Kristi R. Griffiths

Disorder specificity despite comorbidity: Resting EEG alpha asymmetry in major depressive disorder and post-traumatic stress disorder

The approach-withdrawal and valence-arousal models highlight that specific brain laterality profiles may distinguish depression and anxiety. However, studies remain to be conducted in multiple clinical populations that directly test the diagnostic specificity of these hypotheses. The current study compared electroencephalographic data under resting state, eyes closed conditions in patients with major depressive disorder (MDD) (N=15) and post-traumatic stress disorder (PTSD) (N=14) relative to healthy controls (N=15) to examine the specificity of brain laterality in these disorders. Key findings included (1) reduced left-frontal activity in MDD, (2) a positive correlation between PTSD severity and right-frontal lateralisation, (3) greater activity in PTSD patients relative to MDD within the right-parietotemporal region, and (4) globally increased alpha power in MDD. Findings partially support the diagnostic applicability of the theoretical frameworks. Future studies may benefit from examining task-driven differences between groups.

Oxytocin increases heart rate variability in humans at rest: implications for social approach-related motivation and capacity for social engagement.

Context Oxytocin (OT) plays a key regulatory role in human social behaviour. While prior studies have examined the effects of OT on observable social behaviours, studies have seldom examined the effects of OT on psychophysiological markers such as heart rate variability (HRV), which provides an index of individual’s motivation for social behaviour. Furthermore, no studies have examined the impact of OT on HRV under resting conditions, which provides an index of maximal capacity for social engagement. Objective To examine the effects of OT on HRV measures in healthy male participants while at rest. OT was hypothesised to increase HRV, compared to placebo, and that the effects would be greatest for a non-linear measure of HRV (the detrended fluctuation scaling exponent). Methods Twenty-one male participants were recruited for this study. Participants were non-smokers, not on any medications and reported no history of psychiatric illness, neurological disorder, or any other serious medical condition (e.g. diabetes, cardiovascular disease). The study employed a randomised, placebo-controlled, within-subject, crossover, experimental design. Main Outcome Measures HRV was calculated from electrocardiography under a standardized, 10-minute, resting state condition. Results As hypothesised, OT increased HRV and these effects were largest using the detrended fluctuation scaling exponent, a non-linear measure. These changes were observed in the absence of any change in state mood, as measured by the profile of mood states. Importantly, participants were unable to correctly guess which treatment they had been assigned at either of the two assessments. Conclusions Together with the broader literature on OT and HRV, findings suggest that acute administration of OT may facilitate a fundamental psychophysiological feature of social behaviour, increasing capacity for social engagement. Findings also suggest that HRV changes may provide a novel biomarker of response to OT nasal spray that can be incorporated into research on response to treatment.

Corticostriatal Control of Goal-Directed Action Is Impaired in Schizophrenia

BACKGROUND Goal-directed actions depend on our capacity to integrate the anticipated consequences of an action with the value of those consequences, with the latter derived from direct experience or inferred from predictive stimuli. Schizophrenia is associated with poor goal-directed performance, but whether this reflects a deficit in experienced or predicted value or in integrating these values with action-outcome information is unknown, as is the locus of any associated neuropathology. METHODS We assessed the contribution of these sources of value to goal-directed actions in people with schizophrenia (SZ) (n = 18) and healthy adults (n = 18). Participants learned to use specific actions to liberate snack foods from a vending machine. They also learned about the reward value of the foods, changes in reward value, and the relationship between various predictive stimuli and food delivery. We then evaluated the ability of subjects to use experienced or predicted value to guide goal-directed actions while undergoing functional magnetic resonance imaging. RESULTS Acquisition and sensitivity to experienced changes in outcome value did not differ in SZ and healthy adults. The SZ were, however, deficient in their ability to integrate action-outcome learning with outcome values to guide choice, more so when actions were guided by experienced than by predicted values. These effects were differentially associated with reductions in activity in caudate and limbic structures, respectively. CONCLUSIONS This novel assessment of goal-directed learning revealed dysfunction in corticostriatal control associated with a profound deficit in integrating changes in experienced value with the action-outcome association in schizophrenia.

Translational studies of goal-directed action as a framework for classifying deficits across psychiatric disorders

The ability to learn contingencies between actions and outcomes in a dynamic environment is critical for flexible, adaptive behavior. Goal-directed actions adapt to changes in action-outcome contingencies as well as to changes in the reward-value of the outcome. When networks involved in reward processing and contingency learning are maladaptive, this fundamental ability can be lost, with detrimental consequences for decision-making. Impaired decision-making is a core feature in a number of psychiatric disorders, ranging from depression to schizophrenia. The argument can be developed, therefore, that seemingly disparate symptoms across psychiatric disorders can be explained by dysfunction within common decision-making circuitry. From this perspective, gaining a better understanding of the neural processes involved in goal-directed action, will allow a comparison of deficits observed across traditional diagnostic boundaries within a unified theoretical framework. This review describes the key processes and neural circuits involved in goal-directed decision-making using evidence from animal studies and human neuroimaging. Select studies are discussed to outline what we currently know about causal judgments regarding actions and their consequences, action-related reward evaluation, and, most importantly, how these processes are integrated in goal-directed learning and performance. Finally, we look at how adaptive decision-making is impaired across a range of psychiatric disorders and how deepening our understanding of this circuitry may offer insights into phenotypes and more targeted interventions.

Microstructural White Matter Changes in the Corpus Callosum of Young People with Bipolar Disorder: A Diffusion Tensor Imaging Study

To date, most studies of white matter changes in Bipolar Disorder (BD) have been conducted in older subjects and with well-established disorders. Studies of young people who are closer to their illness onset may help to identify core neurobiological characteristics and separate these from consequences of repeated illness episodes or prolonged treatment. Diffusion tensor imaging (DTI) was used to examine white matter microstructural changes in 58 young patients with BD (mean age 23 years; range 16–30 years) and 40 controls. Whole brain voxelwise measures of fractional anisotropy (FA), parallel diffusivity (λ//) and radial diffusivity (λ⊥) were calculated for all subjects. White matter microstructure differences (decreased FA corrected p<.05) were found between the patients with BD and controls in the genu, body and splenium of the corpus callosum as well as the superior and anterior corona radiata. In addition, significantly increased radial diffusivity (p<.01) was found in the BD group. Neuroimaging studies of young patients with BD may help to clarify neurodevelopmental aspects of the illness and for identifying biomarkers of disease onset and progression. Our findings provide evidence of microstructural white matter changes early in the course of illness within the corpus callosum and the nature of these changes suggest they are associated with abnormalities in the myelination of axons.

Action-value comparisons in the dorsolateral prefrontal cortex control choice between goal-directed actions

It is generally assumed that choice between different actions reflects the difference between their action values yet little direct evidence confirming this assumption has been reported. Here we assess whether the brain calculates the absolute difference between action values or their relative advantage, that is, the probability that one action is better than the other alternatives. We use a two-armed bandit task during functional magnetic resonance imaging and modelled responses to determine both the size of the difference between action values (D) and the probability that one action value is better (P). The results show haemodynamic signals corresponding to P in right dorsolateral prefrontal cortex (dlPFC) together with evidence that these signals modulate motor cortex activity in an action-specific manner. We find no significant activity related to D. These findings demonstrate that a distinct neuronal population mediates action-value comparisons, and reveals how these comparisons are implemented to mediate value-based decision-making.

The functional epistasis of 5‐HTTLPR and BDNF Val66Met on emotion processing: a preliminary study

An epistatic interaction of 5‐HTTLPR and BDNF Val66Met polymorphisms has been implicated in the structure of rostral anterior cingulate cortex (rACC) and amygdala (AMY): key regions associated with emotion processing. However, a functional epistasis of 5‐HTTLPR and BDNF Val66Met on overt emotion processing has yet to be determined. Twenty‐eight healthy, Caucasian female participants provided saliva samples for genotyping and underwent functional magnetic resonance imaging (fMRI) during which an emotion processing protocol were presented. Confirming the validity of this protocol, we observed blood oxygen level–dependent (BOLD) activity consistent with fMRI meta‐analyses on emotion processing. Region‐of‐interest analysis of the rACC and AMY revealed main effects of 5‐HTTLPR and BDNF Val66Met, and an interaction of 5‐HTTLPR and BDNF Val66Met. The effect of the BDNF Met66 allele was dependent on 5‐HTTLPR alleles, such that participants with S and Met alleles had the greatest rACC and AMY activation during the presentation of emotional images relative to other genetic groupings. Increased activity in these regions was interpreted as increased reactivity to emotional stimuli, suggesting that those with S and Met alleles are more reactive to emotional stimuli relative to other groups. Although limited by a small sample, this study contributes novel and preliminary findings relating to a functional epistasis of the 5‐HTTLPR and BDNF Val66Met genes in emotion processing and provides guidance on appropriate methods to determine genetic epistasis in fMRI.

Right external globus pallidus changes are associated with altered causal awareness in youth with depression.

Cognitive impairment is a functionally disabling feature of depression contributing to maladaptive decision-making, a loss of behavioral control and an increased disease burden. The ability to calculate the causal efficacy of ones actions in achieving specific goals is critical to normal decision-making and, in this study, we combined voxel-based morphometry (VBM), shape analysis and diffusion tensor tractography to investigate the relationship between cortical–basal ganglia structural integrity and such causal awareness in 43 young subjects with depression and 21 demographically similar healthy controls. Volumetric analysis determined a relationship between right pallidal size and sensitivity to the causal status of specific actions. More specifically, shape analysis identified dorsolateral surface vertices where an inward location was correlated with reduced levels of causal awareness. Probabilistic tractography revealed that affected parts of the pallidum were primarily connected with the striatum, dorsal thalamus and hippocampus. VBM did not reveal any whole-brain gray matter regions that correlated with causal awareness. We conclude that volumetric reduction within the indirect pathway involving the right dorsolateral pallidum is associated with reduced awareness of the causal efficacy of goal-directed actions in young depressed individuals. This causal awareness task allows for the identification of a functionally and biologically relevant subgroup to which more targeted cognitive interventions could be applied, potentially enhancing the long-term outcomes for these individuals.

Sustained attention and heart rate variability in children and adolescents with ADHD

The autonomic nervous system (ANS) plays an important role in attention and self-regulation by modulating physiological arousal to meet environmental demands. Core symptoms of ADHD such as inattention and behavioral disinhibition may be related to dysregulation of the ANS, however previous findings have been equivocal. We examined autonomic activity and reactivity by assessing heart rate variability (HRV) in a large sample of un-medicated children and adolescents (6-19 years) with ADHD (n=229) compared to typically-developing controls (n=244) during rest and sustained attention. Four heart rate variability measures were extracted: Root mean square of successive differences between inter-beat-intervals (rMSSD), absolute high frequency (HFA) power, absolute low frequency (LFA) power and ratio of low frequency power to high frequency power (LF/HF). There were no group differences in HFA or rMSSD, even when assessing across child and adolescent groups separately, by gender or ADHD subtype. LF/HF however was higher in ADHD during both rest and sustained attention conditions, particularly in male children. Sustained attention was impaired in ADHD relative to controls, and a higher LF/HF ratio during sustained attention was associated with poorer performance in both groups. Lower rMSSD and HFA were associated with higher anxiety, oppositional behaviors and social problems, supporting prevailing theories that these measures index emotion regulation and adaptive social behavior. Different measures of heart rate variability provide important insights into the sustained attention and emotional and behavioral regulation impairments observed in ADHD and may aid in delineating ADHD pathophysiology.

Altered gray matter organization in children and adolescents with ADHD: a structural covariance connectome study

Although multiple studies have reported structural deficits in multiple brain regions in attention-deficit hyperactivity disorder (ADHD), we do not yet know if these deficits reflect a more systematic disruption to the anatomical organization of large-scale brain networks. Here we used a graph theoretical approach to quantify anatomical organization in children and adolescents with ADHD. We generated anatomical networks based on covariance of gray matter volumes from 92 regions across the brain in children and adolescents with ADHD (n=34) and age- and sex-matched healthy controls (n=28). Using graph theory, we computed metrics that characterize both the global organization of anatomical networks (interconnectivity (clustering), integration (path length) and balance of global integration and localized segregation (small-worldness)) and their local nodal measures (participation (degree) and interaction (betweenness) within a network). Relative to Controls, ADHD participants exhibited altered global organization reflected in more clustering or network segregation. Locally, nodal degree and betweenness were increased in the subcortical amygdalae in ADHD, but reduced in cortical nodes in the anterior cingulate, posterior cingulate, mid temporal pole and rolandic operculum. In ADHD, anatomical networks were disrupted and reflected an emphasis on subcortical local connections centered around the amygdala, at the expense of cortical organization. Brains of children and adolescents with ADHD may be anatomically configured to respond impulsively to the automatic significance of stimulus input without having the neural organization to regulate and inhibit these responses. These findings provide a novel addition to our current understanding of the ADHD connectome.