Decreased Fronto-Limbic Activation and Disrupted Semantic-Cued List Learning in Major Depressive Disorder.

OBJECTIVES: Individuals with major depressive disorder (MDD) demonstrate poorer learning and memory skills relative to never-depressed comparisons (NDC). Previous studies report decreased volume and disrupted function of frontal lobes and hippocampi in MDD during memory challenge. However, it has been difficult to dissociate contributions of short-term memory and executive functioning to memory difficulties from those that might be attributable to long-term memory deficits. METHODS: Adult males (MDD, n=19; NDC, n=22) and females (MDD, n=23; NDC, n=19) performed the Semantic List Learning Task (SLLT) during functional magnetic resonance imaging. The SLLT Encoding condition consists of 15 lists, each containing 14 words. After each list, a Distractor condition occurs, followed by cued Silent Rehearsal instructions. Post-scan recall and recognition were collected. Groups were compared using block (Encoding-Silent Rehearsal) and event-related (Words Recalled) models. RESULTS: MDD displayed lower recall relative to NDC. NDC displayed greater activation in several temporal, frontal, and parietal regions, for both Encoding-Silent Rehearsal and the Words Recalled analyses. Groups also differed in activation patterns in regions of the Papez circuit in planned analyses. The majority of activation differences were not related to performance, presence of medications, presence of comorbid anxiety disorder, or decreased gray matter volume in MDD. CONCLUSIONS: Adults with MDD exhibit memory difficulties during a task designed to reduce the contribution of individual variability from short-term memory and executive functioning processes, parallel with decreased activation in memory and executive functioning circuits. Ecologically valid long-term memory tasks are imperative for uncovering neural correlates of memory performance deficits in adults with MDD.

Individuals with more severe depression fail to sustain nucleus accumbens activity to preferred music over time.

We investigated the ability of preferred classical music to activate the nucleus accumbens in patients with Major depressive disorder (MDD). Twelve males with MDD and 10 never mentally ill male healthy controls (HC) completed measures of anhedonia and depression severity, and listened to 90-second segments of preferred classical music during fMRI. Compared to HCs, individuals with MDD showed less activation of the left nucleus accumbens (NAcc). Individuals with MDD showed attenuation of the left NAcc response in later compared to earlier parts of the experiment, supporting theories that MDD involves an inability to sustain reward network activation. Counter intuitively, we found that NAcc activity during early music listening was associated with greater depression severity. In whole-brain analyses, anhedonia scores predicted activity in regions within the default mode network, supporting previous findings. Our results support theories that MDD involves an inability to sustain reward network activation. It also highlights that pleasant classical music can engage critical neural reward circuitry in MDD.

Improvement in mood and ideation associated with increase in right caudate volume.

BACKGROUND: The basal ganglia, particularly caudate, are hypothesized to play a role in affective and obsessive-compulsive disorders. The depressive syndrome is a feature of untreated Cushing's disease. The objective of this study was to test the hypothesis that after treatment of Cushing's disease reduces elevated cortisol, improvement in mood and related ideations are associated with increase in caudate volume. METHODS: In this longitudinal, interventional study of 23 patients with Cushing's disease, 24-hour urinary free cortisol, structural magnetic resonance imaging and behavioral measures were obtained prior to treatment and approximately one year after pituitary microadenomectomy. Five SCL-90-R subscales measuring change in mood, related ideations and physical symptoms were utilized. RESULTS: Partial correlations (adjusted for age and time since surgery) showed change in caudate, but not hippocampal, volume was significantly associated with change in behavioral SCL-90-R subscales, indicating selectivity for structure. Right but not left caudate showed associations, suggesting selectivity for lateralization. Right caudate volume increase was significantly associated with decreases in Depression, Anxiety, Obsessive-Compulsive, and Paranoid scores, but not with Somatization (physical symptoms), indicating specificity for behavioral but not physical variables. LIMITATIONS: A limitation is that relatively low-resolution scans were utilized. Although most likely not diminishing the significant findings, less sensitive methodology could lead to an increased probability of a type 2 error. CONCLUSIONS: These findings support the concept that caudate, and likely right caudate, participates in human brain circuitry regulating mood.

A new semantic list learning task to probe functioning of the Papez circuit.

INTRODUCTION: List learning tasks are powerful clinical tools for studying memory, yet have been relatively underutilized within the functional imaging literature. This limits understanding of regions such as the Papez circuit that support memory performance in healthy, nondemented adults. METHOD: The current study characterized list learning performance in 40 adults who completed a semantic list learning task (SLLT) with a Brown-Peterson manipulation during functional magnetic resonance imaging (fMRI). Cued recall with semantic cues and recognition memory were assessed after imaging. Internal reliability, convergent, and discriminant validity were evaluated. RESULTS: Subjects averaged 38% accuracy in recall (62% for recognition), with primacy but no recency effects observed. Validity and reliability were demonstrated by showing that the SLLT was correlated with the California Verbal Learning Test (CVLT), but not with executive functioning tests, and by high intraclass correlation coefficient across lists for recall (.91). fMRI measurements during encoding (vs. silent rehearsal) revealed significant activation in bilateral hippocampus, parahippocampus, and bilateral anterior and posterior cingulate cortex. Post hoc analyses showed increased activation in anterior and middle hippocampus, subgenual cingulate, and mammillary bodies specific to encoding. In addition, increasing age was positively associated with increased activation in a diffuse network, particularly frontal cortex and specific Papez regions for correctly recalled words. Gender differences were specific to left inferior and superior frontal cortex. CONCLUSIONS: This is a clinically relevant list learning task that can be used in studies of groups for which the Papez circuit is damaged or disrupted, in mixed or crossover studies at imaging and clinical sites.

Improvement in learning associated with increase in hippocampal formation volume.

BACKGROUND: Patients with spontaneous Cushing's syndrome are exposed to elevated levels of endogenous cortisol for months to years. We previously reported that hippocampal formation volume (HFV) increased in such patients after treatment lowered cortisol to normal concentrations. In the present study, we examined whether the structural increase was associated with improvement in cognition. METHODS: Twenty-four patients with Cushing's disease were studied before treatment and following treatment. Magnetic resonance imaging was used to measure HFV and caudate head volume. Neuropsychologic tests of verbal cognition, learning, and memory were also administered. RESULTS: Patients showed variability in improvement on neuropsychologic test performance. After partialing out age, education, duration of illness, and time since surgical treatment, greater improvement in word list learning, as measured by the Selective Reminding Test was associated with greater increase in HFV (r =.59, p <.02). There were no significant associations between improvement in paragraph or paired-word learning or memory tasks and increase in HFV. Improvement in other verbal tasks not strongly dependent on the hippocampus were not significantly associated with increase in HFV. CONCLUSIONS: After cortisol levels decline to normal concentrations, structural volumetric increase in HFV is accompanied by functional improvement in learning of unrelated words.

Reduced emotion processing efficiency in healthy males relative to females.

This study examined sex differences in categorization of facial emotions and activation of brain regions supportive of those classifications. In Experiment 1, performance on the Facial Emotion Perception Test (FEPT) was examined among 75 healthy females and 63 healthy males. Females were more accurate in the categorization of fearful expressions relative to males. In Experiment 2, 3T functional magnetic resonance imaging data were acquired for a separate sample of 21 healthy females and 17 healthy males while performing the FEPT. Activation to neutral facial expressions was subtracted from activation to sad, angry, fearful and happy facial expressions. Although females and males demonstrated activation in some overlapping regions for all emotions, many regions were exclusive to females or males. For anger, sad and happy, males displayed a larger extent of activation than did females, and greater height of activation was detected in diffuse cortical and subcortical regions. For fear, males displayed greater activation than females only in right postcentral gyri. With one exception in females, performance was not associated with activation. Results suggest that females and males process emotions using different neural pathways, and these differences cannot be explained by performance variations.

Neuropsychiatric findings in Cushing syndrome and exogenous glucocorticoid administration.

This article reviews the neuropsychiatric presentations elicited by spontaneous hypercortisolism and exogenous supraphysiologic glucocorticoids. Patients with Cushing disease and syndrome develop a depressive syndrome: irritable and depressed mood, decreased libido, disrupted sleep and cognitive decrements. Exogenous short-term glucocorticoid administration may elicit a hypomanic syndrome with mood, sleep and cognitive disruptions. Treatment options are discussed. Brain imaging and neuropsychological studies indicate elevated cortisol and other glucocorticoids are especially deleterious to hippocampus and frontal lobe. The research findings also shed light on neuropsychiatric abnormalities in conditions that have substantial subgroups exhibiting elevated and dysregulated cortisol: aging, major depressive disorder and Alzheimer's disease.

Impact of chronic hypercortisolemia on affective processing.

Cushing syndrome (CS) is the classic condition of cortisol dysregulation, and cortisol dysregulation is the prototypic finding in Major Depressive Disorder (MDD). We hypothesized that subjects with active CS would show dysfunction in frontal and limbic structures relevant to affective networks, and also manifest poorer facial affect identification accuracy, a finding reported in MDD. Twenty-one patients with confirmed CS (20 ACTH-dependent and 1 ACTH-independent) were compared to 21 healthy control subjects. Identification of affective facial expressions (Facial Emotion Perception Test) was conducted in a 3 Tesla GE fMRI scanner using BOLD fMRI signal. The impact of disease (illness duration, current hormone elevation and degree of disruption of circadian rhythm), performance, and comorbid conditions secondary to hypercortisolemia were evaluated. CS patients made more errors in categorizing facial expressions and had less activation in left anterior superior temporal gyrus, a region important in emotion processing. CS patients showed higher activation in frontal, medial, and subcortical regions relative to controls. Two regions of elevated activation in CS, left middle frontal and lateral posterior/pulvinar areas, were positively correlated with accuracy in emotion identification in the CS group, reflecting compensatory recruitment. In addition, within the CS group, greater activation in left dorsal anterior cingulate was related to greater severity of hormone dysregulation. In conclusion, cortisol dysregulation in CS patients is associated with problems in accuracy of affective discrimination and altered activation of brain structures relevant to emotion perception, processing and regulation, similar to the performance decrements and brain regions shown to be dysfunctional in MDD. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Location of ectopic adrenocortical hormone-secreting tumors causing Cushing's syndrome in the paranasal sinuses.

BACKGROUND: The majority of ectopic adrenocorticotropic hormone (ACTH)-secreting tumors are localized in the chest or abdomen. Occasionally, these tumors are found in the paranasal sinuses. METHODS: We present 2 unusual cases of ectopic ACTH syndrome whose ACTH-secreting tumors were localized in the paranasal sinuses and describe their biochemical and radiological presentation. RESULTS: The first patient had an ACTH-secreting olphactory neuroblastoma originating in the ethmoid sinuses. The second patient had a clinical course and biochemical findings indistinguishable from pituitary ACTH-dependent Cushing's syndrome, except for negative petrosal sinus sampling. Head imaging showed a "polyp" in the left maxillary sinus-secreting ACTH. Both patients went into remission following surgical resection and recovered normal pituitary-adrenal axis function. CONCLUSION: Ectopic ACTH secretion may originate from lesions in the paranasal sinuses. This accessible location allows for direct immunohistochemical diagnosis with ACTH staining. Surgical resection/radiation therapy can result in complete remission of the disease and restoration of normal pituitary-adrenal function.

Patterns of cognitive change over time and relationship to age following successful treatment of Cushing's disease.

Chronically elevated levels of cortisol have been associated with changes in cognitive functioning and brain morphology. Using Cushing's disease as a model to assess the effects of high levels of cortisol on cognitive functioning, 27 patients with Cushing's disease were examined at baseline and three successive follow-up periods up to 18 months after successful surgical treatment. At all follow-up periods, patients were administered cognitive tests as well as measures of plasma and urinary free cortisol. Structural MRIs and a depression measure were taken at baseline and one-year follow-up. Results showed that there is a specific pattern of significant cognitive and morphological improvement following successful treatment. Verbal fluency and recall showed recovery, although brief attention did not. Age of participants was a significant factor as to when recovery of function occurred; younger patients regained and sustained their improvement in cognitive functioning more quickly than older participants. Improvement in verbal recall also was associated with a decrease in cortisol levels as well as an increase in hippocampal formation volume one year after treatment. Overall, these findings suggest that at least some of the deleterious effects of prolonged hypercortisolemia on cognitive functioning are potentially reversible, up to at least 18 months post treatment.

The terrorist attacks of September 11, 2001, as psychological toxin: increase in suicide attempts.

Previous studies of psychological morbidity produced by September 11, 2001, focused primarily on short-term development of posttraumatic stress disorder or depression in East Coast cities targeted. This study aimed to determine whether suicide attempts medically harmful enough to necessitate admission to the general hospital increased in the 2 years following September 11, 2001, in a region not on the East Coast, and if so, to characterize individuals contributing to this increase. This retrospective study compared two time periods: 2 years preceding and 2 years following September 11, 2001. Psychiatric consultation reports for all suicide attempters medically admitted to the University of Michigan Health Systems Hospital in Ann Arbor, Michigan, were examined (N = 254). In the 2-year period following September 11, 2001, there was a 49% increase in the number of individuals making a harmful suicide attempt (p = 0.002). The effect was greatest in the months following the attacks but continued over the next year, with a stepwise decline corresponding to the number of months elapsed since September 11. In the period following September 11, 2001, fewer subjects reported multiple personal stressors (p = 0.03). The subjects in the two time periods were not significantly different in age, gender, prior suicide attempts, prior psychiatric treatment, alcohol abuse, substance abuse, depression, or psychosis. Overrepresentation by those most vulnerable to suicide attempts did not account for the increased number of suicide attempts. The effects of chronic stress in the general population across the United States elicited by the terrorism of September 11, 2001, may have been of greater magnitude and longer lasting than previously realized.