1. BRAIN IMAGING - PERSPECTIVES FOR STUDIES OF PSYCHIATRIC DISORDERS Jair C. Soares, M.D. Division of Mood and Anxiety Disorders, Dept of Psychiatry, University of Texas Health Sciences Center in San Antonio

2. INTRODUCTION u Major psychiatric disorders - causation still largely unknown u Mechanisms involved currently being investigated u Improved methodologies available u Brain diseases?

3. INTRODUCTION u For many years - no direct access to study the brains of living human subjects u Peripheral blood cell and platelet models, CSF studies, post-mortem samples - very considerable limitations u Lack of satisfactory animal models for psychiatric conditions u Methodological difficulties prevented further advance of this field

4. BRAIN IMAGING METHODS u Brain imaging - potential for studies of pathophysiology of psychiatric disorders u Anatomical and functional investigations –MRI –fMRI, PET u Methods for in vivo neurochemical brain studies –Magnetic resonance spectroscopy (MRS) –Radiotracer imaging - receptors, neurotransmitters

6. INTRODUCTION u Our work: brain imaging investigations in mood disorders - focus on bipolar disorder u Are there detectable anatomical or functional brain abnormalities in bipolar or unipolar patients? u How do such abnormalities related to symptoms, illness course, or treatment response? u Any evidence that those are brain diseases?

7. Brain Circuits - Mood Regulation (Sheline, 2000)

8. MRI - MORPHOMETRIC STUDIES u Subtle anatomical abnormalities - brain regions involved in mood regulation u BP disorder: –prefrontal regions - subgenual, DLPFC –medial temporal lobe - amygdala, hippocampus –thalamus –striatum –cerebellum - vermis –enlarged lateral and 3rd ventricles, cortical atrophy?

9. MRI - MORPHOMETRIC STUDIES

11. HYPERINTENSE LESIONS u Non-specific abnormalities - likely to reflect increased water density, due to minor cerebrovascular damage u Late life depression - increased rates of WMH u may disrupt brain pathways interconnecting regions involved in mood regulation

12. HYPERINTENSE LESION (T2-weighted MRI)

13. FUNCTIONAL STUDIES u largely PET, more recently fMRI studies u main areas of abnormalities: prefrontal cortex - Broadman areas 24 or 25, amygdala (Mayberg et al, Drevets et al) u some conflicting findings, time-course of changes not well characterized

14. Brain Activation in Depression (Drevets, 2000)

15. Brain Activation and Fluoxetine Response (Mayberg et al, 2000)

16. IN VIVO NEUROCHEMICAL BRAIN STUDIES u Recent advances in methods for in vivo neurochemical brain studies –Magnetic resonance spectroscopy (MRS) –SPECT AND PET receptor imaging –PET and fMRI - pharmacological paradigms

17. DLPFC 1 H MRS SPECTRA AT 1.5T - 8CC VOXELS

18. 1 H MRS STUDIES u N-Acetyl Aspartate (NAA) - marker of neuronal viability/function - decreased with various neuronal insults u In bipolar patients: –Reduced NAA levels in DLPC (Winsberg et al, 2000) –Reduced levels in DLPC, and increased in thalamus (Deicken et al, 2000) –No changes in lenticulate nuclei (Ohara et al, 1998) –No changes in anterior cingulate (Soares et al, 1999), and R or L frontal lobe (Hamawaka et al, 1999)

19. Cortical GABA Concentrations in Healthy and Depressed Subjects Sanacora et al. Arch Gen Psychiatry. 1999;56:1043-1047. Cortical GABA mmole s’Kg Brain 1.0 2.0 3.0 0.0 Healthy Males Depressed Males 1.5 2.5 0.5 Healthy Females Depressed Females 1.0 2.0 3.0 0.0 1.5 2.5 0.5

20. RADIOTRACER RECEPTOR STUDIES u New radiotracers for in vivo brain imaging –SPECT: 123 I –PET: 18 F, 11 C u Allow quantitative image studies of receptor systems, or studies of neurotransmitter release

21. [18F]-DEUTEROALTANSERIN

22. 5HT2A STUDIES IN MOOD DISORDERS u decreased 5HT2A receptor binding in frontal regions in depressed UPs - in most studies no abnormalities u may go down with antidepressant treatment u generally small samples u BP patients not examined

23. PET - [11C]-raclopride (Farde et al.)

24. CONCLUSIONS - MOOD DISORDERS u Subtle anatomical, functional, and neurochemical abnormalities in key brain regions involved in mood regulation u Degenerative changes, or developmental abnormalities? u Reflection of vulnerability conferred by specific genes? u How does it interact with stress and environmental factors?

25. Structural abnormalities in schizophrenia - Ventriculomegaly ( lateral and third ventricles) - Diffuse gray matter loss - Decreased Volume in frontal & temporal cortex - Possible thalamic volume reductions - Reduced Corpus callosal size Keshavan et al.

26. Healthy Controls Schizophrenia Patients ShortLong -0.1 -0.05 0 0.05 0.1 0.15 Delay Dorsolateral PFC Left BA 46/9 ShortLong 0 0.05 0.1 0.15 0.2 Delay Left BA 44 ShortLong 0 0.05 0.1 0.15 0.2 Delay Right BA 44 Barch, Carter, MacDonald, Noll and Cohen Archives of General Psychiatry 2000

27. CONCLUSIONS u Brain imaging: likely to result in substantial advances to understanding of pathophysiology of psychiatric disorders u Strategies that will involve longitudinal studies of first- episode patients and high-risk subjects likely to be of particular benefit

28. ACKNOWLEDGEMENTS u MH 01736, MH 29618, MH 30915 - NIMH u Theodore and Vada Stanley Foundation u National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD)