Orbital and Medial Prefrontal Cortex Functional Connectivity of Major Depression Vulnerability and Disease.

BACKGROUND: Pathophysiology models of major depression (MD) center on the dysfunction of various cortical areas within the orbital and medial prefrontal cortex. While independent structural and functional abnormalities in these areas are consistent findings in MD, the complex interactions among them and the rest of the cortex remain largely unexplored. METHODS: We used resting-state functional magnetic resonance imaging connectivity to systematically map alterations in the communication between orbital and medial prefrontal cortex fields and the rest of the brain in MD. Functional connectivity (FC) maps from participants with current MD (n = 35), unaffected first-degree relatives (n = 36), and healthy control subjects (n = 38) were subjected to conjunction analyses to distinguish FC markers of MD vulnerability and FC markers of MD disease. RESULTS: FC abnormalities in MD vulnerability were found for dorsal medial wall regions and the anterior insula and concerned altered communication of these areas with the inferior parietal cortex and dorsal posterior cingulate, occipital areas and the brainstem. FC aberrations in current MD included the anterior insula, rostral and dorsal anterior cingulate cortex, and lateral orbitofrontal areas and concerned altered communication with the dorsal striatum, the cerebellum, the precuneus, the anterior prefrontal cortex, somatomotor cortex, dorsolateral prefrontal cortex, and visual areas in the occipital and inferior temporal lobes. CONCLUSIONS: Functionally delineated parcellation maps can be used to identify putative connectivity markers in extended cortical regions such as the orbital and medial prefrontal cortex. The anterior insula and the rostral anterior cingulate cortex play a central role in the pathophysiology of MD, being consistently implicated both in the MD vulnerability and MD disease states.

The Influence of State Anxiety on Fear Discrimination and Extinction in Females.

Formal theories have linked pathological anxiety to a failure in fear response inhibition. Previously, we showed that aberrant response inhibition is not restricted to anxiety patients, but can also be observed in anxiety-prone adults. However, less is known about the influence of currently experienced levels of anxiety on inhibitory learning. The topic is highly important as state anxiety has a debilitating effect on cognition, emotion, and physiology and is linked to several anxiety disorders. In the present study, healthy female volunteers performed a fear conditioning task, after being informed that they will have to perform the Trier Social Stress Test task (n = 25; experimental group) or a control task (n = 25; control group) upon completion of the conditioning task. The results showed that higher levels of state anxiety corresponded with a reduced discrimination between a stimulus (CS+) typically followed by an aversive event and a stimulus (CS-) that is never followed by an aversive event both during the acquisition and the extinction phase. No effect of state anxiety on the skin conductance response associated with CS+ and CS- was found. Additionally, higher levels of state anxiety coincided with more negative valence ratings of the CSs. The results suggest that increased stress-induced state anxiety might lead to stimulus generalization during fear acquisition, thereby impairing associative learning.

Human orbital and anterior medial prefrontal cortex: Intrinsic connectivity parcellation and functional organization.

The orbital and medial prefrontal cortex (OMPFC) has been implicated in decision-making, reward and emotion processing, and psychopathology, such as depression and obsessive-compulsive disorder. Human and monkey anatomical studies indicate the presence of various cortical subdivisions and suggest that these are organized in two extended networks, a medial and an orbital one. Attempts have been made to replicate these neuroanatomical findings in vivo using MRI techniques for imaging connectivity. These revealed several consistencies, but also many inconsistencies between reported results. Here, we use fMRI resting-state functional connectivity (FC) and data-driven modularity optimization to parcellate the OMPFC to investigate replicability of in vivo parcellation more systematically. By collecting two resting-state data sets per participant, we were able to quantify the reliability of the observed modules and their boundaries. Results show that there was significantly more than chance overlap in modules and their boundaries at the level of individual data sets. Moreover, some of these consistent boundaries significantly co-localized across participants. Hierarchical clustering showed that the whole-brain FC profiles of the OMPFC subregions separate them in two networks, a medial and orbital one, which overlap with the organization proposed by Barbas and Pandya (J Comp Neurol 286:353-375, 1989) and Ongür and Price (Cereb Cortex 10:206-219, 2000). We conclude that in vivo resting-state FC can delineate reliable and neuroanatomically plausible subdivisions that agree with established cytoarchitectonic trends and connectivity patterns, while other subdivisions do not show the same consistency across data sets and studies.

Brain reactivity to alcohol and cannabis marketing during sobriety and intoxication.

Drugs of abuse stimulate striatal dopamine release and activate reward pathways. This study examined the impact of alcohol and cannabis marketing on the reward circuit in alcohol and cannabis users while sober and intoxicated. It was predicted that alcohol and cannabis marketing would increase striatal activation when sober and that reward sensitivity would be less during alcohol and cannabis intoxication. Heavy alcohol (n = 20) and regular cannabis users (n = 21) participated in a mixed factorial study involving administration of alcohol and placebo in the alcohol group and cannabis and placebo in the cannabis group. Non-drug users (n = 20) served as between group reference. Brain activation after exposure to alcohol and cannabis marketing movies was measured using functional magnetic resonance imaging and compared between groups while sober and compared with placebo while intoxicated. Implicit alcohol and cannabis cognitions were assessed by means of a single-category implicit association test. Alcohol and cannabis marketing significantly increased striatal BOLD activation across all groups while sober. Striatal activation however decreased during intoxication with alcohol and cannabis. Implicit associations with cannabis marketing cues were significantly more positive in alcohol and cannabis users as compared with non-drug using controls. Public advertising of alcohol or cannabis use elicits striatal activation in the brain's reward circuit. Reduction of marketing would reduce brain exposure to reward cues that motivate substance use. Conversely, elevated dopamine levels protect against the reinforcing potential of marketing.

Young and Middle-Aged Schoolteachers Differ in the Neural Correlates of Memory Encoding and Cognitive Fatigue: A Functional MRI Study.

This investigation was inspired by growing evidence that middle-aged persons in a cognitively demanding profession might be characterized by subtle cognitive fatigue. We studied young and middle-aged male schoolteachers. They were compared in a study with functional magnetic resonance imaging to evaluate differences during successful memory encoding. The schoolteachers were additionally subjected to an induced fatigue condition involving the sustained performance of cognitively demanding tasks and to a control condition. Results showed age-related brain activation differences underlying behavioral performance including: (1) greater activation in middle-aged vs. young teachers in bilateral prefrontal cortex (PFC) areas; and (2) differential fatigue effects in the left anterior cingulate cortex (ACC) depending on age group. Middle-aged schoolteachers showed decreased ACC activation in the fatigue compared to the control condition, whereas no change in activation was found in young teachers. Findings demonstrate age effects in these middle-aged subjects that are typically found in older adults, specifically in PFC over-activation. Findings also indicate that already in middle age cognitive aging may be associated with greater resource depletion following sustained task performance. The findings underscore the notion that persons in a cognitively demanding profession can experience subtle age effects, which are evident on fMRI and which impact daily functioning. Possible practical implications for middle-aged schoolteachers are discussed.

Top-down modulation of visual and auditory cortical processing in aging.

Age-related cognitive decline has been accounted for by an age-related deficit in top-down attentional modulation of sensory cortical processing. In light of recent behavioral findings showing that age-related differences in selective attention are modality dependent, our goal was to investigate the role of sensory modality in age-related differences in top-down modulation of sensory cortical processing. This question was addressed by testing younger and older individuals in several memory tasks while undergoing fMRI. Throughout these tasks, perceptual features were kept constant while attentional instructions were varied, allowing us to devise all combinations of relevant and irrelevant, visual and auditory information. We found no top-down modulation of auditory sensory cortical processing in either age group. In contrast, we found top-down modulation of visual cortical processing in both age groups, and this effect did not differ between age groups. That is, older adults enhanced cortical processing of relevant visual information and suppressed cortical processing of visual distractors during auditory attention to the same extent as younger adults. The present results indicate that older adults are capable of suppressing irrelevant visual information in the context of cross-modal auditory attention, and thereby challenge the view that age-related attentional and cognitive decline is due to a general deficits in the ability to suppress irrelevant information.

Fear conditioning and extinction in anxiety- and depression-prone persons.

Anxiety and depression frequently co-occur and may share similar deficits in the processing of emotional stimuli. High anxiety is associated with a failure in the acquisition and extinction of fear conditioning. Despite the supposed common deficits, no research has been conducted on fear acquisition and extinction in depression. The main aim of the present study was to investigate and compare fear acquisition and extinction in anxiety- and depression-prone participants. Non-clinical anxious, depressive, anxious-depressive and control participants performed a fear discrimination task. During acquisition, the CS+ predicted an aversive event (unconditioned stimulus, US) and the CS- safety (no US). During extinction, the CS+ was no longer followed by the US, rendering it (temporarily) into a safety signal. On each CS participants rated their US expectancy; skin conductance responses (SCRs) were measured throughout. The expectancy scores indicated that high anxiety resulted in less safety learning during acquisition and extinction; no effect of depression was observed. SCRs showed that high-anxiety persons displayed less discrimination learning (CS+ minus CS-) during acquisition than low-anxiety persons. During extinction, high-depression persons demonstrated more discriminative SCR than low-depression persons. The observed discrepancies in response patterns of high-anxiety and -depression persons seem to indicate distinctive information processing of emotional stimuli.

Visuospatial processing in early Alzheimer's disease: a multimodal neuroimaging study.

INTRODUCTION: Dorsal pathway dysfunctions are thought to underlie visuospatial processing problems in Alzheimer disease (AD). Prior studies reported compensatory mechanisms in the dorsal or ventral pathway in response to these functional changes. Since functional and structural connectivity are interrelated, these functional changes could be interpreted as a disconnection between both pathways. To better understand functional alterations in the dorsal pathway, we combined functional imaging with diffusion tensor imaging (DTI) in patients with mild cognitive impairment (MCI), a likely prodromal stage of AD. METHODS: Eighteen older male individuals with amnestic MCI (aMCI) and 18 male cognitively healthy individuals, matched for age (range 59-75 years) and education, performed an object recognition task in the Magnetic Resonance Imaging (MRI) scanner. Neural activation was measured during recognition of non-canonically versus canonically oriented objects. Regions showing activation differences between groups were also investigated by DTI. RESULTS: Recognition of non-canonical objects elicited increased frontal, temporal and parietal activation. Combining the functional MRI (fMRI) with the DTI results showed less deactivation in areas with decreased diffusion (mediolateral parietal and orbitofrontal) and increased activation in areas with increased diffusion (parietal and temporal) in aMCI patients. Finally, in aMCI patients decreased diffusion was found in the hippocampal cingulum, connecting both pathways. CONCLUSIONS: Our results showed increased activation in early AD patients in ventral and dorsal pathways. A decrease in deactivation and diffusion suggests functional reorganization, while increased activation and diffusion suggests compensatory processes. This is the first study showing structural evidence for functional reorganization, which may be related to connectivity loss in the cingulum.

Working memory in middle-aged males: age-related brain activation changes and cognitive fatigue effects.

We examined the effects of aging and cognitive fatigue on working memory (WM) related brain activation using functional magnetic resonance imaging. Age-related differences were investigated in 13 young and 16 middle-aged male school teachers. Cognitive fatigue was induced by sustained performance on cognitively demanding tasks (compared to a control condition). Results showed a main effect of age on left dorsolateral prefrontal and superior parietal cortex activation during WM encoding; greater activation was evident in middle-aged than young adults regardless of WM load or fatigue condition. An interaction effect was found in the dorsomedial prefrontal cortex (DMPFC); WM load-dependent activation was elevated in middle-aged compared to young in the control condition, but did not differ in the fatigue condition due to a reduction in activation in middle-aged in contrast to an increase in activation in the young group. These findings demonstrate age-related activation differences and differential effects of fatigue on activation in young and middle-aged adults.

Cortisol and induced cognitive fatigue: effects on memory activation in healthy males.

We investigated the relationship between individual differences in acute fatigue and endogenous cortisol changes elicited by the sustained performance of cognitively demanding tasks (fatigue condition). Healthy males provided salivary cortisol measurements and subjective fatigue ratings, and were scanned (functional magnetic resonance imaging) during memory encoding and recognition tasks in fatigue and control conditions. A group of 15 'responders' showed significantly higher cortisol levels in the fatigue condition than 12 'non-responders'. Responders showed higher subjective fatigue and reduced encoding and recognition activation than non-responders in the fatigue condition. An interaction in activation changes in the right hippocampus during encoding reflected decreased activation in responders, but somewhat increased activation in non-responders in the fatigue compared to control condition. Moreover, decreased hippocampal activation in responders was associated with increased subjective fatigue. Findings are consistent with a central role for the hippocampus in differences between responders and non-responders and also implicate the right hippocampus in individual differences in induced cognitive fatigue effects.

The effect of caffeine on working memory load-related brain activation in middle-aged males.

Caffeine is commonly consumed in an effort to enhance cognitive performance. However, little is known about the usefulness of caffeine with regard to memory enhancement, with previous studies showing inconsistent effects on memory performance. We aimed to determine the effect of caffeine on working memory (WM) load-related activation during encoding, maintenance and retrieval phases of a WM maintenance task using functional magnetic resonance imaging (fMRI). 20 healthy, male, habitual caffeine consumers aged 40-61 years were administered 100 mg of caffeine in a double-blind placebo-controlled crossover design. Participants were scanned in a non-withdrawn state following a workday during which caffeinated products were consumed according to individual normal use (range = 145-595 mg). Acute caffeine administration was associated with increased load-related activation compared to placebo in the left and right dorsolateral prefrontal cortex during WM encoding, but decreased load-related activation in the left thalamus during WM maintenance. These findings are indicative of an effect of caffeine on the fronto-parietal network involved in the top-down cognitive control of WM processes during encoding and an effect on the prefrontal cortico-thalamic loop involved in the interaction between arousal and the top-down control of attention during maintenance. Therefore, the effects of caffeine on WM may be attributed to both a direct effect of caffeine on WM processes, as well as an indirect effect on WM via arousal modulation. Behavioural and fMRI results were more consistent with a detrimental effect of caffeine on WM at higher levels of WM load, than caffeine-related WM enhancement. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

The effects of sustained cognitive task performance on subsequent resting state functional connectivity in healthy young and middle-aged male schoolteachers.

Previous studies showed that functional connectivity (FC) within resting state (RS) networks is modulated by previous experience. In this study the effects of sustained cognitive performance on subsequent RS FC were investigated in healthy young (25-30 years; n=15) and middle-aged (50-60 years; n=14) male schoolteachers. Participants were scanned (functional magnetic resonance imaging [MRI]) after a cognitively demanding and a control intervention (randomized tester-blind within-subject design). Independent component analysis (ICA) was used to decompose the data into spatially independent networks. This study focused on the executive control (ExN), the left and right frontoparietal (FPN), and the default mode network (DMN). The effects of cognitive performance and age were calculated with a full-factorial analysis of variance (ANOVA). A main effect of age was found in the left inferior frontal gyrus for the ExN and in the middle frontal gyrus for the DMN with middle-aged teachers having reduced RS FC. Sustained cognitive performance increased subsequent RS FC between the ExN and a lingual/parahippocampal cluster, and between the left FPN and a right calcarine/precuneus cluster. In these clusters, FC strength correlated positively with the perceived amount of effort during the intervention. Further, sustained cognitive performance affected subsequent RS FC between the ExN and the right temporal superior gyrus differently in young and middle-aged men. The results suggest that effects of age on RS FC are already present at middle age. Sustained cognitive performance increased RS FC between task-positive networks and other brain regions, although a change in RS FC within the networks was not found.

Acute tryptophan depletion attenuates brain-heart coupling following external feedback.

External and internal performance feedback triggers neural and visceral modulations such as reactions in the medial prefrontal cortex and insulae or changes of heart period (HP). The functional coupling of neural and cardiac responses following feedback (cortico-cardiac connectivity) is not well understood. While linear time-lagged within-subjects correlations of single-trial EEG and HP (cardio-electroencephalographic covariance tracing, CECT) indicate a robust negative coupling of EEG magnitude 300 ms after presentation of an external feedback stimulus with subsequent alterations of heart period (the so-called N300H phenomenon), the neurotransmitter systems underlying feedback-evoked cortico-cardiac connectivity are largely unknown. Because it has been shown that acute tryptophan depletion (ATD), attenuating brain serotonin (5-HT), decreases cardiac but not neural correlates of feedback processing, we hypothesized that 5-HT may be involved in feedback-evoked cortico-cardiac connectivity. In a placebo-controlled double-blind cross-over design, 12 healthy male participants received a tryptophan-free amino-acid drink at one session (TRP-) and a balanced amino-acid control-drink (TRP+) on another and twice performed a time-estimation task with feedback presented after each trial. N300H magnitude and plasma tryptophan levels were assessed. Results indicated a robust N300H after TRP+, which was significantly attenuated following TRP-. Moreover, plasma tryptophan levels during TRP+ were correlated with N300H amplitude such that individuals with lower tryptophan levels showed reduced N300H. Together, these findings indicate that 5-HT is important for feedback-induced covariation of cortical and cardiac activity. Because individual differences in anxiety have previously been linked to 5-HT, cortico-cardiac coupling and feedback processing, the present findings may be particularly relevant for futures studies on the relationship between 5-HT and anxiety.

The effect of perspective and content on brain activation during mentalizing in young females.

In the present functional magnetic resonance imaging (fMRI) study, we investigated the role of different brain regions in separate aspects of mentalizing. Young females aged 18-19 years were asked to imagine a social situation and answer a question. Perspective, self and other, as well as content, emotion, and behavior, were varied. Activation was observed in the left precuneus, left temporoparietal junction, left medial prefrontal cortex and left middle temporal gyrus. Left precuneus and left temporoparietal junction were recruited more when taking the perspective of other than when taking the perspective of self. Medial prefrontal areas might be more involved during mentalizing about emotion versus baseline than about behavior versus baseline.

Age, sex, and pubertal phase influence mentalizing about emotions and actions in adolescents.

This study examined (1) emotional versus cognitive developmental trajectories and (2) the influence of age-extrinsic factors (i.e., sex and puberty). Using a cross-sectional design, adolescents (N = 252) divided into four age-groups (ages 13, 15, 17, 19) performed two versions of a mentalizing task, about emotions and actions, as well as the Tower task. First, performance on all tasks improved linearly into late adolescence (age 19). Thus no differential trajectories were found for emotional versus cognitive development. Second, girls outperformed boys in mentalizing speed regarding both emotions and actions. In boys, a later pubertal phase was associated with increased mentalizing speed after controlling for age-group.

Differential brain activation patterns in adult attention-deficit hyperactivity disorder (ADHD) associated with task switching.

OBJECTIVE: The main aim of the study was to examine blood oxygen level-dependent response during task switching in adults with attention-deficit/hyperactivity disorder (ADHD). METHOD: Fifteen male adults with ADHD and 14 controls participated and performed a task-switching paradigm. RESULTS: Behaviorally, no specific executive control problems were observed in the ADHD participants, although they did display more errors in general. The neuroimaging data did show remarkable differences between the ADHD and control adults: Adults with ADHD engaged more strongly the dorsal anterior cingulate cortex, middle temporal gyrus, precuneus, lingual gyrus, precentral gyrus, and insula than did the healthy controls during task switching. Controls displayed more task-related activity in the putamen, posterior cingulate gyrus, medial frontal gyrus, thalamus, orbitofrontal cortex, and postcentral gyrus. CONCLUSIONS: ADHD adults did not display specific executive control problems at a behavioral level, but did engage different brain areas during task switching compared with healthy controls. The results are discussed in the framework of the executive frontostriatal circuitry, conflict detection, and attentional networks.

Acute tryptophan depletion in healthy males attenuates phasic cardiac slowing but does not affect electro-cortical response to negative feedback.

RATIONALE: Recent studies have shown that serotonin might be involved in performance monitoring, although the results have been inconclusive. Inconsistent results might be related to the type of pharmacological manipulation and the used behavioral and physiological measures. OBJECTIVES: The present study aimed at further specifying the role of serotonin in performance monitoring. MATERIALS AND METHODS: The effect of serotonin on performance monitoring was studied by using acute tryptophan depletion (ATD), a well-known method to transiently lower central serotonin levels. Twenty healthy male volunteers performed a time-estimation task and their event-related brain potential (ERP), behavioral, and cardiac responses to feedback stimuli were measured. Furthermore, subjective mood and amino-acid levels were determined. RESULTS: As expected, ATD did not affect mood and lowered tryptophan levels. ATD attenuated cardiac slowing to negative feedback but did not affect responses to positive feedback, ERPs, and performance measures. CONCLUSIONS: The data point in the direction of a dissociation between cardiac and electro-cortical responses. Cardiac responses appear to be more sensitive to changes in serotonin metabolism and appear to reflect different aspects of the feedback stimulus. The phasic cardiac response appears to be an important measure that provides additional information about the impact of feedback stimuli and serotonergic functioning.

Effects of acute tryptophan depletion on mood and facial emotion perception related brain activation and performance in healthy women with and without a family history of depression.

The present study examined the effects of acute tryptophan (Trp) depletion (ATD), a well-recognized method to lower central serotonin (5-HT) metabolism, on brain activation during a facial emotion perception task. Brain activation was measured using fMRI, and healthy female volunteers with a positive family history of unipolar depression (FH+) were compared to healthy female volunteers without such a history (FH-). Participants viewed two morphed faces and were instructed to choose between the faces based either on the intensity of the emotional expression (direct task) or the gender of the face (incidental task). In the FH+ group, depletion led to the expected lowering of mood, which partly determined the effect of depletion on performance and brain activation. A stronger mood lowering effect was associated with less accurate performance on faces expressing a negative emotion in the incidental task and a stronger right amygdala response to fearful faces in comparison to happy faces. These results were explained in terms of a mood-induced bias leading to a stronger impact of the expressed negative emotion which subsequently leads to more interference in the incidental task and a stronger amygdala response. It was concluded that the effects of ATD on mood, performance, and brain activation in a facial emotion perception task depend on family history of depression. Performance and brain activation partly depend on the effect of ATD on mood.

The effect of acute tryptophan depletion on the BOLD response during performance monitoring and response inhibition in healthy male volunteers.

RATIONALE: Serotonin (5-HT) was implicated in both clinical and experimental studies in flexible, goal-directed behavior. However, the way in which 5-HT manipulations affect brain activation patterns underlying different subprocesses of cognitive flexibility remains largely unknown. OBJECTIVES: The aim of this study was to investigate the effect of a transient lowering of 5-HT on brain activation during performance monitoring and response inhibition. MATERIALS AND METHODS: We used acute tryptophan depletion (ATD), a well-known method to reduce central 5-HT, to investigate the effect of a transient lowering of 5-HT on the blood-oxygen-level dependent (BOLD) response in an event-related functional MRI study. Thirteen healthy male volunteers performed a modified Go/NoGo task in a counterbalanced, placebo-controlled, within-subject design. RESULTS: ATD significantly lowered plasma tryptophan but did not affect mood and cognitive performance. ATD decreased the BOLD response in the dorsomedial prefrontal cortex (BA 8) during performance monitoring. ATD did not affect the BOLD response during response inhibition. CONCLUSIONS: This study provides more evidence for the suggested role of 5-HT in performance monitoring. Because ATD studies have revealed inconsistent effects of ATD on performance and on brain activation, it was suggested that gender and personality traits are important variables to take into account for future research.

Acute tryptophan depletion reduces activation in the right hippocampus during encoding in an episodic memory task.

Acute tryptophan depletion (ATD), a well-recognized method to lower central serotonin levels, was used to examine the effects of lower central serotonin levels on memory function in healthy males. Functional Magnetic Resonance Imaging (fMRI) was used to examine changes in brain activation during the encoding and the retrieval phase of a visual verbal episodic memory task. ATD led to more positively rated words in the encoding phase and to poorer recognition of these positively rated words in the retrieval phase. Furthermore, encoding was accompanied by enhanced brain activation in occipital, middle and superior frontal, anterior and posterior cingulate and striatal areas. Retrieval attempt was accompanied by enhanced activation in the cuneus, inferior occipital gyrus and inferior and middle frontal areas. Retrieval success was accompanied by activation in an extensive network including frontal, parietal, temporal, cingulate, striatal and cerebellar areas. In the encoding phase ATD attenuated activation in the right hippocampus and ATD did not affect brain activity in the retrieval phase. These results show that serotonin is important in long term memory processes, and that serotonin acts on the encoding phase and not on the retrieval phase.