Scott A. Langenecker

fMRI of Healthy Older Adults During Stroop Interference

The Stroop interference effect, caused by difficulty inhibiting overlearned word reading, is often more pronounced in older adults. This has been proposed to be due to declines in inhibitory control and frontal lobe functions with aging. Initial neuroimaging studies of inhibitory control show that older adults have enhanced activation in multiple frontal areas, particularly in inferior frontal gyrus, indicative of recruitment to aid with performance of the task. The current study compared 13 younger and 13 older adults, all healthy and well educated, who completed a Stroop test during functional magnetic resonance imaging. Younger adults were more accurate across conditions, and both groups were slower and less accurate during the interference condition. The groups exhibited comparable activation regions, but older adults exhibited greater activation in numerous frontal areas, including the left inferior frontal gyrus. The results support the recruitment construct and suggest, along with previous research, that the inferior frontal gyrus is important for successful inhibition.

Face emotion perception and executive functioning deficits in depression.

Frontal, limbic and temporal regions of the brain important in emotion perception and executive functioning also have been implicated in the etiology and maintenance of depression; yet, the relationships among these topics remain poorly understood. The present study evaluated emotion perception and executive functioning among 21 depressed women and 20 nondepressed women controls. Depressed women performed significantly worse than controls in emotion perception accuracy and in inhibitory control, an aspect of executive functioning, whereas the groups did not differ in other cognitive tests assessing memory, visual-spatial, motor, and attention skills. The findings suggest that emotion perception and executive functioning are disproportionately negatively affected relative to other cognitive functions, even in a high-functioning group of mildly depressed women. Measures of emotion perception and executive functioning may be of assistance in objectively measuring functional capability of the ventral and dorsal neural systems, respectively, as well as in the diagnosis of depression. We would like to thank Rachel Burns, Luis Casenas, Najat Hamid, Jessica Layne, Justin Miller, Rebecca Reiten and Megan Shaheen for their assistance in data collection and coding. We gratefully acknowledge the comments and suggestions for this manuscript by Dr. Angela Freymuth Caveney, Ph.D. This project was supported in large part by a Rachel Upjohn Clinical Scholars Award and through the assistance of the Neuropsychology Division

Frontal and Limbic Activation During Inhibitory Control Predicts Treatment Response in Major Depressive Disorder

BACKGROUND Inhibitory control or regulatory difficulties have been explored in major depressive disorder (MDD) but typically in the context of affectively salient information. Inhibitory control is addressed specifically by using a task devoid of affectively-laden stimuli, to disentangle the effects of altered affect and altered inhibitory processes in MDD. METHODS Twenty MDD and 22 control volunteer participants matched by age and gender completed a contextual inhibitory control task, the Parametric Go/No-go (PGNG) task during functional magnetic resonance imaging. The PGNG includes three levels of difficulty, a typical continuous performance task and two progressively more difficult versions including Go/No-go hit and rejection trials. After this test, 15 of 20 MDD patients completed a full 10-week treatment with s-citalopram. RESULTS There was a significant interaction among response time (control subjects better), hits (control subjects better), and rejections (patients better). The MDD participants had greater activation compared with the control group in frontal and anterior temporal areas during correct rejections (inhibition). Activation during successful inhibitory events in bilateral inferior frontal and left amygdala, insula, and nucleus accumbens and during unsuccessful inhibition (commission errors) in rostral anterior cingulate predicted post-treatment improvement in depression symptoms. CONCLUSIONS The imaging findings suggest that in MDD subjects, greater neural activation in frontal, limbic, and temporal regions during correct rejection of lures is necessary to achieve behavioral performance equivalent to control subjects. Greater activation in similar regions was further predictive of better treatment response in MDD.

Response of the μ-opioid system to social rejection and acceptance.

The endogenous opioid system, which alleviates physical pain, is also known to regulate social distress and reward in animal models. To test this hypothesis in humans (n=18), we used an μ-opioid receptor (MOR) radiotracer to measure changes in MOR availability in vivo with positron emission tomography during social rejection (not being liked by others) and acceptance (being liked by others). Social rejection significantly activated the MOR system (i.e., reduced receptor availability relative to baseline) in the ventral striatum, amygdala, midline thalamus and periaqueductal gray (PAG). This pattern of activation is consistent with the hypothesis that the endogenous opioids have a role in reducing the experience of social pain. Greater trait resiliency was positively correlated with MOR activation during rejection in the amygdala, PAG and subgenual anterior cingulate cortex (sgACC), suggesting that MOR activation in these areas is protective or adaptive. In addition, MOR activation in the pregenual ACC was correlated with reduced negative affect during rejection. In contrast, social acceptance resulted in MOR activation in the amygdala and anterior insula, and MOR deactivation in the midline thalamus and sgACC. In the left ventral striatum, MOR activation during acceptance predicted a greater desire for social interaction, suggesting a role for the MOR system in social reward. The ventral striatum, amygdala, midline thalamus, PAG, anterior insula and ACC are rich in MORs and comprise a pathway by which social cues may influence mood and motivation. MOR regulation of this pathway may preserve and promote emotional well being in the social environment.

Frontal recruitment during response inhibition in older adults replicated with fMRI

Recent research has explored age-related differences in multiple areas of cognitive functioning using fMRI, PET, and SPECT. However, because these studies used different tasks, subjects, and methods, little is known about whether the results of these studies are generalizable or repeatable. The present study replicated a previous study [Psychol. Aging 17 (2002) 56] using the same Go/No-go task with a subset of 11 of the original older adult subjects, and using the same fMRI scanner and imaging methods. A direct comparison was made between these participants at Time 1 and Time 2 for both behavioral and functional data. These participants were also compared to a new young adult group of 11 participants. Although the current young adult group did not perform as well as the original young adult group, the original finding of enhanced left prefrontal activation in older adults relative to younger adults was replicated. Furthermore, when comparing Time 1 to Time 2, older adults exhibited comparable areas of activation, but significantly greater magnitude of activation at Time 1 in a few clusters. The findings indicate that older adults exhibit more bilateral brain activity during this task than young adults, which appears compensatory and is repeatable over time. The magnitude of regional activation, however, may vary with extraneuronal factors such as signal-to-noise ratio or task experience. This study adds to existing research suggesting that bilateral frontal activation is a predominant finding in the aging literature, and not specific to certain tasks in age group comparisons.

A task to manipulate attentional load, set-shifting, and inhibitory control: Convergent validity and test–retest reliability of the Parametric Go/No-Go Test

Traditional neuropsychological measures of executive functioning are difficult to employ in functional imaging and clinical trial contexts and have tremendous practice effects. They also have poor sensitivity and specificity, while test–retest reliability is often not assessed in computer-based tests. The present study evaluates some psychometric properties of a new Parametric Go/No-Go (PGNG) Task. The PGNG consists of three levels of difficulty assessing attention, set-shifting, and processing speed, with the two more difficult levels assessing inhibitory control. A total of 63 healthy control participants were recruited at two sites to evaluate the psychometric properties of the PGNG. The PGNG was found to have solid parametric characteristics and strong test–retest reliability. Modest convergent validity was also demonstrated with other executive-functioning tests. Learning effects were significantly less than those for the Trail Making Test. The present results provide solid initial support for the validity and reliability of the PGNG.

Intermediate: Cognitive phenotypes in bipolar disorder

BACKGROUND Intermediate cognitive phenotypes (ICPs) are measurable and quantifiable states that may be objectively assessed in a standardized method, and can be integrated into association studies, including genetic, biochemical, clinical, and imaging based correlates. The present study used neuropsychological measures as ICPs, with factor scores in executive functioning, attention, memory, fine motor function, and emotion processing, similar to prior work in schizophrenia. METHODS Healthy control subjects (HC, n=34) and euthymic (E, n=66), depressed (D, n=43), or hypomanic/mixed (HM, n=13) patients with bipolar disorder (BD) were assessed with neuropsychological tests. These were from eight domains consistent with previous literature; auditory memory, visual memory, processing speed with interference resolution, verbal fluency and processing speed, conceptual reasoning and set-shifting, inhibitory control, emotion processing, and fine motor dexterity. RESULTS Of the eight factor scores, the HC group outperformed the E group in three (Processing Speed with Interference Resolution, Visual Memory, Fine Motor Dexterity), the D group in seven (all except Inhibitory Control), and the HM group in four (Inhibitory Control, Processing Speed with Interference Resolution, Fine Motor Dexterity, and Auditory Memory). LIMITATIONS The HM group was relatively small, thus effects of this phase of illness may have been underestimated. Effects of medication could not be fully controlled without a randomized, double-blind, placebo-controlled study. CONCLUSIONS Use of the factor scores can assist in determining ICPs for BD and related disorders, and may provide more specific targets for development of new treatments. We highlight strong ICPs (Processing Speed with Interference Resolution, Visual Memory, Fine Motor Dexterity) for further study, consistent with the existing literature.

Emotion processing, major depression, and functional genetic variation of neuropeptide Y.

CONTEXT Despite recent progress in describing the common neural circuitry of emotion and stress processing, the bases of individual variation are less well understood. Genetic variants that underlie psychiatric disease have proven particularly difficult to elucidate. Functional genetic variation of neuropeptide Y (NPY) was recently identified as a source of individual differences in emotion. Low NPY levels have been reported in major depressive disorder (MDD). OBJECTIVE To determine whether low-expression NPY genotypes are associated with negative emotional processing at 3 levels of analysis. DESIGN Cross-sectional, case-control study. SETTING Academic medical center. PARTICIPANTS Among 44 individuals with MDD and 137 healthy controls, 152 (84%) had an NPY genotype classified as low, intermediate, or high expression according to previously established haplotype-based expression data. MAIN OUTCOME MEASURES Healthy subjects participated in functional magnetic resonance imaging while viewing negative (vs neutral) words (n = 58) and rated positive and negative affect during a pain-stress challenge (n = 78). Genotype distribution was compared between 113 control subjects and 39 subjects with MDD. RESULTS Among healthy individuals, negatively valenced words activated the medial prefrontal cortex. Activation within this region was inversely related to genotype-predicted NPY expression (P = .03). Whole-brain regression of responses to negative words showed that the rostral anterior cingulate cortex activated in the low-expression group and deactivated in the high-expression group (P < .05). During the stress challenge, individuals with low-expression NPY genotypes reported more negative affective experience before and after pain (P = .002). Low-expression NPY genotypes were overrepresented in subjects with MDD after controlling for age and sex (P = .004). Population stratification did not account for the results. CONCLUSIONS These findings support a model in which NPY genetic variation predisposes certain individuals to low NPY expression, thereby increasing neural responsivity to negative stimuli within key affective circuit elements, including the medial prefrontal and anterior cingulate cortices. These genetically influenced neural response patterns appear to mediate risk for some forms of MDD.

Abnormal anterior cingulate cortical activity during emotional n-back task performance distinguishes bipolar from unipolar depressed females.

BACKGROUND Depression in the context of bipolar disorder (BDd) is often misdiagnosed as unipolar disorder depression (UDd) leading to poor clinical outcomes for many bipolar sufferers. We examined neural circuitry supporting emotion regulation in females with either BDd or UDd as a first stage toward identifying biomarkers that may differentiate BDd from UDd. METHOD Fifty-seven females aged 18-45 years participated in this study: 23 with UDd, 18 with bipolar disorder type I depression (BDId) and 16 healthy females. During 3-T functional magnetic resonance imaging (fMRI), the participants performed an emotional face n-back (EFNBACK) task, that is an n-back task with high (2-back) and low (0-back) memory load conditions flanked by two positive, negative or neutral face distracters. This paradigm examines executive control with emotional distracters-emotion regulation. RESULTS High memory load with neutral face distracters elicited greater bilateral and left dorsal anterior midcingulate cortex (dAMCC) activity in UDd than in healthy and BDId females respectively, and greater bilateral putamen activity in both depressed groups versus healthy females. High memory load with happy face distracters elicited greater left putamen activity in UDd than in healthy females. Psychotropic medication was associated with greater putamen activity to these contrasts in UDd females. CONCLUSIONS During high memory load with neutral face distracters, elevated dAMCC activity in UDd suggests abnormal recruitment of attentional control circuitry to maintain task performance, whereas elevated putamen activity unrelated to psychotropic medication in BDId females may suggest an attentional bias toward ambiguous neutral face distracters. Differential patterns of functional abnormalities in neural circuitry supporting attentional control during emotion regulation, especially in the dAMCC, is a promising neuroimaging measure to distinguish UDd from BDId in females.

Identifying a cognitive impairment subgroup in adults with mood disorders.

BACKGROUND We hypothesized that only a minority of patients with mood disorders have measurable cognitive impairment, and this minority drives the small-to-medium effect sizes detected in group studies. Removal of this minority from group statistical analyses will illustrate that the majority appear to have broadly normal cognitive functioning. METHODS Participants were adults between the ages of 20 and 54, including 659 healthy control subjects, 84 unmedicated outpatients diagnosed with depression, 59 outpatients diagnosed with depression who were on medications at the time of the evaluation, and 43 outpatients with bipolar disorder. All completed the CNS Vital Signs computerized cognitive screening battery. RESULTS The prevalence rates of low cognitive test scores were calculated for the healthy control subjects and the patients with mood disorders. Having two scores at or below the 5th percentile occurred in 31.2% of the patients and only 8.2% of the control subjects [χ(2)(1)=66.67, p<.0001; Odds Ratio=5.1, 95% CI=3.4-7.7]. For the control subjects, this low false positive rate for cognitive impairment was maintained across age groups, sexes, and education levels. A larger proportion of patients with bipolar disorder (41.9%) than patients with depression (27.1-28.6%) met this criterion for cognitive impairment. CONCLUSIONS This study suggests that cognitive impairment associated with mood disorders is limited to a minority of patients with the majority being broadly cognitively normal. Future research should determine if this identified subgroup has neuroanatomical, neurophysiological, or neuroendocrine abnormalities. Cognitive screening tools of this type might be useful in selecting participants for studies.