Biopsychology

Gerard Bruder, Ph.D. Chief of Psychiatric Research
W. Crawford Clark, Ph.D., Research Scientist VI
Steven Fairhurst, M.A., Research Scientist III
Jürgen Kayser, Ph.D., Research Scientist IV
John Kuhl, Ph.D., Research Scientist III
M. Mila Macchi, Ph.D., Research Scientist III
Chara Malapani, M.D., Ph.D., Research Scientist V
Brian Rakitin, Ph.D., Associate Research Scientist
Craig Tenke, Ph.D., Research Scientist IV
Jiuan Su Terman, Ph.D., Research Scientist IV
Michael Terman, Ph.D., Research Scientist VI
James Towey, Ph.D., Research Scientist IV

OVERVIEW
Using behavioral, cognitive, and physiological techniques, the Biopsychology Department investigates brain-behavior relationships and the neurobiological and cognitive mechanisms underlying neuropsychiatric disorders. Research involves basic and preclinical studies, development and application of laboratory-based assessment, and clinical trials. The department comprises four units - Psychophysiology, Clinical Chronobiology, Temporal Cognition, and Somatosensory and Pain, as well as a training component focusing on under-represented minorities.

CURRENT RESEARCH
Psychophysiology Laboratory Drs. Gerard Bruder, Craig Tenke and Jurgen Kayser, in collaboration with the Depression Evaluation Service, continued their NIMH-funded studies of right-left brain asymmetries in depressive disorders. Using both electrophysiologic measures and neurocognitive tests, they have found that abnormalities of regional brain asymmetry in depressive disorders are related to important clinical features, in particular diagnosis subtype and clinical responsiveness to treatments for depression. During the past year, they submitted for publication the findings of two studies, which confirm that patients who respond favorably to an SSRI antidepressant (Prozac) differ from non-responders and healthy controls on dichotic listening tests of functional brain asymmetry. These findings suggest the potential clinical value of dichotic listening tests for predicting therapeutic responsiveness to an SSRI. In collaboration with the Anxiety Disorders Clinic, they reported in the American Journal of Psychiatry evidence of left hemisphere dysfunction during verbal dichotic listening tests in patients having social phobia with or without a comorbid depressive disorder. Drs. Bruder, Kayser and Tenke also continued their NIMH-funded studies of brain event-related potentials and cognitive function in schizophrenia, in collaboration with members of the Schizophrenia Research Unit and the Lieber Center. In a recent article, they reported evidence of a selective deficit in verbal working memory in a subgroup of schizophrenia. These patients had difficulty remembering the position of words in a series, but performed as well as healthy adults on nonverbal tests. A different subgroup of patients with schizophrenia performed poorly on both verbal and nonverbal memory tests, which is more consistent with a generalized cognitive deficit. These findings have important implications for addressing the clinical heterogeneity of schizophrenia, which has been a major obstacle to understanding the pathophysiology of this disorder. Testing of a large sample of over 400 healthy adults was completed in a study of the genetics of working memory, which is being conducted in collaboration with the Columbia Genome Center. In addition to their electrocortical studies in patients, Drs. Tenke and Kayser advanced the development of sophisticated methods for processing and analyzing electrophysiologic data, work that is broadly acknowledged by the international research community.

Clinical Chronobiology Unit Drs. Michael Terman and Jiuan Su-Terman completed six years of an NIMH-supported clinical trial for patients with seasonal affective disorder (SAD). Three distinct treatments were compared: post-awakening bright light therapy, dawn simulation, and high-intensity negative air ionization (the latter two administered during sleep). All three treatments showed significant benefit relative to a low-density negative ion placebo control. In a separate placebo-controlled trial of light and ion therapies for nonseasonal chronic depression, response and remission rates were similar to those seen for SAD, a result that may greatly extend the application of these nonpharmaceutical interventions. A multicenter trial of light therapy for antepartum depression (NYSPI, Pittsburgh, Yale), published in American Journal of Psychiatry, likewise indicated efficacy for patients without a seasonal pattern.

Drs. Terman and Dr. Gregory Sullivan of the Department of Neuroscience participated in a multicenter study of extended release bupropion for SAD, using a novel prophylactic protocol with treatment begun in fall before expected recurrence of the major depressive episode, and terminated in spring.

In collaboration with Dr. Jeffrey Bruce of Neurological Institute, Dr. Mariana Macchi has begun a polysomnographic analysis for brain surgery patients with pineal gland resection for removal of tumors or cysts. Lack of the pineal gland prevents synthesis of melatonin, a hormone secreted during nocturnal sleep. Preliminary results suggest potentiated rapid eye movement sleep after pinealectomy, while other sleep parameters appear normal. In an earlier survey study, the investigators found high rates of self-reported insomnia and depression in this group.

In collaboration with Dr. Thomas White of NYS Office of Mental Health, Dr. Terman posted an on-line version of his Personalized Inventory for Depression and SAD (www.cet.org), which identifies probable cases, with referral to treatment. More than 1000 people responded with a strong latitude cline (proportion of seasonal cases relative to total cases) spanning North America and peaking at 45 deg N and higher in Canada, where winter nights are longest. Respondents with blue or gray eyes were significantly less affected by seasonal variation than those with darker iris pigmentation, which can be attributed to greater wintertime photon transmission to the retina.

Dr. Terman and Dr. Namni Goel, a former Psychobiology fellow now at Wesleyan University, were guest editors of a special “virtual meeting” issue of Chronobiology International, which published peer-reviewed proceedings of the Society for Light Treatment and Biological Rhythms in lieu of the society’s 15th annual meeting, which had to be canceled in Toronto at the time of the SARS scare.

Somatosensory and Pain Laboratory Dr. Clark directs this laboratory and continues to study the dimensions underlying painful and non-painful and emotional experiences. In a study funded by the National Institute of Dental and Craniofacial Research, Drs. Clark and Kuhl have employed the statistical or medical decision theory model to quantify gender, ethnocultural and menstrual cycle differences in (a) the ability to discriminate among low and noxious intensities of calibrated heat and cold stimuli, and (b) the subject’s pain report bias, which quantitates the location of the decision criterion for reporting pain (e.g., degree of stoicism). They have demonstrated that differences in pain thresholds frequently reported when using the traditional method of serial exploration or limits are not due to large differences in neurosensory sensitivity but are mostly caused by nonsensory psychosocial and attitudinal factors that influence pain report bias. The Wharton Fund for Research in Brain, Body and Behavior supported a factor analysis study (conducted with Drs. M.L. Keohan, CPMC, Department of Medicine and H. Knotkova, a Fullbright Scholar from the Czech Republic) of responses to the Multidimensional Affect and Pain Survey (MAPS) by cancer patients. All the MAPS factors were found to be homogeneous, making it superior to the widely used McGill Pain Questionnaire. The McGill factors are more difficult to interpret because they frequently are a heterogeneous mixture of the sensory and emotional dimensions of pain. The Fund also supported a cross-cultural study conducted by M. Hobara, which found both gender and nationality differences between Japanese and American attitudes towards the public expressions of pain. Item-analysis was used to construct a 30 item Short MAPS (SMAPS), which is being studied with Drs. N. Sonty, Department of Anesthesiology, CPMC and S. Chokhavatia, Department of Medicine, New Jersey School of Medicine and Dentistry. The 101 item MAPS has been translated into the Japanese, Polish and Slovak languages and studies with investigators in these countries are underway. A USA copyright has been received for the MAPS pain questionnaire. Dr. Clark with Drs. J.P. Mohr (Neurology), R.N. Wharton (Psychiatry) and S. Bennett Clark (Biopsychology), continue a study of sensory measures that predict the occurrence of post-stroke central pain and depression, and the relation of this to the effect of treatment with the antidepressant Sertraline.

Temporal Cognition Unit Dr. Chara Malapani directs this unit, which she had previously co-directed with its founder, the late Dr. John Gibbon. Dr. Malapani and her staff continue their federally funded studies of functional and neural mechanisms of time perception and temporal memory in humans as well as animals. Their human research focuses upon abnormalities of the time sense in patients with degenerative diseases, especially of the basal ganglia, e.g., Parkinson’s disease (PD) and Huntington’s disease (HD). This research employs Scalar Expectancy Theory, first developed by Dr. Gibbon in his animal research. The ongoing animal research continues to focus on clarifying further the mechanisms whereby the time sense indexes the passage of time and records relevant time intervals in memory that are subsequently retrieved for a timed decision.

Dr. Malapani added new lines of animal research, including drug studies with pigeons and rats, in collaboration with Dr. Peter Balsam of Columbia University, to help clarify the role of dopaminergic systems in animal and human timing behavior. This new direction of animal research remains closely linked with their human research. It aims to develop and implement animal models of human diseases (i.e., PD, HD and Schizophrenia) known to involve specific brain areas (the basal ganglia - cortical frontal loops) and central dopaminergic systems. Last year, NIMH awarded a new RO1 grant to Drs. Balsam and Malapani, the broad aim of which is to understand temporal information processing and its involvement in learning, memory and performance. In the course of developing new techniques for studying appetitive associative learning and timing in mice, they are discovering that temporal factors affect the expression of learning rather than learning itself. This year, NIDA awarded a new 3-year grant to Dr Balsam to study the pharmacological and neural basis of learning about time.

In the last two years, Prof. Randy Gallistel (Rutgers University) joined an effort initiated by Drs. Malapani and Balsam to develop quantitative learning models. This resulted in a “Proceedings of the National Academy of Sciences” publication. Comparative research from different animal species - rodents (mice and rats) and pigeons – has been involved in this collaborative effort and is currently being pursued by developing the behavioral assessment tools of the lab to include transgenic mice (dopamine transporter knock-downs, dopamine D2-receptor knock-outs). Dr. Daniela Bruner, who is highly experienced in this area, is now a part time Research Scientist in the Temporal Cognition Laboratory.

Dr. Michael Drew, a new post-doctoral fellow in the Laboratory, sponsored by Dr. Malapani and co-sponsored by Dr. Rene Hen (Center of Neurobiology and Behavior at Columbia University), is exploring the functional significance of neurogenesis in the adult mouse brain, notably in specific areas of the hippocampus. The project asks whether neurogenesis inhibition (using radiation techniques developed in Dr. Hen’s laboratory) blocks the effect of environmental enrichment on different learning strategies. Through this project, a new collaboration has been developed between the Temporal Cognition Laboratory and the Rodent Models Laboratory directed by Dr. Holly Moore. Drs. Malapani, Balsam, Moore and Bruner are now jointly working to obtain new funding that would support a collaborative research project with DA transgenic mice using behavioral and neurophysiologic techniques developed in the two units.

In recent years, Dr. Malapani and her staff also added new lines of human research aimed at isolating the neural substrates underlying the storage and/or retrieval process of temporal memory. Using deep brain stimulation with PD patients, for example, they demonstrated that the subthalamic nucleus, in the indirect pathway from striatum to the frontal cortex, is specifically involved in the retrieval process. The retrieval distortion associated with PD led to a new line of experiments exploring the role of distinct kinds of feedback in correcting those deficits. This research has also led to a new study that looks at the effects of dopaminergic drugs on timing distortions seen with aging, (in collaboration with Drs. Yaakov Stern and Brian Rakitin, Sergievsky Center, Department of Neurology and Cognitive Neuroscience). Using the same timing tasks with young children, college students and healthy seniors, Drs. Malapani and James Towey have begun to study how the neurobiology of temporal learning and memory changes across the lifespan, in collaboration with Drs. Warren Meck (Duke University) and Claudette Fortin (Laval University, Canada). Dr. Towey has been also involved in a collaborative fMRI project, currently under-development between the laboratory and the Sergievsky Center, aimed at imaging interval timing in young individuals and characterizing changes in brain activity of elderly subjects performing the same timing tasks.

Finally, Dr. Malapani pursued a fruitful collaboration with Prof. John Rinzel (Director of the Computational Neuroscience Department at New York University). This project involves modeling the separable encoding and retrieval distortions in PD with the implementation of Gibbon’s model of temporal psychophysics. Dr. Malapani and Dr. Rinzel co-sponsored the successful application of a prominent fellow, Dr. Eric Brown, for a NSF Mathematical Sciences Postdoctoral Fellowship. Dr. Brown is working on modeling DA-dependent encoding and decoding effects. Deepening our understanding of the neurobiology of learning and memory for time across animal species including humans should provide new insights into the diagnosis, prognosis and treatment of psychiatric and neurological diseases.

EDUCATION AND TRAINING
received training in conducting electrophysiologic and behavioral research. Dr. Towey received continuing support for an NIMH Career Opportunities in Research (COR) training program to help increase the number of undergraduates from ethnic minority groups who gain entry to graduate school to pursue careers in mental health. Dr. Clark gives lectures to graduate students at City College, CUNY, and mentors a Fullbright Scholar and two students from Teacher’s College. He served on the dissertation committee for G. Griswold who received her Ph.D. from the Sackler Institute, Albert Einstein College of Medicine, Yeshiva University. He also served as a visiting external examiner for a Ph.D. dissertation in the Department of Nursing, Polytechnic University, Hong Kong.

CLINICAL SERVICES
The Psychophysiology Laboratory provides the clinical EEG recordings for the Institute.

GRANTS
Dr. Bruder received a 5-year NIMH grant to use event-related brain potentials to study working memory and recognition memory deficits in subtypes of schizophrenia having different cognitive deficits.

As part of a multicenter study, Dr. Terman received a contract from GlaxoSmithKline for a “Controlled Trial of Bupropion Extended-Release for Prophylactic Treatment of the Winter Depressive Episode in Seasonal Affective Disorder”.

Drs. Peter Balsam and Chara Malapani received a 5-year NIMH grant whose aim is to understand temporal information processing and its involvement in learning, memory and performance.

Dr. Macchi received a Clinical Trials Pilot Award from Columbia University, entitled "In Vivo Pharmacokinetics of Melatonin Supplement for Primary Insomnia."

BIBLIOGRAPHY
Bruder GE, Wexler BE, Sage MM, Gil RB, Gorman JM: Verbal memory in schizophrenia: additional evidence of subtypes having different cognitive deficits. Schizophrenia Research 68:37-147, 2004.

Bruder GE, Schneier FR, Stewart JW, McGrath PJ, Quitkin F. Left hemisphere dysfunction during verbal dichotic listening test in patients who have social phobias with or without comorbid depressive disorder. American Journal of Psychiatry 161:72-78, 2004.

Clark WC, Kuhl JP, Keohan ML, Knotkova H, Winer RT, Griswold G: Factor analysis validates the cluster structure of the dendrogram underlying the Multidimensional Affect and Pain Survey (MAPS) and challenges the a priori classification of the descriptors in the McGill Pain Questionnaire (MPQ). Pain 106:357-363, 2003.

Clark WC: Review of: Anxiety, Depression and Anger in Pain by E. Fernandez. American Pain Society Bulletin 13:15, 2003.

Clark WC: Pain, Emotion and Drug Induced Subjective States: Applications of Multivariate Scaling. In: G Adelman and B Smith (eds.), Encyclopedia of Neuroscience (3rd edition), Elsevier, Amsterdam, 2003. (Available on CD-Rom.)

Clark WC: Somatosensory and Pain Measurement by Statistical and Sensory Decision Theory. In: G Adelman and B Smith (eds.), Encyclopedia of Neuroscience (3rd edition), Elsevier, Amsterdam, 2003. (Available on CD-Rom.)

Drew M, Yang C, Balsam PD: Temporal specificity of extinction in autoshaping. Journal of Experimental Psychology. Animal Behavior Processes, 30:163-176, 2004.

Epperson CN, Terman M, Terman JS, Hanusa BH, Oren DA, Peindl KS, Wisner KL: Randomized clinical trial of bright light therapy for antepartum depression: preliminary findings. Journal of Clinical Psychiatry, 65:421-425, 2004.

Gallistel CR, Fairhurst S, Balsam PD: The learning curve: Implication of a quantitative analysis. Proceedings of the National Academy of Sciences, 101:13124-13131, 2004.

Goel N, Terman JS, Macchi MM, Stewart JW, Terman M: A placebo-controlled trial of light and negative ion treatment for chronic depression: preliminary results. Chronobiology International, 20:1207-1209, 2003.

Goel N, Terman M, Terman JS: Dimensions of temperament and bright light response in seasonal affective disorder. Psychiatry Research, 119:89-97, 2003.

Hobara M, Fujiwara H, Clark WC, Wharton RN: A translation of Multidimensional Affect and Pain Survey (MAPS) from English to Japanese. Japanese Journal of Cancer and Chemotherapy 30:721-729, 2003.

Kayser J, Tenke CE: Optimizing PCA methodology for ERP component identification and measurement: Theoretical rationale and empirical evaluation. Clinical Neurophysiology 114:2307-2325, 2003.

Kayser J, Tenke CE, Bruder GE: Evaluating the quality of ERP measures across recording systems: a commentary on Debener et al. (2002). International Journal of Psychophysiology 48:315, 2003.

Meck HW, Malapani C: The neuroimaging of interval timing. Cognitive Brain Research 21:133-137, 2004.

Seidman LJ, Bruder GE: Neuropsychological testing and neurophysiological assessment. In A. Tasman, J. Kay, J. Leiberman (eds.), Psychiatry, 2nd Edition, John Wiley & Sons, London, 2003.

Stewart JW, Bruder GE, McGrath PJ, Quitkin FM: Do age of onset and course of illness define biologically distinct groups within atypical depression? Journal of Abnormal Psychology 12:253-262, 2003.

Terman, M: The dangers posed by tanning [letter]. New York Times, April 6, Section 14LI, p. 21, 2003.

Terman M, Macchi MM, Goel N, Rifkin JB, Terman JS, Williams JBW: Diagnostic reliability and symptom pattern of DSM-IV atypical features in seasonal and nonseasonal depression. Chronobiology International, 20:1157-1159, 2003.

Weissman MM, Warner VP, Wickramaratne P, Nomura Y, Merikangas K, Bruder GE, Tenke C, Grillon C: Offspring at high risk for anxiety and depression: Preliminary findings from a three generation study. In J.M. Gorman (Ed.), Fear and Anxiety: The Benefits of Tranlsational Research, American Psychiatric Press, Washington, 2004.

White TM, Terman M. Effect of iris pigmentation and latitude on chronotype and sleep timing. Chronobiology International, 20:1193-1195, 2003.

Williams JBW, Terman M: Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS). New York, New York State Psychiatric Institute, 2003.

Wirz-Justice A, Terman M, Oren DA, Goodwin FK, Kripke DF, Whybrow PC, Wisner KL, Wu JC, Lam RW, Berger M, Danilenko KV, Kasper K, Smeraldi E, Takahashi K, Thompson C, van den Hoofdakker RH: Brightening depression [letter]. Science 303-467-469, 2004.