Robin L. Aupperle

Dorsolateral Prefrontal Cortex Activation During Emotional Anticipation and Neuropsychological Performance in Posttraumatic Stress Disorder

CONTEXT Posttraumatic stress disorder (PTSD) has been associated with executive or attentional dysfunction and problems in emotion processing. However, it is unclear whether these two domains of dysfunction are related to common or distinct neurophysiological substrates. OBJECTIVE To examine the hypothesis that greater neuropsychological impairment in PTSD relates to greater disruption in prefrontal-subcortical networks during emotional anticipation. DESIGN Case-control, cross-sectional study. SETTING General community and hospital and community psychiatric clinics. PARTICIPANTS Volunteer sample of 37 women with PTSD related to intimate partner violence and 34 age-comparable healthy control women. MAIN OUTCOME MEASURES We used functional magnetic resonance imaging (fMRI) to examine neural responses during anticipation of negative and positive emotional images. The Clinician-Administered PTSD Scale was used to characterize PTSD symptom severity. The Wechsler Adult Intelligence Scale, Third Edition, Digit Symbol Test, Delis-Kaplan Executive Function System Color-Word Interference Test, and Wisconsin Card Sorting Test were used to characterize neuropsychological performance. RESULTS Women with PTSD performed worse on complex visuomotor processing speed (Digit Symbol Test) and executive function (Color-Word Interference Inhibition/Switching subtest) measures compared with control subjects. Posttraumatic stress disorder was associated with greater anterior insula and attenuated lateral prefrontal cortex (PFC) activation during emotional anticipation. Greater dorsolateral PFC activation (anticipation of negative images minus anticipation of positive images) was associated with lower PTSD symptom severity and better visuomotor processing speed and executive functioning. Greater medial PFC and amygdala activation related to slower visuomotor processing speed. CONCLUSIONS During emotional anticipation, women with PTSD show exaggerated activation in the anterior insula, a region important for monitoring internal bodily state. Greater dorsolateral PFC response in PTSD patients during emotional anticipation may reflect engagement of cognitive control networks that are beneficial for emotional and cognitive functioning. Novel treatments could be aimed at strengthening the balance between cognitive control (dorsolateral PFC) and affective processing (medial PFC and amygdala) networks to improve overall functioning for PTSD patients.

Three screening batteries to detect cognitive impairment in multiple sclerosis

To compare the sensitivities for detecting cognitive impairment in patients with multiple sclerosis (MS) and administration times of three brief batteries of neuropsychological tests, 64 patients with MS completed the Neuropsychological Screening Battery for Multiple Sclerosis (NPSBMS), the Screening Examination for Cognitive Impairment (SEFCI), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Failure on a particular test was defined as a score below the 5th percentile for healthy controls, and the number of patients who failed at least one or two tests (out of four) was determined for each battery. Both the SEFCI and the NPSBMS identified significantly more patients with impairment than the RBANS, which was no more sensitive than the Mini-Mental State Exam (MMSE). Results were similar at both the one- and two-failed-tests criteria, but there were no significant differences between the SEFCI and the NPSBMS at either failure criterion. Mean administration time was 22.6 min for the SEFCI compared to 31.7 min for the NPSBMS (p <0.001). Eleven (17%) of the patients refused to attempt the Paced Auditory Serial Addition Test (PASAT), one component of the NPSBMS. For screening patients on a single occasion, the SEFCI is preferred because its administration time is shorter than the NPSBMS.

Sex differences in cognitive impairment in multiple sclerosis.

Multiple sclerosis (MS) is twice as prevalent in females as in males, but the possibility of sex differences in the cognitive sequellae of the disease has not been considered. In this study male patients with MS performed more poorly than female patients on tests of verbal and nonverbal memory, visuospatial construction, and on the Mini Mental State Exam (MMSE) and the Wisconsin Card Sorting Test (WCST). The groups of male and female patients were similar in age, education, and on several measures of neurologic and emotional disturbance. Among normals there are no sex differences on the MMSE and WCST. Sex differences on the memory and visuospatial construction tests were larger in magnitude for the patients than for normal controls, implying that male patients are somehow especially vulnerable to cognitive deficits. Reanalysis of existing databases could clarify questions about the existence and source of cognitive sex differences in MS.

Pregabalin Influences Insula and Amygdala Activation During Anticipation of Emotional Images

Pregabalin (PGB) has shown potential as an anxiolytic for treatment of generalized and social anxiety disorder. PGB binds to voltage-dependent calcium channels, leading to upregulation of GABA inhibitory activity and reduction in the release of various neurotransmitters. Previous functional magnetic resonance imaging (fMRI) studies indicate that selective serotonin reuptake inhibitors and benzodiazepines attenuate amygdala, insula, and medial prefrontal cortex activation during anticipation and emotional processing in healthy controls. The aim of this study was to examine whether acute PGB administration would attenuate activation in these regions during emotional anticipation. In this double-blind, placebo-controlled, randomized crossover study, 16 healthy controls completed a paradigm involving anticipation of negative and positive affective images during fMRI approximately 1 h after administration of placebo, 50, or 200 mg PGB. Linear mixed model analysis revealed that PGB was associated with (1) decreases in left amygdala and anterior insula activation and (2) increases in anterior cingulate (ACC) activation, during anticipation of positive and negative stimuli. There was also a region of the anterior amygdala in which PGB dose was associated with increased activation during anticipation of negative and decreased activation during anticipation of positive stimuli. Attenuation of amygdala and insula activation during anticipatory or emotional processing may represent a common regional brain mechanism for anxiolytics across drug classes. PGB induced increases in ACC activation could be a unique effect related to top–down modulation of affective processing. These results provide further support for the viability of using pharmaco-fMRI to determine the anxiolytic potential of pharmacologic agents.

Neural responses during emotional processing before and after cognitive trauma therapy for battered women

Therapy for combat and accident-related posttraumatic stress disorder (PTSD) has been reported to influence amygdala and anterior cingulate cortex (ACC) response during emotional processing. It is not yet understood how therapy influences different phases of emotional processing, and whether previous findings generalize to other PTSD populations. We hypothesized that cognitive trauma therapy for battered women (CTT-BW) would alter insula, amygdala, and cingulate responses during anticipation and presentation of emotional images. Fourteen female patients with PTSD related to domestic violence completed the Clinician Administered PTSD Scale (CAPS) and functional magnetic resonance imaging (fMRI) before and after CTT-BW. The fMRI task involved cued anticipation followed by presentation of positive versus negative affective images. CTT-BW was associated with decreases in CAPS score, enhanced ACC and decreased anterior insula activation during anticipation, and decreased dorsolateral prefrontal cortex and amygdala response during image presentation (negative-positive). Pre-treatment ACC activation during anticipation and image presentation exhibited positive and negative relationships to treatment response, respectively. Results suggest that CTT-BW enhanced efficiency of neural responses during preparation for upcoming emotional events in a way that reduced the need to recruit prefrontal-amygdala responses during the occurrence of the event. Results also suggest that enhancing ACC function during anticipation may be beneficial for PTSD treatment.

Neural substrates of approach‐avoidance conflict decision‐making

Animal approach‐avoidance conflict paradigms have been used extensively to operationalize anxiety, quantify the effects of anxiolytic agents, and probe the neural basis of fear and anxiety. Results from human neuroimaging studies support that a frontal–striatal–amygdala neural circuitry is important for approach‐avoidance learning. However, the neural basis of decision‐making is much less clear in this context. Thus, we combined a recently developed human approach‐avoidance paradigm with functional magnetic resonance imaging (fMRI) to identify neural substrates underlying approach‐avoidance conflict decision‐making. Fifteen healthy adults completed the approach‐avoidance conflict (AAC) paradigm during fMRI. Analyses of variance were used to compare conflict to nonconflict (avoid‐threat and approach‐reward) conditions and to compare level of reward points offered during the decision phase. Trial‐by‐trial amplitude modulation analyses were used to delineate brain areas underlying decision‐making in the context of approach/avoidance behavior. Conflict trials as compared to the nonconflict trials elicited greater activation within bilateral anterior cingulate cortex, anterior insula, and caudate, as well as right dorsolateral prefrontal cortex (PFC). Right caudate and lateral PFC activation was modulated by level of reward offered. Individuals who showed greater caudate activation exhibited less approach behavior. On a trial‐by‐trial basis, greater right lateral PFC activation related to less approach behavior. Taken together, results suggest that the degree of activation within prefrontal‐striatal‐insula circuitry determines the degree of approach versus avoidance decision‐making. Moreover, the degree of caudate and lateral PFC activation related to individual differences in approach‐avoidance decision‐making. Therefore, the approach‐avoidance conflict paradigm is ideally suited to probe anxiety‐related processing differences during approach‐avoidance decision‐making. Hum Brain Mapp 36:449–462, 2015.

Neural correlates of a computerized attention modification program in anxious subjects

Computerized attention modification is a relatively new and empirically validated treatment approach for different types of anxiety disorders. However, its neural basis and processes involved are poorly understood. This study examined the effect of a one-time application of an attention modification program (AMP) on neural substrates underlying emotion processing in individuals with high social anxiety. Fourteen individuals with elevated social anxiety symptoms completed an emotional face processing task during functional magnetic resonance imaging before and after AMP, and were subsequently exposed to a laboratory stressor. Results revealed the following: First, there was attenuated activation from pre- to post-AMP in the bilateral amygdala, bilateral insula and subgenual anterior cingulate cortex. Second, post-AMP, individuals exhibited increased activation in several regions of the prefrontal cortex (PFC). Third, those individuals with greater enhancement of ventromedial PFC activation after AMP showed diminished attentional allocation for threat and attenuated anxiety reactivity to the stressor. We conclude that AMP exerts effects that are similar to those previously reported for standard anxiolytics; however, it also appears to foster deployment of top-down brain processes aimed to regulate anxiety.

An fMRI Study Examining Effects of Acute D-Cycloserine During Symptom Provocation in Spider Phobia

BACKGROUND Exposure-based therapy for anxiety disorders is believed to operate on the basis of fear extinction. Studies have shown acute administration of D-cycloserine (DCS) enhances fear extinction in animals and facilitates exposure therapy in humans, but the neural mechanisms are not completely understood. To date, no study has examined neural effects of acute DCS in anxiety-disordered populations. METHODS Two hours prior to functional magnetic resonance imaging scanning, 23 spider-phobic and 23 non-phobic participants were randomized to receive DCS 100 mg or placebo. During scanning, participants viewed spider, butterfly, and Gaussian-blurred baseline images in a block-design paradigm. Diagnostic and treatment groups were compared regarding differential activations to spider versus butterfly stimuli. RESULTS In the phobic group, DCS enhanced prefrontal (PFC), dorsal anterior cingulate (ACC), and insula activations. For controls, DCS enhanced ventral ACC and caudate activations. There was a positive correlation between lateral PFC and amygdala activation for the placebo-phobic group. Reported distress during symptom provocation was correlated with amygdala activation in the placebo-phobic group and orbitofrontal cortex activation in the DCS-phobic group. CONCLUSIONS Results suggest that during initial phobic symptom provocation DCS enhances activation in regions involved in cognitive control and interoceptive integration, including the PFC, ACC, and insular cortices for phobic participants.

Omega-3 fatty acids and multiple sclerosis: relationship to depression

Depression is a common problem among patients with multiple sclerosis (MS). Previous research has shown differences between MS patients and controls in the levels of certain fatty acids, and differences in many of these same fatty acids have also been reported in psychiatric patients with major depression. The current study sought to determine whether fatty acid levels in MS patients might be associated with depression. Fatty acids were measured in red blood cells (RBCs) for 38 patients with relapsing-remitting MS and 33 healthy controls who also completed 3-day dietary records and depression questionnaires. Levels of certain omega-3 and omega-6 fatty acids were lower and levels of certain monounsaturated and saturated fatty acids were higher in the MS patients. These differences were generally of medium effect size and occurred despite the fact that no differences were found between the two groups in dietary intake of any fatty acids. However, neither RBC nor dietary fatty acid levels were related to depression in the MS sample.

Can Neural Activation in Dorsolateral Prefrontal Cortex Predict Responsiveness to Information? An Application to Egg Production Systems and Campaign Advertising

Consumers prefer to pay low prices and increase animal welfare; however consumers are typically forced to make tradeoffs between price and animal welfare. Campaign advertising (i.e., advertising used during the 2008 vote on Proposition 2 in California) may affect how consumers make tradeoffs between price and animal welfare. Neuroimaging data was used to determine the effects of brain activation in dorsolateral prefrontal cortex (dlPFC) on choices making a tradeoff between price and animal welfare and responsiveness to campaign advertising. Results indicated that activation in the dlPFC was greater when making choices that forced a tradeoff between price and animal welfare, compared to choices that varied only by price or animal welfare. Furthermore, greater activation differences in right dlPFC between choices that forced a tradeoff and choices that did not, indicated greater responsiveness to campaign advertising.