential activation of working memory-associated frontal cortex using a dopamine agonist after mild traumatic brain injury (MTBI) Thomas W. McAllister, Laura A. Flashman, Patricia K. Shaw, Richard B. Ferrell, Heather A. Wishart, Brenna C. McDonald, Alexander C. Mamourian, Jennifer S. Ramirez, Andrew J. Saykin (Section of Neuropsychiatry and Brain Imaging Lab, Dartmouth Medical School, Lebanon, NH). [email protected]

Background: Using functional MRI (fMRI), we have previously reported abnormalities consistent with changes in the activation and modulation of working memory (WM) processing resources 1 month and 1 year after MTBI (McAllister et al, Neurology 1999, 53:1300–1308; McAllister et al, Neuroimage 2001; 14:1004–1012) A growing literature suggests that catecholaminergic agonists play a critical role in the modulation of WM, particularly in the dorsolateral prefrontal cortex (DLPFC). We hypothesized that administration of dopaminergic agonists would improve the allocation of WM processing resources. Methods: In a prospective, randomized, double-blind study we administered 1.25 mg of bromocriptine (dopamine D₂ agonist) or placebo 2.5 hours before fMRI scanning to 6 healthy control subjects and 8 individuals with MTBI one month after their injury, on two separate occasions. Subjects performed a verbal WM task (3-back) while in the scanner. Statistical analyses were completed by using SPM99. Results: Both groups showed significant, task-related increases in activation (P<0.01) in frontal WM-related areas on bromocriptine relative to placebo. A significant group-by-drug interaction (P<0.01) indicated a different pattern of drug-induced activation along an anterior-posterior gradient within the frontal lobes. The MTBI group activated more posterior regions, whereas the control subjects activated bilateral anterior DLPFC. Conclusions: Dopamine D₂ agonists are associated with localized increases in activation of DLPFC during WM tasks. One month after injury, MTBI subjects and controls showed differing responses to dopamine agonists. It is not clear if this difference is a direct result of the injury or a compensatory response. The combined use of fMRI and psychopharmacological probes shows promise as a means of further elucidating the memory problems following MTBI. Support from NIDRR Grants H133 G70031 and H133 G000136; NINDS Grant R01 NS40472-01; the Ira W. DeCamp Foundation; and New Hampshire Hospital.

P87. Prediction of return to work after treated mild traumatic brain injury Chris E. Paniak, G. Toller-Lobe, J. Nagy (Glenrose Rehabilitation Hospital, Edmonton, AB, Canada). [email protected]

Background: Mild traumatic brain injury (MTBI) is the most common and most controversial category of TBI. While some research has explored predictors of return to work after MTBI, little or no research has explored such predictors in a sample that received specialized treatment for their MTBI. Methods: Subjects were 106 adults who had MTBI, were enrolled in a treatment study within a month of injury, and were followed up for 1 year or until they had resumed full preinjury work. The treatment study compared a single session of information and reassurance with a more extensive intervention. The latter also involved neuropsychological and physical therapy assessments, followed by treatment as needed (although few people needed it) in an outpatient, hospital-based brain injury rehabilitation program (Paniak et al, Brain Inj 1998; 12:1011–1023). As outcomes did not differ, the subjects were pooled for the present study. A direct multiple regression analysis was used, primarily employing predictor variables that prior research had found useful in predicting outcomes. Results: Older age, more severe initial pain problems, seeking or receiving financial compensation, and being female were all associated with taking longer to return to work in the statistically significant regression equation (F=3.59, df=16,89, P<0.001). Severity of initial postconcussion symptoms and other injury severity and demographic variables did not contribute significantly to the regression analysis. Conclusions: Variables useful in predicting return to work after treated MTBI largely overlap with those found useful in primarily untreated MTBI samples. However, severity of initial pain problems has not been frequently investigated as a predictor in MTBI research. Its predictive value in the present study suggests that previous MTBI research may have often overlooked an important predictor variable.

P88. The relationship of apathy to executive functioning and frontal lobe lesions in TBI Laurie M. Ryan, Thomas D. Maryniak, Molly B. Sparling, Kara S. Comins, James Smirniotopolis, Deborah L. Warden (Defense and Veterans Brain Injury Center; Department of Neurology, Walter Reed Army Medical Center; and Department of Neurology, Uniformed Services University of Health Sciences, Bethesda, MD; and Henry M. Jackson Foundation for the Advancement of Military Medicine). [email protected]

Background: Apathy or diminished motivation has been found to be related to frontal-executive dysfunction (e.g., McPherson et al, J Int Neuropsychol Soc 2002; 8:373–381). Many studies have focused on Alzheimer's disease (AD), but little information is available on the relationship between apathy and frontal-executive functioning in traumatic brain injury (TBI). Methods: Subjects included 107 active-duty soldiers with moderate to severe TBI seen within 3 months of injury. Apathy ratings were taken from a structured psychiatric interview (PANSS), and 13 of the 107 patients were classified as apathetic. All patients underwent comprehensive neuropsychological assessment including measures of executive functioning (e.g., WCST, Stroop). MRI lesion data were available for 96 patients, including all 13 apathetic patients. Results: There were no differences between groups on demographic variables. In general, apathetic patients performed more poorly on neuropsychological measures involving executive skills, showing significant differences on a number of measures (P<0.05; e.g., Stroop, FAS, CVLT Discriminability). Moreover, apathetic patients were more likely to have identifiable frontal lesions on MRI than nonapathetic patients (P<0.05). Conclusions: Apathy was related to executive dysfunction and frontal lesions on MRI in our sample of 107 TBI patients.

P89. Remote evaluation of postconcussion symptoms utilizing telemedicine technology Molly B. Sparling, Kara S. Comins, Laurie M. Ryan, Col. Robert J. Labutta, MC, Deborah L. Warden (Defense and Veterans Brain Injury Center and Department of Neurology, Walter Reed Army Medical Center; Bethesda, MD; and Henry M. Jackson Foundation for the Advancement of Military Medicine). [email protected]

Background: Patients and families often report postconcussion symptoms (PCS) including irritability, decreased frustration tolerance, depressed mood, worry, decreased concentration, and reduced cognitive efficiency following traumatic brain injury. Identifying and monitoring the recovery process permits full education about recovery and treatment of possible symptoms to promote subsequent return to full function. Therefore, identification of PCS is critical for appropriate and timely treatment. Methods: A Web-based telemedicine protocol has been implemented to provide a brief screen of PCS. Patients seen for full multidisciplinary evaluation at Walter Reed Army Medical Center are also tested by using several computerized measures, including a brief cognitive evaluation and mood and symptom scales. Results: The telemedicine Web site has been developed, and all measures are currently working online. The Web site and testing instruments are presented for demonstration. Using a Web-based telemedicine system, the project will demonstrate the potential for remote evaluation of PCS after TBI. We plan to establish the equivalence of Web-based screening to traditional in-person screening measures. Conclusions: Remote assessment of PCS has been successfully implemented. We anticipate the Web-based instruments will not be significantly different from the in-person instruments, thus demonstrating the value of telemedicine in this field.

P90. Use of the Modified 2×3 Test to assess executive functioning in traumatic brain injury Margaret A. Struchen, Laura Rosas (Baylor College of Medicine and The Institute for Rehabilitation and Research, Houston, TX). [email protected]

Background: Executive dysfunctions are regarded as common sequelae of TBI. Such impairments are hypothesized to pose obstacles to social integration and employment. Direct investigation of the relationship between executive functioning and functional outcome is limited. Assessment of executive functioning poses challenges because it requires a structured test to measure how others develop and implement structure to accomplish goals. The Modified 2×3 Test (M2×3) assesses executive functioning by having participants complete two exemplars of three real-world tasks while conforming to a set of rules. Methods: Eight participants with TBI, all of whom had received inpatient rehabilitation and were at least 1 year postinjury, and 8 noninjured matched control participants completed the M2×3 and the Community Integration Questionnaire (CIQ). Results: Persons with TBI did not differ significantly compared with control participants on Task Accomplishment for the M2×3. They made significantly more Rule Violation errors (mean=5.13, SD=3.87) than did control subjects (mean=0.75, SD=1.17; t=3.06, P<0.02). For persons with TBI, both Task Accomplishment (r=0.79, P<0.01) and number of Rule Violation errors (r=0.65, P<0.05) were significantly correlated with functional outcome, as measured by total scores on the CIQ. Support from NIDRR Research Grant H133 G010152.

P91. Phenomenology and course of stress-related symptoms one month and one year after mild traumatic brain injury (MTBI) Kaloyan S. Tanev, Laura A. Flashman, Andrew J. Saykin, Thomas W. McAllister (Section of Neuropsychiatry, Dartmouth Medical School, Lebanon, NH). [email protected]

Background: The link between MTBI and stress-related symptoms such as acute stress disorder (ASD) and posttraumatic stress disorder (PTSD) is controversial; both high and low rates of ASD and PTSD have been reported in unselected MTBI populations. We hypothesized that some of this variance might be accounted for by preexisting psychiatric disorders in the MTBI population. Methods: We studied 28 healthy control subjects and 38 individuals 1 month after MTBI (ACRM criteria). A subset of these subjects was restudied at 1 year. All subjects received a PTSD Symptoms Scale (PCL-S), the Head Injury Symptom Checklist, and the SCID. Subjects with prior psychiatric history were excluded. Results: MTBI subjects had significantly more stress-related symptoms than control subjects on the PCL-S 1 month after injury. After elimination of items reasonably attributed to the physiological effects of the MTBI itself (e.g., incomplete memory of event), the two groups did not differ. There was no statistically significant between-group difference for stress-related symptoms at 1 year. There was no correlation between stress-related symptoms and postconcussive symptoms either at 1 month or 1 year after TBI. Two patients (12%) had significant persistent postconcussive symptoms 1 year after injury. Conclusions: The low rate of stress-related symptoms 1 month and 1 year after injury in this carefully selected group of MTBI patients free of preinjury psychiatric illness is striking and suggests that ASD and PTSD following MTBI may result from an interaction between preinjury vulnerabilities, the profile of injury, and the meaning of the injury. Support from NIDRR Grants H133 G70031 and H133 G000136; NINDS Grant R01 NS40472-01; and New Hampshire Hospital.

P92. Pathological laughing and crying following traumatic brain injury Amane Tateno, Ricardo E. Jorge, Robert G. Robinson (University of Iowa, Iowa City, IA). [email protected]

Background: Although pathological laughing and crying (PLC) is a relatively frequent consequence of brain damage, few studies have focused on PLC following traumatic brain injury. This study examined the prevalence and clinical correlates of PLC following TBI. Methods: Background, neurological, and neuroradiological data for 92 consecutive patients who were hospitalized following acute TBI were collected. Patients had follow-up evaluations at 3, 6, and 12 months after trauma. The severity of PLC was assessed by using the Pathological Laughter and Crying Scale (PLACS). Neuropsychiatric assessment included the SCID for DSM-1V Axis I Disorders, Ham-D, Ham-A, Overt Aggression Scale (OAS), MMSE, Functional Independence Measure (FIM) and Social Functioning Exam (SFE). Results: 10 patients (10.9%) met the clinical criteria for PLC during the first year after injury. Patients with PLC showed significantly higher Ham-D, Ham-A, OAS, and SFE scores and higher frequency of anxiety disorders and frontal lobe lesions than patients without PLC. Conclusions: PLC is a relatively frequent consequence of TBI and is associated with anxiety disorder as well as depressive symptoms, aggression, and impaired social functioning. We do not know whether PLC leads to anxiety and depression or whether they are comorbid disorders. Prefrontal regulation of limbic circuits may be involved in the pathophysiology of disturbed emotional expression. Support from NIMH Grants MH40355, MH52879, MH53592, and Research Award MH00163.

P93. Clinical characteristics of posttraumatic stress disorder after traumatic brain injury Amane Tateno, Ricardo E. Jorge, Robert G. Robinson (University of Iowa, Iowa City, IA). [email protected]

Background: We examined the prevalence and clinical correlates of posttraumatic stress disorder (PTSD) during the first year following TBI. Methods: Background, neurological, and neuroradiological data for 92 consecutive acute hospitalized TBI patients and 26 control patients with acute trauma not involving the central nervous system (CNS) were collected at in-hospital period, 3, 6, and 12 months after trauma. The diagnosis of PTSD and acute stress disorder (ASD) were based on the SCID for DSM-IV. Neuropsychiatric assessment included the Ham-D, Ham-A, Overt Aggression Scale (OAS), MMSE, Functional Independence Measure, and Social Functioning Exam. Results: Of the 92 TBI patients, 13 (14.1%) developed PTSD, and 3 (3.3%) developed ASD. These frequencies were not significantly different from those in the 26 control patients with trauma but no CNS involvement (PTSD 11.5%, ASD 3.8%). TBI patients with PTSD had significantly higher Ham-D and OAS scores than TBI patients who did not develop PTSD. In addition, focal pattern of traumatic brain injury was significantly more frequent among patients with PTSD than patients without PTSD. ASD and initial sleep disturbances were significantly associated with the later occurrence of PTSD. Conclusions: PTSD constitutes a relatively frequent psychiatric complication among TBI patients during the first year following TBI. However, PTSD did not appear to be related to brain injury per se but may have been caused by depression or agitation, or alternatively PTSD may have caused these depressive and irritability symptoms. The mechanism of PTSD may also include biological factors, such as abnormal serotonergic modulation of limbic structures. Support from NIMH Grants MH40355, MH52879, MH53592, Research Award MH00163, and a grant from the Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.

P94. Association of PTSD with comorbid psychiatric disorders and outcome after traumatic brain injury Deborah L. Warden, Molly B. Sparling, Laurie M. Ryan, Elisabeth Moy-Martin (Defense and Veterans Brain Injury Center; Department of Neurology, Walter Reed Army Medical Center; and Department of Neurology, Uniformed Services University of Health Sciences, Bethesda, MD). [email protected]

Background: Although anxiety following TBI has been described for some time, PTSD after TBI has been more controversial because traumatic amnesia might prevent memory encoding and development of symptoms such as flashbacks and nightmares. This study examines the incidence of PTSD and factors associated with PTSD in a sample of soldiers with TBI. Methods: 129 patients with complete psychological evaluations were examined from a sample of 148 soldiers with moderate-severe TBI participating in a trial of home/inpatient rehabilitation (Salazar et al, JAMA 2000; 283:3075–3081). Diagnosis of PTSD was calculated from the Present State Examination corresponding to DSM-IV criteria. Individuals who developed PTSD were compared with those who did not on measures of psychiatric symptoms, prior history, and demographic measures. Results: 12 patients met criteria for the calculated diagnosis of PTSD. This group had significantly higher rates of comorbid depression, generalized anxiety disorder, obsessive-compulsive disorder, and panic attacks and greater sleep disturbances including changes in sleep onset and waking. Individuals with PTSD were significantly less likely to be found fit for duty at 12 months postinjury. Conclusions: Diagnosis of PTSD is associated with significant psychiatric comorbidity and poorer functional outcome. Early identification and treatment of PTSD may improve outcome and reduce psychiatric morbidity.

P95. Comparison of psychiatric symptoms in patients with hepatitis C, human immunodeficiency virus, and co-infection Robin C. Hilsabeck, Meghan D. Carlson, Elizabeth A. Ziegler, Deanna L. Oliver, Christopher Mathews, Tarek I. Hassanein, William Perry (Texas Tech University Health Sciences Center, Lubbock, TX, and University of California, San Diego, Medical Center, San Diego, CA). [email protected]

Background: Psychiatric problems, such as depression and anxiety, are common in patients with hepatitis C (HCV) and human immunodeficiency virus infection (HIV). The purpose of this study was to test the hypothesis that co-infected patients have more severe psychiatric symptomatology than patients with either HCV or HIV alone. Methods: Participants were 29 males with HCV, 24 with HIV, and 15 with both HCV and HIV. The HCV group was significantly older than the other two groups; thus, age was entered as a covariate in the subsequent analyses. All patients completed the SF-36 symptom checklist and measures of depression, anxiety, fatigue, hostility, and cognitive inefficiency. Results: The co-infection group reported significantly more physical symptoms, hostility, and cognitive problems than the HCV and HIV groups. No significant group differences were found on the SF-36, although the co-infected group endorsed greater role limitations. There were no group differences in depression, anxiety, or fatigue. Conclusions: Co-infection results in greater self-reported physical symptoms, hostility, and cognitive inefficiency than infection with HCV or HIV alone. These difficulties may help explain why co-infected patients feel more limited in their ability to carry out physical and emotional roles. Implementing interventions for these problems may increase the functional abilities of co-infected patients.

P96. Effects of nutrients on enhanced rebound hyperphagia induced by maternal separation and/or space restriction stress Shinichi Iwasaki, Koki Inoue, Katsuhito Hikiji, Kyuichiro Ichihara, Akihiro Nakada, Tomohiro Muramatsu, Nobuo Kiriike (Department of Neuropsychiatry, Osaka City University Medical School, Osaka, Japan). [email protected]

Background: Previously we found that rebound hyperphagia in rats following 2 hours of restricted feeding for 6 days was enhanced by maternal separation in childhood and/or by space restriction as psychological stress. Effects of three major nutrients on enhanced rebound hyperphagia were examined in this study. Methods: 16 groups of rats [(MS, 6-hour maternal separation for postnatal days 1–21; or NS, non-separated) × (contents of food: S, standard; CH, carbohydrate-rich; PR, protein-rich; FA, fat-rich food) × (SR, space-restricted; or NR, nonrestricted)} were reared to 9 weeks of age. Then time-restricted scheduled feeding (2 hours per day for 6 days) was given. Following the scheduled feeding, rats were fed freely for 24 hours (rebound hyperphagia). Before rebound hyperphagia, SR rats were put in a small wire-meshed cage. Body weight and food consumption were measured daily. Results: Food consumption during rebound hyperphagia was affected by maternal separation, and the strength was varied by contents of food. A correlation between space restriction stress and contents of food was observed. Conclusions: This result suggests that enhanced rebound hyperphagia with psychological stress changes preference of food or changes the need for nutrients. Support from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.

P97. Diminished flexibility of central nervous system in never-medicated panic disorder: quantitative EEG analysis Tomokazu Kidani, Mitsuru Kikuchi, Ryutaro Komuro, Hiroshi Oka, Akira Hanaoka, Yoshifumi Koshino (Kanazawa University, Kanazawa, Japan). [email protected]

Background: Photic driving response (PDR) of EEG has been studied in various psychiatric disorders. However, few studies of PDR have focused on panic disorder. Methods: Quantitative EEG analysis for 9–11 Hz band (with correspondence to the stimulus frequency) was performed to investigate EEG differences at rest and during intermittent photic stimulation (PS) in 14 drug-naive panic patients and 14 sex- and age-matched control subjects. After EEG recording at resting condition (10 to 15 minutes), PS was administered to the subject. The PS consisted of white flickers at 10 flashes per second, which were given for the duration of 10 s and repeated six times after intervals of 10 s. The differences of 9–11 Hz band power between two groups were assessed for three conditions (at rest, during PS, and inter-PS). Results: In the control group, 9–11 Hz band power at the occipital region was different between the three conditions. The power during PS was higher than at rest, which was followed by attenuation during inter-PS. In the panic group, however, the differences were not remarkable among the three conditions. Conclusions: The decreased responsiveness of 9–11 Hz band activity in panic patients may reflect diminished flexibility of the central nervous system.

P98. Greater homozygosity on the Huntington's disease gene in persons with tardive dyskinesia Patricia Lowrimore, Yuh-Hwa Wang, Andrew Epstein, David Mulvehill, Michael McCormack (University of Medicine and Dentistry of New Jersey, Piscataway, NJ). [email protected]

Background: Tardive dyskinesia (TD) is a drug-induced syndrome of involuntary movements that has a similar phenotypic presentation to Huntington's disease. HD and other neurological conditions are known to be related to CAG trinucleotide expansions on specific genes. We explore the hypothesis that TD may have its own characteristic CAG distribution on the HD gene. Methods: Of 19 persons with either schizophrenia or schizoaffective disorders, 10 had and 9 did not have TD according to the Abnormal Involuntary Movement Scale. Whole blood from all subjects was examined, using a commercially available gene test for HD. Results: No subjects had HD. Although the two alleles in each group were significantly different from each other, the difference was greater between the two alleles in the control group (P<0.01) than between the two alleles in the TD group (P<0.03). This may be accounted for by a finding of four (40%) homozygous gene samples in the TD group compared with only one (11%) in the control group. The overall variability was greater in the TD group. Conclusions: There is a suggestion of greater homogeneity in samples from the TD group, which may offer weak support of TD as a recessive phenomenon.

P99. Brain activation patterns in frontal and temporal memory circuitry following temporal lobe resection for intractable epilepsy: an fMRI study Brenna C. McDonald, Andrew J. Saykin, Barbara C. Jobst, Peter D. Williamson, David W. Roberts, Vijay M. Thadani, Jennifer D. Schoenfeld, Heather A. Wishart, Laura A. Flashman, Thomas W. McAllister (Departments of Psychiatry, Neurology, and Neurosurgery, Dartmouth Medical School, Hanover, NH). [email protected]

Background: Previous studies have used functional MRI (fMRI) to evaluate language and memory systems in presurgical epilepsy patients. Little research, however, has examined fMRI activation patterns postsurgery. We present fMRI activation patterns during memory processing for 7 epilepsy patients following temporal lobectomy, including 1 subject studied both presurgery and postsurgery. Methods: All participants underwent Wada testing and pre- and postoperative neuropsychological assessment and completed an event-related fMRI protocol including tasks measuring verbal and nonverbal novelty detection and working and episodic memory. fMRI studies were conducted 2–8 years after surgery. Results: Activation patterns in 5 right temporal lobectomy subjects demonstrated bilateral frontal and left mesial temporal activation during recognition of familiar words. In 1 left temporal lobectomy subject, fMRI activation postsurgery as compared with presurgery demonstrated diminished activation in left lateral temporal cortex and bilateral frontal regions. These findings were noted in the context of decreased performance accuracy on working and episodic memory items (but not in novelty detection during fMRI tasks) and decreased verbal memory and naming skills on neuropsychological testing. Conclusions: These data suggest that fMRI is a useful technique for characterizing postoperative changes in memory circuitry, including material-specific changes associated with laterality of seizure foci and resection. Further prospective studies will be important to exploit the potential of fMRI for understanding reorganization of memory processes. Support from the Hitchcock Foundation, the Ira W. Decamp Foundation, and the Epilepsy Foundation.

P100. Beneficial effects of quetiapine treatment in patients with fibromyalgia Mary Shemo, J.P.D. Shemo, M. Anderson (Psychiatric Alliance of the Blue Ridge, Inc., Charlottesville, VA). [email protected]

Background: The objective of this case report review was to determine whether quetiapine had beneficial effects in adult patients with fibromyalgia, which affects 2% to 4% of the U.S. population and is characterized by chronic musculoskeletal pain, severe fatigue, nonrestorative sleep, and mood abnormalities. Methods: Patients included 7 women with a mean age of 45 years (range 39–57 years) who had been diagnosed with fibromyalgia and psychiatric disorders. Various medication regimens had been tried in these patients, but disabling symptoms, with a core element of insomnia, remained. Results: Improvement was noted in all 7 patients when low-dose quetiapine (range 25–200 mg/day) was added to their treatment regimens. In these patients, quetiapine decreased mood fluctuations, decreased pain symptoms, and improved the quality of sleep. No adverse effects of quetiapine were reported by any of the patients. Conclusions: Quetiapine was effective in reducing the disabling symptoms in these patients with fibromyalgia in which there was a core element of insomnia. Controlled trials should be conducted to confirm these results.

P101. Reversal of the ERP old/new effect during word recognition in a patient with amnesia Mark I. Boulos, Konstantine K. Zakzanis*, Alvin A. Ashamalla (Faculty of Medicine and Division of Life Sciences, University of Toronto, Toronto, ON, Canada). [email protected]

Background: The effects of time delay (between study and test) and brain damage on the event-related potentials (ERPs) elicited during word recognition were examined. Previous research has shown that on frontal recording sites, the correct recognition of old words is typically associated with two topographically distinct ERP old/new effects: an early, bilateral effect and a late, right-sided effect. Methods: 26 students were taught a list of words and returned 1, 2, or 3 weeks later to perform a recognition task. A patient who had frontal and hippocampal lesions was tested during a single session and had a 20-minute delay between study and recognition trial. During all recognition tasks, right prefrontal activity was measured by EEG. Results and Conclusions: Analysis of the ERPs in all the healthy participants revealed an old/new effect, which did not diminish with increasing retention intervals. The subjects tested after a 1-week delay elicited the greatest early, bilateral frontal activity. The subjects with 2- and 3-week delays elicited the greatest late, right frontal activity. These results support the view that the early effect is familiarity-driven, whereas the late effect functions to monitor retrieval. In the patient, however, the correctly classified new words, relative to the correctly classified old words, elicited the two positive-going deflections. To our knowledge, this is the first report of a reversal in the electrophysiology of the old/new effect. This effect can be thought of as a new/old effect and may be a marker for certain brain injuries.