Amygdala Volume and Verbal Memory Performance in Schizophrenia and Bipolar Disorder William D. S. Killgore, PhD,* Isabelle M. Rosso, PhD,* Staci A. Gruber, PhD,* and Deborah A. Yurgelun-Todd, PhD*w Objective: To clarify the relationship between amygdala- hippocampal volume and cognitive performance in schizophre- nia and bipolar disorder. Background: Abnormalities of the amygdala-hippocampal com- plex and memory deficits have been reported in both schizo- phrenia and bipolar illness. Method: We examined memory performance and its relationship to the volumes of the whole brain, lateral ventricles, hippocam- pus, and amygdala using morphometric magnetic resonance imaging in 19 patients with schizophrenia, 11 bipolar patients, and 20 healthy controls. Results: Schizophrenia patients performed more poorly than bipolar patients and controls on indices of memory functioning, whereas patients with bipolar disorder showed milder impair- ments relative to controls. The schizophrenia group showed reduced total cerebral volume and enlarged ventricles relative to controls, but no group differences were found for amygdala or hippocampal volume. Left amygdala volume was predictive of memory performance in both groups, correlating positively with better immediate and delayed verbal memory for bipolar patients and negatively with immediate and delayed verbal recall for schizophrenia patients. Amygdala volume was unrelated to memory performance in healthy subjects. Conclusions: Schizophrenia and bipolar disorder both seem to be associated with anomalous and differential limbic volume- function relationships, such that the amygdala may facilitate hippocampal-dependent memory processes in bipolar disorder but impair these same processes in schizophrenia. Key Words: bipolar disorder, schizophrenia, MRI, amygdala, hippocampus, memory (Cog Behav Neurol 2009;22:28–37) P atients suffering from bipolar affective disorder experience severe disturbances of mood, energy level, sleep, and psychosocial functioning. 1 This population also demonstrates persistent impairments in cognitive functioning, including impulsivity and deficits in execu- tive control, 2,3 impaired verbal memory, 2–5 and difficulties correctly identifying affective facial expressions. 6–8 Many of these deficits are present very early in the course of the disorder 9 and persist even when patients are tested in a stable euthymic state, 2 suggesting that they may represent residual trait markers indicative of the underlying neuropathology of the illness. Because both declarative memory and affective perception processes depend heavily upon the functioning of structures within the mesial temporal lobe regions such as the amygdala and the hippocampus, 10–13 the verbal memory and face perception deficits observed in patients with bipolar disorder suggest neurobiologic alterations of the amyg- dala-hippocampal complex. The pattern of cognitive deficits seen in bipolar disorder is not unique to that illness, however, as many of these same deficits are also found in schizophrenia. 2 Compared with healthy controls, schizophrenia patients have demonstrated a pattern of generalized cognitive deficits 2 in conjunction with differential deficits in cognitive domains that are mediated by mesial temporal lobe regions including verbal memory, 14–18 olfactory functioning, 19 spatial memory, 20 visual memory, 17 and emotional facial perception, 21–24 along with other more cortically mediated capacities such as executive function- ing, 17 working memory, 25 and attention. 17 Although both schizophrenia and bipolar patients show deficits in these cognitive capacities relative to healthy subjects, studies that have examined both groups commonly report that patients with schizophrenia perform significantly worse than patients with bipolar disorder on most cognitive domains assessed. 26,27 Despite this difference in severity, both disorders seem to share a number of qualitatively similar cognitive deficits consistent with medial temporal lobe dysfunction. A number of researchers have used morphometric magnetic resonance imaging (MRI) to quantify brain volume in patients with schizophrenia and bipolar disorder in order to clarify whether there may be distinct and identifiable patterns of neuropathology within medial temporal limbic structures such as the amygdala-hippo- campal complex. Schizophrenia is associated with a number of morphometric brain abnormalities, including reduced total brain volume, 28–30 abnormal regional white matter distribution, 31 enlarged ventricles, 29,30,32 and Copyright r 2009 by Lippincott Williams & Wilkins Received for publication April 4, 2008; accepted October 26, 2008. From the *Department of Psychiatry, Neuroimaging Center, McLean Hospital, Harvard Medical School, Belmont, MA, wDepartment of Psychiatry, Brain Institute, University of Utah, Salt Lake City, UT. Reprints: William D. S. Killgore, PhD, Department of Psychiatry, Neuroimaging Center, McLean Hospital, 115 Mill Street, Belmont, MA 02478 (e-mail: killgore@mclean.harvard.edu). ORIGINAL STUDY 28 Cog Behav Neurol  Volume 22, Number 1, March 2009