1) Neuroimaging studies of schizophrenia have found reductions in gray matter volume in brain regions like the left superior temporal gyrus, hippocampus, and amygdala. 2) White matter abnormalities have also been found in fiber tracts like the corpus callosum, uncinate fasciculus, and inferior fronto-occipital fasciculus in patients with schizophrenia. 3) Studies of first-episode patients suggest these changes may occur within the first year of illness, especially in auditory processing regions of the superior temporal gyrus.

1. Neuroimaging and Mental Illness Brian Wells, MS3, MSM, MPH

2. Why neuroimaging? The research agenda for DSM-V emphasizes a need to translatebasic and clinical neuroscience research findings into a newclassification system for all psychiatric disorders based uponpathophysiologic and etiological processes Etiologic and pathophysiologically-based diagnostic system v. symptomatologic and syndromic approach of DSM-III and DSM-IV Philips, ML. The Emerging Role of Neuroimaging in Psychiatry: Characterizing Treatment-Relevant Endophenotypes Am J Psychiatry 164:697-699, May 2007

3. Why neuroimaging? Although structural imaging techniques are most useful for ruling out medical etiologies of mental status disturbances, functional neuroimaging techniques currently have an adjunctive role in the evaluation of dementia and seizure disorders and show promise for the evaluation of primary psychiatric disorders in the future. Rauch SL, Renshaw PF. Clinical neuroimaging in psychiatry. HarvRev Psychiatry. 1995 Mar-Apr;2(6):297-312.

5. Culpepper L et al. Are antipsychotics overprescribed? http://www.medscape.com/viewarticle/737587?src=mp&spon=17

7. Neuroimaging Modalities CT MRI PET SPECT fMRI MRS *schizophrenics show over-activation of the cingulate gyrus, while controls seem to activate prefrontal cortex more than schizophrenics. Rauch SL, Renshaw PF. Clinical neuroimaging in psychiatry. HarvRev Psychiatry. 1995 Mar-Apr;2(6):297-312.

8. http://pnl.bwh.harvard.edu/index.html

9. Research Areas Schizotypal personality disorder Schizophrenia PTSD Bipolar disorder Multiple others

10. Schizotypal Personality Disorder Cluster A: Odd/Eccentric Cluster A patients tend to be detached and distrustful SPD involves social withdrawal and emotional coldness but also includes oddities of thinking, perception, and communication, such as magical thinking, clairvoyance, ideas of reference, or paranoid ideation. These oddities suggest schizophrenia but are never severe enough to meet its criteria. People with schizotypal personality are believed to have a muted expression of the genes that cause schizophrenia. http://www.merckmanuals.com/professional/sec15/ch201/ch201a.html?qt=schizotypal&alt=sh

11. Schizotypal personality disorder STG is involved in the perception of emotions in facial stimuli Contains Brodmann areas 41, 42 (primary auditory) and 22p (Wernicke’s) Reduction of left STG gray matter volume in SPD subjects when compared to normal controls. Comparisons with chronic schizophrenics previously studied showed the SPD group had a similarity of left STG gray matter volume reduction, but fewer medial temporal lobe abnormalities. This finding supports the hypothesis of the importance of STG involvement in the schizophrenia spectrum disorders. Possible that presence of medial temporal lobe abnormalities may help to differentiate who will develop schizophrenia and who will develop SPD 3D reconstruction of the cortex and superior temporal gyrus, shown in red. Chandlee, CD et al. Schizotypal Personality Disorder and MRI Abnormalities of Temporal Lobe Gray Matter. Biol Psychiatry 1999;45:1393–1402

12. Imaging Summary SPD - Reduction of left STG gray matter volume; fewer medial temporal lobe abnormalities

13. Schizophrenia A recent World Health Organization (WHO) report estimates that nearly 1% of the population in the US is affected by schizophrenia. A growing body of evidence suggests that early detection and treatment of schizophrenia (and many other brain disorders) is critical in forming and predicting the course and outcome of the disorder. McGlashan, T.: Early detection and intervention in schizophrenia: editors introduction. Schizophr Bull 22(2), 197–199 (1996)

14. Schizophrenia Schizophrenia is characterized by psychosis (loss of contact with reality), hallucinations (false perceptions), delusions (false beliefs), disorganized speech and behavior, flattened affect (restricted range of emotions), cognitive deficits (impaired reasoning and problem solving), and occupational and social dysfunction. Although its specific cause is unknown, schizophrenia has a biologic basis, as evidenced by alterations in brain structure (eg, enlarged cerebral ventricles, decreased size of the anterior hippocampus and other brain regions) and by changes in neurotransmitters, especially altered activity of dopamine and glutamate. 5 Subtypes: Paranoid, Catatonic, Disorganized, Residual, Undifferentiated

15. Schizophrenia No definitive test for schizophrenia exists Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR), the diagnosis requires both of the following: ≥ 2 characteristic symptoms (delusions, hallucinations, disorganized speech, disorganized behavior, negative symptoms) for a significant portion of a 1-mo period Prodromal or attenuated signs of illness with social, occupational, or self-care impairments evident for a 6-mo period that includes 1 mo of active symptoms Treatment is with antipsychotic drugs, psychotherapy and rehabilitation/community support http://www.merckmanuals.com/professional/sec15/ch202/ch202e.html

16. Schizophrenia MRI has been useful in revealing subtle structural brain abnormalities in schizophrenia patients, including ventricular enlargement, volume reduction in the frontal and parietal lobes, and gray matter reduction of medial temporal lobe structures It is unknown whether the brain abnormalities observed with MRI in schizophrenia are confounded by chronicity or whether there is a continual degenerative process. Chronic schizophrenia patients may demonstrate pathology secondary to chronic neuroleptic medication and long-term institutionalization. Heschl'sgyrus and planumtemporale regions drawn on a coronal MR slice (left), and a 3D rendering shown overlayedon an axial MR slice. Shenton, ME et al. A review of MRI findings in schizophrenia Schizophrenia Research 49 (2001) 1-52.

17. Schizophrenia Heschl’sgyrus (AKA transverse temporal gyrus) Found in primary auditory cortex - Brodmann 41, 42 First cortical structure to process incoming auditory information Active during auditory processing under fMRI for tone and semantic tasks. Planumtemporale Posterior to Heschl’sgyrus within Sylvian fissure Most asymmetrical of all brain structures Significant L/R asymmetry is normal 5x larger on left in some individuals Evolutionary ancestral origins shown in primates Functions in sound location, language, music Heschl'sgyrus and planumtemporale regions drawn on a coronal MR slice (left), and a 3D rendering shown overlayedon an axial MR slice.

18. Schizophrenia Inferior fronto-occipital fasciculus The ability to suppress one's impulses and actions constitutes a fundamental mechanism of cognitive control, thought to be subserved by the right inferior frontal cortex (rIFC) Uncinate fasciculus Function unknown but traditionally assigned to the limbic system links the forward portions of the temporal lobe with the inferior frontal gyrus and the lower surfaces of the frontal lobe Tract integrity measured by fractional ansiotropy; higher values mean diffusion occurs along one axis FOF displayed in green Forstmann, BU et al. Function and Structure of the Right Inferior Frontal Cortex Predict Individual Differences in Response Inhibition: A Model-Based Approach. The Journal of Neuroscience, 24 September 2008, 28(39): 9790-9796; doi: 10.1523/​

19. Schizophrenia Examining first episode patients can thus obviate chronicity-related confounders. Findings suggest that within the first year changes are observed in the superior temporal gyrus region of the temporal lobe, including Heschl'sgyrus and planumtemporale, brain regions important in primary and secondary auditory processing. Data suggests that first-episode schizophrenia might also be associated with disruptions in extensive portions of white matter fiber tracts, especially in the corpus callosum, uncinate fasciculus, inferior fronto-occipital fasciculus and internal capsule, and that negative symptoms are associated with white matter abnormalities related to the right inferior fronto-occipital fasciculus. Heschl'sgyrus and planumtemporale regions drawn on a coronal MR slice (left), and a 3D rendering shown overlayedon an axial MR slice. LaVenture A et al. Abnormalities in White Matter Integrity in First Episode Schizophrenia Using Atlas-Based Segmentation. Mysell Harvard Research Day, Psychiatry Annual Meeting 2010

20. Schizophrenia Left-lateralized reductions in gray matter volume in anterior hippocampus / amygdala, parahippocampalgyrus, and superior temporal gyrus Hallmark clinical symptom of thought disorder is associated with a specific reduction in the volume of left posterior superior temporal gyrus gray matter, which encompasses primary auditory cortex and association cortex, including planumtemporale (neuroanatomical substrates of language) Coronal MR scans from a chronic schizophrenic (right) and normal comparison subject (left). Note increase in CSF in left amygdala-hippocampal complex.

21. Coronal MR scans from a chronic schizophrenic (right) and normal comparison subject (left). Note increase in CSF in left amygdala-hippocampal complex(smaller amygdala on left)

22. Imaging Summary SPD - Reduction of left STG gray matter volume; fewer medial temporal lobe abnormalities Schizophrenia - first year changes are observed in the superior temporal gyrus region of the temporal lobe, including Heschl'sgyrus and planumtemporale Schizophrenia – chronic changes - left-lateralized reductions in gray matter volume in anterior hippocampus / amygdala, parahippocampalgyrus, and superior temporal gyrus

23. Posttraumatic stress disorder Posttraumatic stress disorder (PTSD) causes recurring, intrusive recollections of an overwhelming traumatic incident that persist > 1 mo, as well as emotional numbing and hyperarousal. Traumatic events commonly associated with these disorders include assaults, sexual assaults, car accidents, dog attacks, and injuries (especially burns). In young children, domestic violence is the most common cause of PTSD. Treatment is with behavioral therapy, SSRIs, and antiadrenergic drugs. SSRIs often help reduce emotional numbing and reexperiencing of symptoms but are less effective for hyperarousal. Antiadrenergic drugs (clonidine, prazosine) may help relieve hyperarousal symptoms, but supportive data are preliminary.

24. Posttraumatic stress disorder Studies in PTSD Vietnam combat veterans revealed: Reduced left and right hippocampal volume Volume reductions were associated with severity of combat exposure, suggesting that the severe stress of military combat both damages the hippocampus A similar study was undertaken with Gulf war veterans in Israel, and these data are have shown similar findings Hippocampus (green), Fornix (blue) and Mammilary Bodies (gray) are shown in 3D. Boone, Omar et al. Longitudinal MRI Study of Hippocampal Volume in Trauma Survivors With PTSD. Am J Psychiatry 2001; 158:1248–1251

25. Posttraumatic stress disorder Smaller hippocampal volume is not a necessary risk factor for developing PTSD and does not occur within 6 months of expressing the disorder This brain abnormality might occur in individuals with chronic or complicated PTSD. Boone, Omar et al. Longitudinal MRI Study of Hippocampal Volume in Trauma Survivors With PTSD. Am J Psychiatry 2001; 158:1248–1251

26. Posttraumatic stress disorder A study reported in Nature-Neuroscience evaluated MR brain morphometry of the hippocampus in monozygotic twins discordant for PTSD. The PTSD twin was diagnosed with PTSD as a result of combat exposure in the Vietnam War. The twin aspect of this study was important as it showed that individuals discordant for PTSD showed reduced hippocampal volume compared with twins where PTSD was present in neither twin. This finding suggests that there may be a predisposition or vulnerability factor involved in the genesis of PTSD Gilberson, MW et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nature-Neuroscience, October 2002

27. Imaging Summary SPD - Reduction of left STG gray matter volume; fewer medial temporal lobe abnormalities Schizophrenia - first year changes are observed in the superior temporal gyrus region of the temporal lobe, including Heschl'sgyrus and planumtemporale Schizophrenia – chronic changes - left-lateralized reductions in gray matter volume in anterior hippocampus / amygdala, parahippocampalgyrus, and superior temporal gyrus PTSD – reduced hippocampal volume past 6 months

28. Bipolar Disorder Bipolar I disorder (BPI) affects at least 1% of the population, is associated with increased mortality, and is among the top 10 most disabling illnesses worldwide. Bipolar disorders usually begin in the teens, 20s, or 30s. When one takes into account those with bipolar II and subthreshold bipolar disorder capturing those with briefer or only treatment-emergent hypomania, lifetime prevalence rates approach 5%. Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2007;64:543–552.

29. Bipolar disorder Diagnosis is based on identification of symptoms of mania or hypomania plus a history of remission and relapse Thyroxine (T4) and thyroid-stimulating hormone levels to exclude hyperthyroidism Exclusion of stimulant drug abuse clinically or by urine testing

30. Bipolar disorder Bipolar disorders are classified as Bipolar I disorder: Defined by the presence of at least one full-fledged (ie, disrupting normal social and occupational function) manic or mixed episode and usually depressive episodes Bipolar II disorder: Defined by the presence of major depressive episodes with at least one hypomanic episode but no full-fledged manic episodes Bipolar disorder not otherwise specified (NOS): Disorders with clear bipolar features that do not meet the specific criteria for other bipolar disorders Bipolar disorder. Merck Manual – http://www.merckmanuals.com/professional/sec15/ch200/ch200c.html?qt=bipolar&alt=sh

31. Bipolar disorder Treatment is with Mood stabilizers (eg lithium) and certain anticonvulsants (eg carbamazepine), 2ndgeneration antipsychotic (egaripiprazole, risperidone) or both Support and psychotherapy ECT for depression refractory to treatment Treatment in 3 phases Acute – To stabilize and control the initial, sometimes severe manifestations Continuation – To attain full remission Maintenance – To keep paients in remission

32. Bipolar disorder One major issue in diagnosing and treating bipolar disorder is the high rate of misdiagnosis or late diagnosis In one community sample of diagnosed bipolar disorder patients, approximately 70% had a missed diagnosis. A total of 60% of those were diagnosed with major depressive disorder, with one third going 10 years or more without a correct diagnosis. In addition, these patients had on average 3.5 other diagnoses and saw on average four physicians before receiving the correct diagnosis. Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the National Depressive and Manic-depressive Association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 2003;64:161–174.

33. Bipolar disorder Fewer than half of the people who were previously diagnosed with bipolar disorder could be said to have the disorder when strict diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders-IV were applied. Dangers to overdiagnosis, chief among them unnecessary exposure to mood stabilizers and all their powerful side effects Role for neuroimaging Reference Zimmerman. Journal of Clinical Psychiatry. May 2008 http://www.webmd.com/bipolar-disorder/news/20080506/bipolar-disorder-overdiagnosed

34. Bipolar disorder Identifying endophenotypic markers for bipolar disorder at this time would seek to serve two main goals: To clarify diagnosis and discriminate the depression in bipolar disorder from that of UPD to treat accordingly To identify at-risk individuals for early diagnosis with the goal of intervening before illness onset. Keener, MT et al. Neuroimaging in bipolar disorder: A critical review of current findings. Curr Psychiatry Rep. 2007 December; 9(6): 512–520

35. Two overlapping neural systems implicated in bipolar disorder. An anterior limbic subcortical system (left) is responsible for emotion processing. Lateral prefrontal cortical regions (right) are implicated in executive control. These two systems interact and overlap in ventral frontal areas such as the orbitofrontal cortex (OFC) that are responsible for decision making about emotional material and attentional control during emotional stimuli processing. Directional findings in bipolar disorder are represented by size of nodes and vertical arrows. DLFPC—dorsolateral prefrontal cortex; DMPFC—dorsomedial prefrontal cortex; Dorsal ACG—dorsal cingulate gyrus; VLPFC—ventrolateral prefrontal cortex; VMPFC—ventromedial prefrontal cortex.

37. Bipolar Disorder arly Onset. Studies show markedly increased perfusion in bilateral frontal and posterior parietal lobes. There is also hypoperfusion of both orbito-frontal areas, anterior and mesial temporal areas. Mena, Ismael. et al. Bipolar affective disorders: Assessment of functional brain changes by means of Tc99m HMPAO NeuroSPECT. Alasbimn Journal 6(23): January 2004. Article N° AJ23-2.

38. Bipolar disorder PET studies in depressed BPI, bipolar II, and manic individuals have shown increased amygdalar and ventral striatal limbic subcortical activity compared with healthy controls In adults, there are findings of enlarged (or shrunken) amygdalae, decreased dorsal and ventral prefrontal cortices, and smaller or no change in hippocampi. Altshuler LL, Bartzokis G, Grieder T, et al. An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia. Biol Psychiatry. 2000;48:147–162. Blumberg et al. 2003 "Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder". Arch Gen Psychiatry60 (12): 1201–8.

39. Imaging Summary SPD - Reduction of left STG gray matter volume; fewer medial temporal lobe abnormalities Schizophrenia - first year changes are observed in the superior temporal gyrus region of the temporal lobe, including Heschl'sgyrus and planumtemporale Schizophrenia – chronic changes - left-lateralized reductions in gray matter volume in anterior hippocampus / amygdala, parahippocampalgyrus, and superior temporal gyrus PTSD – reduced hippocampal volume past 6 months Bipolar - increased perfusion in bilateral frontal and posterior parietal lobes. There is also hypoperfusion of both orbito-frontal areas, anterior and mesial temporal areas. Structure - Enlarged amygdalae, decreased dorsal and ventral prefrontal cortices, and smaller or no change in hippocampi.

40. Summary Neuroimaging of psychiatric illness is a rapidly developing field Helps explain biologic basis of mental illness Promises to aid diagnosis and identify early-onset and predisposition to disease Could enhance treatment and reduce misdiagnosis/overdiagnosis

41. Thank you!