Differentiating among prefrontal substrates in psychopathy: neuropsychological test findings

Frontal lobe and consequent executive dysfunction have long been related to psychopathy. More recently, there have been suggestions that specific regions of frontal cortex, rather than all of frontal cortex, may be implicated in psychopathy. To examine this issue, the authors presented 25 individuals with psychopathy and 30 comparison individuals with measures preferentially indexing the orbitofrontal cortex (OFC; object alternation task), dorsolateral prefrontal cortex (DLPFC; spatial alternation task), and anterior cingulate cortex (ACC; number-Stroop reading and counting tasks). The individuals with psychopathy showed significant impairment on the measure preferentially sensitive to OFC functioning. In contrast, the 2 groups did not show impairment on the measures preferentially sensitive to the functioning of the DLPFC or ACC. These results are interpreted with reference to executive dysfunction accounts of the disorder.     

Assessment of Hot and Cool Executive Function in Young Children: Age-Related Changes and Individual Differences

Although executive function (EF) is often considered a domain-general cognitive function, a distinction has been made between the "cool" cognitive aspects of EF more associated with dorsolateral regions of prefrontal cortex and the "hot" affective aspects more associated with ventral and medial regions (Zelazo & M?ller, 2002). Assessments of EF in children have focused almost exclusively on cool EF. In this study, EF was assessed in 3- to 5-year-old children using 2 putative measures of cool EF (Self-Ordered Pointing and Dimensional Change Card Sort) and 2 putative measures of hot EF (Children's Gambling Task and Delay of Gratification). Findings confirmed that performance on both types of task develops during the preschool period. However, the measures of hot and cool EF showed different patterns of relations with each other and with measures of general intellectual function and temperament. These differences provide preliminary evidence that hot and cool EF are indeed distinct, and they encourage further research on the development of hot EF.     

Cannabis abuse is associated with decision-making impairment among first-episode patients with schizophrenia-spectrum psychosis

BACKGROUND: Cannabis use appears to be a risk factor for schizophrenia. Moreover, cannabis abusers show impaired decision-making capacities, linked to the orbitofrontal cortex (OFC). Although there is substantial evidence that first-episode schizophrenia patients show impairments in cognitive tasks associated with the dorsolateral prefrontal cortex (DLPFC), it is not clear whether decision making is impaired at schizophrenia onset. In this study, we examined the association between antecedents of cannabis abuse and cognitive impairment in cognitive tasks associated with the DLPFC and the OFC in a sample of first-episode patients with schizophrenia-spectrum disorders.MethodOne hundred and thirty-two patients experiencing their first episode of a schizophrenia-spectrum psychosis were assessed with a cognitive battery including DLPFC-related tasks [backward digits, verbal fluency (FAS) and the Trail Making Test (TMT)] and an OFC-related task [the Iowa Gambling Task (GT)]. Performance on these tasks was compared between patients who had and had not abused cannabis before their psychosis onset. RESULTS: No differences were observed between the two groups on the performance of any of the DLPFC-related tasks. However, patients who had abused cannabis before their psychosis onset showed a poorer total performance on the gambling task and a lower improvement on the performance of the task compared to no-abusers. CONCLUSIONS: Pre-psychotic cannabis abuse is associated with decision-making impairment, but not working memory and executive function impairment, among first-episode patients with a schizophrenia-spectrum psychosis. Further studies are needed to examine the direction of causality of this impairment; that is, does the impairment make the patients abuse cannabis, or does cannabis abuse cause the impairment?     

Activity of primate orbitofrontal and dorsolateral prefrontal neurons: task-related activity during an oculomotor delayed-response task

The orbitofrontal cortex (OFC) has strong reciprocal connections to the dorsolateral prefrontal cortex (DLPFC), which is known to participate in spatial working memory processes. However, it is not known whether or not the OFC also participates in spatial working memory and whether the OFC and DLPFC contribute equally to this process. To address these issues, we collected single-neuron activity from both areas while a monkey performed an oculomotor delayed-response task, and compared the characteristics of task-related activities between the OFC and DLPFC. All of the task-related activities observed in the DLPFC were also observed in the OFC. However, the proportion and response characteristics of task-related activities were different between the two areas. While most delay-period activity observed in the DLPFC was directionally selective and showed tonic sustained activation, most delay-period activity observed in the OFC was omni-directional and showed gradually increasing activity. Reward-period activity was predominant among task-related activities in the OFC. The proportion of neurons showing reward-period activity was significantly higher in the OFC than in the DLPFC. These results suggest that, although both the OFC and DLPFC participate in spatial working memory processes, the OFC is related more to the expectation and the detection of reward delivery, while the DLPFC is related more to the temporary maintenance of spatial information and its processing.     

Executive functioning, memory, and learning in phenylketonuria

The executive deficit hypothesis of treated phenylketonuria (PKU) suggests that dopaminergic depletion in the lateral prefrontal cortex leads to selective executive impairment. This was examined by comparing adults with PKU on a lifelong diet with a matched healthy control group. Those with PKU were impaired on selective and sustained attention, working memory (Self-Ordered Pointing), and letter fluency. However, they failed to show differential sensitivity to increased cognitive load on the attentional and working memory tasks, and they did not differ significantly on the remaining executive tasks (rule finding, inhibition, and multitasking). Nor did they differ significantly on recall or recognition memory. Overall, the findings provided little support for the executive deficit hypothesis. A possible explanation in terms of slowed information processing speed is explored.     

A brain network instantiating approach and avoidance motivation

Research indicates that dorsolateral prefrontal cortex (DLPFC) is important for pursuing goals, and areas of DLPFC are differentially involved in approach and avoidance motivation. Given the complexity of the processes involved in goal pursuit, DLPFC is likely part of a network that includes orbitofrontal cortex (OFC), cingulate, amygdala, and basal ganglia. This hypothesis was tested with regard to one component of goal pursuit, the maintenance of goals in the face of distraction. Examination of connectivity with motivation-related areas of DLPFC supported the network hypothesis. Differential patterns of connectivity suggest a distinct role for DLPFC areas, with one involved in selecting approach goals, one in selecting avoidance goals, and one in selecting goal pursuit strategies. Finally, differences in trait motivation moderated connectivity between DLPFC and OFC, suggesting that this connectivity is important for instantiating motivation.     

Resting-State Functional Connectivity Within Medial Prefrontal Cortex Mediates Age Differences in Risk Taking

To investigate the association between age-related changes in risk taking and resting-state functional activity, we recorded resting-state scans from both young (n = 26) and older adults (n = 27). In addition, all participants completed two decision-making tasks: the Cambridge Gambling Task and the Balloon Analogue Risk Task. We found that older adults showed decreased functional connectivity within the medial prefrontal cortex, particularly between the ventromedial prefrontal cortex and the dorsal medial prefrontal cortex. Moreover, these changes in resting-state functional connectivity were associated with the individuals’ risk-taking behavior, and mediated the influence of age on risk taking.     

tDCS selectively improves working memory in older adults with more education

Cognitive performance, including performance on working memory (WM) tasks declines with age. Changes in brain activations are one presumed contributor to WM decline in the healthy aging population. In particular, neuroimaging studies show that when older adults perform WM tasks there tends to be greater bilateral frontal activity than in younger adults. We hypothesized that stimulating the prefrontal cortex in healthy older adults would improve WM performance. To test this hypothesis we employed transcranial direct current stimulation (tDCS), a neurostimulation technique in which small amounts of electrical current are applied to the scalp with the intent of modulating the activity in underlying neurons. Across three testing sessions we applied sham stimulation or anodal tDCS to the left (F3) or right (F4) prefrontal cortex to healthy older adults as they performed trials of verbal and visual 2-back WM tasks. Surprisingly, tDCS was uniformly beneficial across site and WM task, but only in older adults with more education. In the less educated group, tDCS provided no benefit to verbal or visual WM performance. We interpret these findings as evidence for differential frontal recruitment as a function of strategy when older adults perform WM tasks.     

Dopamine D1 receptors and age differences in brain activation during working memory

In an fMRI study, 20 younger and 20 healthy older adults were scanned while performing a spatial working-memory task under two levels of load. On a separate occasion, the same subjects underwent PET measurements using the radioligand [¹¹C] SCH23390 to determine dopamine D₁ receptor binding potential (BP) in caudate nucleus and dorsolateral prefrontal cortex (DLPFC). The fMRI study revealed a significant load modulation of brain activity (higher load > lower load) in frontal and parietal regions for younger, but not older, adults. The PET measurements showed marked age-related reductions of D₁ BP in caudate and DLPFC. Statistical control of caudate and DLPFC D₁ binding eliminated the age-related reduction in load-dependent BOLD signal in left frontal cortex, and attenuated greatly the reduction in right frontal and left parietal cortex. These findings suggest that age-related alterations in dopaminergic neurotransmission may contribute to underrecruitment of task-relevant brain regions during working-memory performance in old age.     

Thalamocortical Connections between the Mediodorsal Nucleus of the Thalamus and Prefrontal Cortex in the Human Brain: A Diffusion Tensor Tractographic Study

Purpose

The elucidation of thalamocortical connections between the mediodorsal nucleus (MD) of thalamus and the prefrontal cortex (PFC) is important in the clinical fields of neurorehabilitation and psychiatry. However, little is known about these connections in human brain. We attempted to identify and investigate the anatomical characteristics of the thalamocortical connection between MD and PFC in human brain using diffusion tensor tractography (DTT).

Materials and Methods

Thirty-two healthy volunteers were recruited for this study. Diffusion tensor images were scanned using a 1.5-T. A seed region of interest was placed at the MD of the thalamus on coronal images, and target regions of interest were placed on the dorsolateral prefrontal cortex (DLPFC), the ventrolateral prefrontal cortex (VLPFC), and the orbitofrontal cortex (OFC), respectively. The three thalamocortical connections found were reconstructed using Functional Magnetic Resonance Imaging of the Brain (FMRIB) software.

Results

The three thalamocortical connections were arranged in subcortical white matter in the following order from upper to lower levels: the DLPFC, the VLPFC, and the OFC. In terms of fractional anisotropy and mean diffusivity values, no significant differences were observed between the DLPFC, VLPFC and OFC (p>0.05). In contrast, the OFC tract volume was higher than those of the DLPFC and the VLPFC (p<0.05).

Conclusion

Three thalamocortical connections were reconstructed between MD and PFCs in human brain using DTT. We believe that the results of this study would be helpful to clinicians in treating frontal network syndrome and psychiatric diseases.     

Structural and functional abnormalities in migraine patients without aura

Migraine is a primary headache disorder characterized by recurrent attacks of throbbing pain associated with neurological, gastrointestinal and autonomic symptoms. Previous studies have detected structural deficits and functional impairments in migraine patients. However, researchers have failed to investigate the functional connectivity alterations of regions with structural deficits during the resting state. Twenty‐one migraine patients without aura and 21 age‐ and gender‐matched healthy controls participated in our study. Voxel‐based morphometric (VBM) analysis and functional connectivity were employed to investigate the abnormal structural and resting‐state properties, respectively, in migraine patients without aura. Relative to healthy comparison subjects, migraine patients showed significantly decreased gray matter volume in five brain regions: the left medial prefrontal cortex (MPFC), dorsal anterior cingulate cortex (dACC), right occipital lobe, cerebellum and brainstem. The gray matter volume of the dACC was correlated with the duration of disease in migraine patients, and thus we chose this region as the seeding area for resting‐state analysis. We found that migraine patients showed increased functional connectivity between several regions and the left dACC, i.e. the bilateral middle temporal lobe, orbitofrontal cortex (OFC) and left dorsolateral prefrontal cortex (DLPFC). Furthermore, the functional connectivity between the dACC and two regions (i.e. DLPFC and OFC) was correlated with the duration of disease in migraine patients. We suggest that frequent nociceptive input has modified the structural and functional patterns of the frontal cortex, and these changes may explain the functional impairments in migraine patients. Copyright © 2012 John Wiley & Sons, Ltd.     

Propensity and sensitivity measures of fear and disgust are differentially related to emotion-specific brain activation

Neuroimaging studies on individual differences in experiencing disgust and fear have indicated that disgust propensity and trait anxiety are able to moderate brain activity. The moderating role of disgust sensitivity and anxiety sensitivity has not been investigated thus far. Both sensitivity traits refer to the tendency of a person to perceive harmful consequences of experiencing fear and disgust. Eighteen female subjects viewed and subsequently rated pictures for the elicitation of disgust, fear and a neutral affective state. The viewing of the aversive pictures was associated with activation of visual processing areas, the amygdala, the insula and the orbitofrontal cortex (OFC). In the disgust condition, disgust propensity was positively correlated with activation of attention-related areas (parietal cortex, anterior cingulate cortex (ACC)) and brain regions involved in valence and arousal processing (OFC, insula). For the fear condition, we observed positive correlations between trait anxiety and activation of the ACC, the insula, and the OFC. Correlations between brain activity and sensitivity measures were exclusively negative and concerned areas crucial for emotion regulation, such as the medial and dorsolateral prefrontal cortex (MPFC, DLPFC). Thus, individuals high in disgust/anxiety sensitivity might have difficulties to successfully control the specific affective experience.     

Anatomical measurements of the orbitofrontal cortex in child and adolescent patients with bipolar disorder

Imaging studies indicate smaller orbitofrontal cortex (OFC) volume in mood disorder patients compared with healthy subjects. We sought to determine whether child and adolescent patients with bipolar disorder have smaller OFC volumes than healthy controls. Fourteen children and adolescents meeting DSM-IV criteria for bipolar disorder (six males and eight females with a mean age+/-S.D.=15.5+/-3.2 years) and 20 healthy controls (11 males and nine females with mean age+/-S.D.=16.9+/-3.8 years) were studied. Orbitofrontal cortex volume was measured using magnetic resonance imaging. Male bipolar patients had smaller gray matter volumes in medial (p=0.044), right medial (0.037) and right (p=0.032) lateral OFC subdivisions compared to male controls. In contrast, female patients had larger gray matter volumes in left (p=0.03), lateral (p=0.012), left lateral (p=0.007), and trends for larger volumes in right lateral and left medial OFC subdivisions compared with female controls. Male patients exhibit smaller gray matter volumes, while female patients exhibit larger volumes in some OFC sub-regions. Gender differences in OFC abnormalities may be involved in illness pathophysiology among young bipolar patients.     

Executive functions and neurocognitive aging: dissociable patterns of brain activity

Studies of neurocognitive aging report altered patterns of brain activity in older versus younger adults performing executive function tasks. We review the extant literature, using activation likelihood estimation meta-analytic methods, to compare age-related differences in the pattern of brain activity across studies examining 2 categories of tasks associated with executive control processing: working memory and inhibition. In a direct contrast of young and older adult activations, older adults engaged bilateral regions of dorsolateral prefrontal cortex as well as supplementary motor cortex and left inferior parietal lobule during working memory. In contrast, age-related changes during inhibitory control were observed in right inferior frontal gyrus and presupplementary motor area. Additionally, when we examined task-related differences within each age group we observed the predicted pattern of differentiated neural response in the younger subjects: lateral prefrontal cortex activity associated with working memory versus right anterior insula/frontal opercular activity associated with inhibition. This separation was largely maintained in older subjects. These data provide the first quantitative meta-analytic evidence that age-related patterns of functional brain change during executive functioning depend on the specific control process being challenged.     

Prefrontal mediation of age differences in cognitive reappraisal

Despite cognitive and physical declines, it has been suggested that older adults remain able to regulate their emotions effectively. However, whether this is true for all emotion regulation processes has not been established. We hypothesized that cognitive reappraisal, a form of emotion regulation requiring intact cognitive control ability, may be compromised in older age, and that this age difference would be mediated by reduced activation in prefrontal cortex (PFC). Sixteen younger and 15 older adults used gaze-directed reappraisal to increase and decrease emotion in response to unpleasant pictures. This was compared with simply viewing the pictures. Relative to younger adults, older adults were less successful using reappraisal to decrease unpleasant emotion but more successful using reappraisal to increase unpleasant emotion. They also exhibited reduced activation in dorsomedial and left ventrolateral prefrontal cortex. Importantly, activation in these regions differentially mediated the effect of age on emotion. This pattern confirms the importance of cognitive control in reappraising unpleasant situations and suggests that older age may (but does not always) confer effective emotion regulation.     

Altered functional brain networks in Prader–Willi syndrome

Prader–Willi syndrome (PWS) is a genetic imprinting disorder characterized mainly by hyperphagia and early childhood obesity. Previous functional neuroimaging studies used visual stimuli to examine abnormal activities in the eating‐related neural circuitry of patients with PWS. It was found that patients with PWS exhibited both excessive hunger and hyperphagia consistently, even in situations without any food stimulation. In the present study, we employed resting‐state functional MRI techniques to investigate abnormal brain networks related to eating disorders in children with PWS. First, we applied amplitude of low‐frequency fluctuation analysis to define the regions of interest that showed significant alterations in resting‐state brain activity levels in patients compared with their sibling control group. We then applied a functional connectivity (FC) analysis to these regions of interest in order to characterize interactions among the brain regions. Our results demonstrated that patients with PWS showed decreased FC strength in the medial prefrontal cortex (MPFC)/inferior parietal lobe (IPL), MPFC/precuneus, IPL/precuneus and IPL/hippocampus in the default mode network; decreased FC strength in the pre‐/postcentral gyri and dorsolateral prefrontal cortex (DLPFC)/orbitofrontal cortex (OFC) in the motor sensory network and prefrontal cortex network, respectively; and increased FC strength in the anterior cingulate cortex/insula, ventrolateral prefrontal cortex (VLPFC)/OFC and DLPFC/VLPFC in the core network and prefrontal cortex network, respectively. These findings indicate that there are FC alterations among the brain regions implicated in eating as well as rewarding, even during the resting state, which may provide further evidence supporting the use of PWS as a model to study obesity and to provide information on potential neural targets for the medical treatment of overeating. Copyright © 2013 John Wiley & Sons, Ltd.     

N-acetylaspartate levels of left frontal cortex are associated with verbal intelligence in women but not in men: a proton magnetic resonance spectroscopy study

The left frontal cortex plays an important role in executive function and complex language processing inclusive of spoken language. The purpose of this work was to assess metabolite levels in the left and right prefrontal cortex and left anterior cingulum by proton magnetic resonance spectroscopy and relate results to verbal intelligence (Wechsler Adult Intelligence Scale revised) in a sample of college-educated healthy volunteers (dorsolateral prefrontal cortex [DLPFC]: n=52, 23 females, and left anterior cingulum: n=62, 22 females; age range: 20-75 years). In women only, N-acetylaspartate in the DLPFC and in the left anterior cingulate cortex was positively correlated with vocabulary scores. Our data support the hypothesis of existing gender differences regarding the involvement of the left frontal cortex in verbal processing as reflected in different correlations of specific metabolites with verbal scores.     

Neurophysiological correlates of age-related changes in working memory capacity

Cognitive abilities such as working memory (WM) capacity decrease with age. To determine the neurophysiological correlates of age-related reduction in working memory capacity, we studied 10 young subjects (<35 years of age; mean age=29) and twelve older subjects (>55 years of age; mean age=59) with whole brain blood oxygenation-level dependent (BOLD) fMRI on a 1.5 T GE MR scanner using a SPIRAL FLASH pulse sequence (TE=24 ms, TR=56 ms, FA=60 degrees , voxel dimensions=3.75 mm(3)). Subjects performed a modified version of the "n" back working memory task at different levels of increasing working memory load (1-Back, 2-Back and 3-Back). Older subjects performed as well as the younger subjects at 1-Back (p=0.4), but performed worse than the younger subjects at 2-Back (p<0.01) and 3-Back (p=0.06). Older subjects had significantly longer reaction time (RT) than younger subjects (p<0.04) at all levels of task difficulty. Image analysis using SPM 99 revealed a similar distribution of cortical activity between younger and older subjects at all task levels. However, an analysis of variance revealed a significant group x task interaction in the prefrontal cortex bilaterally; within working memory capacity, as in 1-Back when the older subjects performed as well as the younger subjects, they showed greater prefrontal cortical (BA 9) activity bilaterally. At higher working memory loads, however, when they performed worse then the younger subjects, the older subjects showed relatively reduced activity in these prefrontal regions. These data suggest that, within capacity, compensatory mechanisms such as additional prefrontal cortical activity are called upon to maintain proficiency in task performance. As cognitive demand increases, however, they are pushed past a threshold beyond which physiological compensation cannot be made and, a decline in performance occurs.     

The role of non‐rapid eye movement slow‐wave activity in prefrontal metabolism across young and middle‐aged adults

Electroencephalographic slow‐wave activity (0.5–4 Hz) during non‐rapid eye movement (NREM) sleep is a marker for cortical reorganization, particularly within the prefrontal cortex. Greater slow wave activity during sleep may promote greater waking prefrontal metabolic rate and, in turn, executive function. However, this process may be affected by age. Here we examined whether greater NREM slow wave activity was associated with higher prefrontal metabolism during wakefulness and whether this relationship interacted with age. Fifty‐two participants aged 25–61 years were enrolled into studies that included polysomnography and a ¹⁸[F]‐fluoro‐deoxy‐glucose positron emission tomography scan during wakefulness. Absolute and relative measures of NREM slow wave activity were assessed. Semiquantitative and relative measures of cerebral metabolism were collected to assess whole brain and regional metabolism, focusing on two regions of interest: the dorsolateral prefrontal cortex and the orbitofrontal cortex. Greater relative slow wave activity was associated with greater dorsolateral prefrontal metabolism. Age and slow wave activity interacted significantly in predicting semiquantitative whole brain metabolism and outside regions of interest in the posterior cingulate, middle temporal gyrus and the medial frontal gyrus, such that greater slow‐wave activity was associated with lower metabolism in the younger participants and greater metabolism in the older participants. These results suggest that slow‐wave activity is associated with cerebral metabolism during wakefulness across the adult lifespan within regions important for executive function.     

Patterns of brain activation in people at risk for Alzheimer's disease

BACKGROUND: The epsilon4 allele of the apolipoprotein E gene (APOE) is the chief known genetic risk factor for Alzheimer's disease, the most common cause of dementia late in life. To determine the relation between brain responses to tasks requiring memory and the genetic risk of Alzheimer's disease, we performed APOE genotyping and functional magnetic resonance imaging (MRI) of the brain in older persons with intact cognition. METHODS: We studied 30 subjects (age, 47 to 82 years) who were neurologically normal, of whom 16 were carriers of the APOE epsilon4 allele and 14 were homozygous for the APOE epsilon3 allele. The mean age and level of education were similar in the two groups. Patterns of brain activation during functional MRI scanning were determined while subjects memorized and recalled unrelated pairs of words and while subjects rested between such periods. Memory was reassessed in 14 subjects two years later. RESULTS: Both the magnitude and the extent of brain activation during memory-activation tasks in regions affected by Alzheimer's disease, including the left hippocampal, parietal, and prefrontal regions, were greater among the carriers of the APOE epsilon4 allele than among the carriers of the APOE epsilon3 allele. During periods of recall, the carriers of the APOE epsilon4 allele had a greater average increase in signal intensity in the hippocampal region (1.03 percent vs. 0.62 percent, P<0.001) and a greater mean (+/-SD) number of activated regions throughout the brain (15.9+/-6.2 vs. 9.4+/-5.5, P=0.005) than did carriers of the APOE epsilon3 allele. Longitudinal assessment after two years indicated that the degree of base-line brain activation correlated with degree of decline in memory. CONCLUSIONS: Patterns of brain activation during tasks requiring memory differ depending on the genetic risk of Alzheimer's disease and may predict a subsequent decline in memory.