Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome.

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.

Resting-State Correlations of Fatigue Following Military Deployment.

OBJECTIVE: Persistent fatigue is common among military servicemembers returning from deployment, especially those with a history of mild traumatic brain injury (mTBI). The purpose of this study was to characterize fatigue following deployment using the Multidimensional Fatigue Inventory (MFI), a multidimensional self-report instrument. The study was developed to test the hypothesis that if fatigue involves disrupted effort/reward processing, this should manifest as altered basal ganglia functional connectivity as observed in other amotivational states. METHODS: Twenty-eight current and former servicemembers were recruited and completed the MFI. All 28 participants had a history of at least one mTBI during deployment. Twenty-six participants underwent resting-state functional MRI. To test the hypothesis that fatigue was associated with basal ganglia functional connectivity, the investigators measured correlations between MFI subscale scores and the functional connectivity of the left and right caudate, the putamen, and the globus pallidus with the rest of the brain, adjusting for the presence of depression. RESULTS: The investigators found a significant correlation between functional connectivity of the left putamen and bilateral superior frontal gyri and mental fatigue scores. No correlations with the other MFI subscales survived multiple comparisons correction. CONCLUSIONS: This exploratory study suggests that mental fatigue in military servicemembers with a history of deployment with at least one mTBI may be related to increased striatal-prefrontal functional connectivity, independent of depression. A finding of effort/reward mismatch may guide future treatment approaches.

Testosterone and Resting State Connectivity of the Parahippocampal Gyrus in Men With History of Deployment-Related Mild Traumatic Brain Injury.

INTRODUCTION: The purpose of this study was to explore the effect of low testosterone level on whole-brain resting state (RS) connectivity in male veterans with symptoms such as sleep disturbance, fatiguability, pain, anxiety, irritability, or aggressiveness persisting after mild traumatic brain injury (mTBI). Follow-up analyses were performed to determine if sleep scores affected the results. MATERIALS AND METHODS: In our cross-sectional design study, RS magnetic resonance imaging scans on 28 veterans were performed, and testosterone, sleep quality, mood, and post-traumatic stress symptoms were measured. For each participant, we computed the average correlation of each voxel's time-series with the rest of the voxels in the brain, then used AFNI's 3dttest++ on the group data to determine whether the effects of testosterone level on whole-brain connectivity were significant. We then performed follow-up region of interest-based RS analyses of testosterone, with and without sleep quality as a covariate. The study protocol was approved by the National Institute of Health's Combined Neuroscience Institutional Review Board. RESULTS: Sixteen participants reported repeated blast exposure in theater, leading to symptoms; the rest reported exposure to a single blast or a nonblast TBI. Thirty-three percent had testosterone levels <300 ng/dL. Testosterone level was lower in participants who screened positive for post-traumatic stress disorder compared to those who screened negative, but it did not reach statistical significance. Whole-brain connectivity and testosterone level were positively correlated in the left parahippocampal gyrus (LPhG), especially in its connectivity with frontal areas, the lingual gyrus, cingulate, insula, caudate, and right parahippocampal gyrus. Further analysis revealed that the effect of testosterone on LPhG connectivity is only partially mediated by sleep quality. Sleep quality by itself had an effect on connectivity of the thalamus, cerebellum, precuneus, and posterior cingulate. CONCLUSION: Lower testosterone levels were correlated with lower connectivity of the LPhG. Weaknesses of this study include a retrospective design based on self-report of mTBI and the lack of a control group without TBI. Without a control group or pre-injury testosterone measures, we were not able to attribute the rate of low testosterone in our participants to TBI per se. Also testosterone levels were checked only once. The high rate of low testosterone level that we found suggests there may be an association between low testosterone level and greater post-traumatic stress disorder symptoms following deployment, but the causality of the relationships between TBI and deployment stress, testosterone level, behavioral symptomatology, and LPhG connectivity remains to be determined. Our study on men with persistent symptoms postdeployment and post-mTBI may help us understand the role of low testosterone and sleep quality in persistent symptoms and may be important in developing therapeutic interventions. Our results highlight the role of the LPhG, as we found that whole-brain connectivity in that region was positively associated with testosterone level, with only a limited portion of that effect attributable to sleep quality.

Canonical correlation analysis of brain prefrontal activity measured by functional near infra-red spectroscopy (fNIRS) during a moral judgment task.

Individuals differ in the extent to which they make decisions in different moral dilemmas. In this study, we investigated the relationship between functional brain activities during moral decision making and psychopathic personality traits in a healthy population. We measured the hemodynamic activities of the brain by functional near-infrared spectroscopy (fNIRS). FNIRS is an evolving non-invasive neuroimaging modality which is relatively inexpensive, patient friendly and robust to subject movement. Psychopathic traits were evaluated through a self-report questionnaire called the Psychopathic Personality Inventory Revised (PPI-R). We recorded functional brain activities of 30 healthy subjects while they performed a moral judgment (MJ) task. Regularized canonical correlation analysis (R-CCA) was applied to find the relationships between activation in different regions of prefrontal cortex (PFC) and the core psychopathic traits. Our results showed a significant canonical correlation between PFC activation and PPI-R content scale (PPI-R-CS). Specifically, coldheartedness and carefree non-planfulness were the only PPI-R-CS factors that were highly correlated with PFC activation during personal (emotionally salient) MJ, while Machiavellian egocentricity, rebellious nonconformity, coldheartedness, and carefree non-planfulness were the core traits that exhibited the same dynamics as PFC activation during impersonal (more logical) MJ. Furthermore, ventromedial prefrontal cortex (vmPFC) and left lateral PFC were the most positively correlated regions with PPI-R-CS traits during personal MJ, and the right vmPFC and right lateral PFC in impersonal MJ.

The role of prefrontal cortex in a moral judgment task using functional near-infrared spectroscopy.

BACKGROUND: Understanding the neural basis of moral judgment (MJ) and human decision-making has been the subject of numerous studies because of their impact on daily life activities and social norms. Here, we aimed to investigate the neural process of MJ using functional near-infrared spectroscopy (fNIRS), a noninvasive, portable, and affordable neuroimaging modality. METHODS: We examined prefrontal cortex (PFC) activation in 33 healthy participants engaging in MJ exercises. We hypothesized that participants presented with personal (emotionally salient) and impersonal (less emotional) dilemmas would exhibit different brain activation observable through fNIRS. We also investigated the effects of utilitarian and nonutilitarian responses to MJ scenarios on PFC activation. Utilitarian responses are those that favor the greatest good while nonutilitarian responses favor moral actions. Mixed effect models were applied to model the cerebral hemodynamic changes that occurred during MJ dilemmas. RESULTS AND CONCLUSIONS: Our analysis found significant differences in PFC activation during personal versus impersonal dilemmas. Specifically, the left dorsolateral PFC was highly activated during impersonal MJ when a nonutilitarian decision was made. This is consistent with the majority of relevant fMRI studies, and demonstrates the feasibility of using fNIRS, with its portable and motion tolerant capacities, to investigate the neural basis of MJ dilemmas.

Effective connectivity of brain regions underlying third-party punishment: Functional MRI and Granger causality evidence.

Third-party punishment (TPP) for norm violations is an essential deterrent in large-scale human societies, and builds on two essential cognitive functions: evaluating legal responsibility and determining appropriate punishment. Despite converging evidence that TPP is mediated by a specific set of brain regions, little is known about their effective connectivity (direction and strength of connections). Applying parametric event-related functional MRI in conjunction with multivariate Granger causality analysis, we asked healthy participants to estimate how much punishment a hypothetical perpetrator deserves for intentionally committing criminal offenses varying in levels of harm. Our results confirmed that TPP legal decisions are based on two domain-general networks: the mentalizing network for evaluating legal responsibility and the central-executive network for determining appropriate punishment. Further, temporal pole (TP) and dorsomedial prefrontal cortex (PFC) emerged as hubs of the mentalizing network, uniquely generating converging output connections to ventromedial PFC, temporo-parietal junction, and posterior cingulate. In particular, dorsomedial PFC received inputs only from TP and both its activation and its connectivity to dorsolateral PFC correlated with degree of punishment. This supports the hypothesis that dorsomedial PFC acts as the driver of the TPP activation pattern, leading to the decision on the appropriate punishment. In conclusion, these results advance our understanding of the organizational elements of the TPP brain networks and provide better insights into the mental states of judges and jurors tasked with blaming and punishing legal wrongs.

Shifts in connectivity during procedural learning after motor cortex stimulation: A combined transcranial magnetic stimulation/functional magnetic resonance imaging study.

Inhibitory transcranial magnetic stimulation (TMS), of which continuous theta burst stimulation (cTBS) is a common form, has been used to inhibit cortical areas during investigations of their function. cTBS applied to the primary motor area (M1) depresses motor output excitability via a local effect and impairs procedural motor learning. This could be due to an effect on M1 itself and/or to changes in its connectivity with other nodes in the learning network. To investigate this issue, we used functional magnetic resonance imaging to measure changes in brain activation and connectivity during implicit procedural learning after real and sham cTBS of M1. Compared to sham, real cTBS impaired motor sequence learning, but caused no local or distant changes in brain activation. Rather, it reduced functional connectivity between motor (M1, dorsal premotor & supplementary motor areas) and visual (superior & inferior occipital gyri) areas. It also increased connectivity between frontal associative (superior & inferior frontal gyri), cingulate (dorsal & middle cingulate), and temporal areas. This potentially compensatory shift in coupling, from a motor-based learning network to an associative learning network accounts for the behavioral effects of cTBS of M1. The findings suggest that the inhibitory TMS affects behavior via relatively subtle and distributed effects on connectivity within networks, rather than by taking the stimulated area "offline".

Association Between Traumatic Brain Injury-Related Brain Lesions and Long-term Caregiver Burden.

OBJECTIVE: To investigate the association between traumatic brain injury (TBI)-related brain lesions and long-term caregiver burden in relation to dysexecutive syndrome. SETTING: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: A total of 256 participants: 105 combat veterans with TBI, 23 healthy control combat veterans (HCv), and 128 caregivers. OUTCOME MEASURE: Caregiver burden assessed by the Zarit Burden Interview at 40 years postinjury. DESIGN: Participants with penetrating TBI were compared with HCv on perceived caregiver burden and neuropsychological assessment measures. Data of computed tomographic scans (overlay lesion maps of participants with a penetrating TBI whose caregivers have a significantly high burden) and behavioral statistical analyses were combined to identify brain lesions associated with caregiver burden. RESULTS: Burden was greater in caregivers of veterans with TBI than in caregivers of HCv. Caregivers of participants with lesions affecting cognitive and behavioral indicators of dysexecutive syndrome (ie, left dorsolateral prefrontal cortex and dorsal anterior cingulate cortex) showed greater long-term burden than caregivers of participants with lesions elsewhere in the brain. CONCLUSION AND IMPLICATION: The TBI-related brain lesions have a lasting effect on long-term caregiver burden due to cognitive and behavioral factors associated with dysexecutive syndrome.

Anhedonia in combat veterans with penetrating head injury.

Anhedonia is a common symptom following traumatic brain injury. The neural basis of anhedonia is poorly understood, but believed to involve disturbed reward processing, rather than the loss of sense of pleasure. This analysis was undertaken to determine if injury to specific regions of prefrontal cortex (PFC) result in anhedonia. A CT-based lesion analysis was undertaken in 192 participants of the Vietnam Head Injury Study, most with penetrating head injury. Participants were divided into left and right ventrolateral prefrontal, bilateral ventromedial prefrontal, and other injury locations. Anhedonia was measured by self-report in each group using the four-item anhedonia subscale score of the Beck Depression Inventory-II. Individuals with right ventrolateral injury reported greater severity of anhedonia compared to those with injury in the left ventrolateral region. These findings support an association between injury in the right ventrolateral PFC and anhedonia.

Theory of mind impairment in patients with behavioural variant fronto-temporal dementia (bv-FTD) increases caregiver burden.

BACKGROUND: Theory of mind (ToM), the capacity to infer the intention, beliefs and emotional states of others, is frequently impaired in behavioural variant fronto-temporal dementia patients (bv-FTDp); however, its impact on caregiver burden is unexplored. SETTING: National Institute of Neurological Disorders and Stroke, National Institutes of Health. SUBJECTS: bv-FTDp (n = 28), a subgroup of their caregivers (n = 20) and healthy controls (n = 32). METHODS: we applied a faux-pas (FP) task as a ToM measure in bv-FTDp and healthy controls and the Zarit Burden Interview as a measure of burden in patients' caregivers. Patients underwent structural MRI; we used voxel-based morphometry to examine relationships between regional atrophy and ToM impairment and caregiver burden. RESULTS: FP task performance was impaired in bv-FTDp and negatively associated with caregiver burden. Atrophy was found in areas involved in ToM. Caregiver burden increased with greater atrophy in left lateral premotor cortex, a region associated in animal models with the presence of mirror neurons, possibly involved in empathy. CONCLUSION: ToM impairment in bv-FTDp is associated with increased caregiver burden.

Areas of Brain Damage Underlying Increased Reports of Behavioral Disinhibition.

Disinhibition, the inability to inhibit inappropriate behavior, is seen in frontal-temporal degeneration, Alzheimer's disease, and stroke. Behavioral disinhibition leads to social and emotional impairments, including impulsive behavior and disregard for social conventions. The authors investigated the effects of lesions on behavioral disinhibition measured by the Neuropsychiatric Inventory in 177 veterans with traumatic brain injuries. The authors performed voxel-based lesion-symptom mapping using MEDx. Damage in the frontal and temporal lobes, gyrus rectus, and insula was associated with greater behavioral disinhibition, providing further evidence of the frontal lobe's involvement in behavioral inhibition and suggesting that these regions are necessary to inhibit improper behavior.

Association between long-term cognitive decline in Vietnam veterans with TBI and caregiver attachment style.

OBJECTIVE: To examine whether a caregiver's attachment style is associated with patient cognitive trajectory after traumatic brain injury (TBI). SETTING: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: Forty Vietnam War veterans with TBI and their caregivers. MAIN OUTCOME MEASURE: Cognitive performance, measured by the Armed Forces Qualification Test percentile score, completed at 2 time points: preinjury and 40 years postinjury. DESIGN: On the basis of caregivers' attachment style (secure, fearful, preoccupied, dismissing), participants with TBI were grouped into a high or low group. To examine the association between cognitive trajectory of participants with TBI and caregivers' attachment style, we ran four 2 × 2 analysis of covariance on cognitive performances. RESULTS: After controlling for other factors, cognitive decline was more pronounced in participants with TBI with a high fearful caregiver than among those with a low fearful caregiver. Other attachment styles were not associated with decline. CONCLUSION AND IMPLICATION: Caregiver fearful attachment style is associated with a significant decline in cognitive status after TBI. We interpret this result in the context of the neural plasticity and cognitive reserve literatures. Finally, we discuss its impact on patient demand for healthcare services and potential interventions.

Object and space perception - is it a matter of hemisphere?

In the 1980s, following Newcombe's observations, Ungerleider and Mishkin put forward the functional subdivision of the visual system into a ventral stream dedicated to object perception and a dorsal stream dedicated to space perception. Ten years after this discovery, the perception-action model re-defined the dorsal stream as responsible for non-conscious visual guidance, and most recently a tripartition has been suggested to account for a variety of visuospatial functions. Here, we investigated the neural underpinnings of object and space perception by combining the administration of the Visual Object Space Perception (VOSP) battery with a voxel-based lesion symptom mapping (VLSM) approach in a large sample of patients with penetrating traumatic brain injury (pTBI). First, our results provided new support for the complementary role of both hemispheres in object recognition. The right lateral occipital complex was found to be critical in early perceptual discrimination, whereas more anterior temporal and frontal regions in the left hemisphere were found to be critical in more complex forms of object discrimination and recognition. Second, our findings confirmed that space perception depended on the integrity of the right inferior parietal lobule (IPL) and revealed that a network linking the right IPL with the right premotor cortex was critical for the perception of spatial relationships in both 2D and 3D representations. Taken together, our results supported the functional subdivision of the visual system and shed new light on the specific processes involved along both the dorsal and the ventral streams.

Neural correlates of apathy revealed by lesion mapping in participants with traumatic brain injuries.

Apathy, common in neurological disorders, is defined as disinterest and loss of motivation, with a reduction in self-initiated activity. Research in diseased populations has shown that apathy is associated with variations in the volume of brain regions such as the anterior cingulate and the frontal lobes. The goal of this study was to determine the neural signatures of apathy in people with penetrating traumatic brain injuries (pTBIs), as to our knowledge, these have not been studied in this sample. We studied 176 male Vietnam War veterans with pTBIs using voxel-based lesion-symptom mapping (VLSM) and apathy scores from the UCLA Neuropsychiatric Inventory (NPI), a structured inventory of symptoms completed by a caregiver. Our results revealed that increased apathy symptoms were associated with brain damage in limbic and cortical areas of the left hemisphere including the anterior cingulate, inferior, middle, and superior frontal regions, insula, and supplementary motor area. Our results are consistent with the literature, and extend them to people with focal pTBI. Apathy is a significant symptom since it can reduce participation of the patient in family and other social interactions, and diminish affective decision-making.

Injured brain regions associated with anxiety in Vietnam veterans.

Anxiety negatively affects quality of life and psychosocial functioning. Previous research has shown that anxiety symptoms in healthy individuals are associated with variations in the volume of brain regions, such as the amygdala, hippocampus, and the bed nucleus of the stria terminalis. Brain lesion data also suggests the hemisphere damaged may affect levels of anxiety. We studied a sample of 182 male Vietnam War veterans with penetrating brain injuries, using a semi-automated voxel-based lesion-symptom mapping (VLSM) approach. VLSM reveals significant associations between a symptom such as anxiety and the location of brain lesions, and does not require a broad, subjective assignment of patients into categories based on lesion location. We found that lesioned brain regions in cortical and limbic areas of the left hemisphere, including middle, inferior and superior temporal lobe, hippocampus, and fusiform regions, along with smaller areas in the inferior occipital lobe, parahippocampus, amygdala, and insula, were associated with increased anxiety symptoms as measured by the Neurobehavioral Rating Scale (NRS). These results were corroborated by similar findings using Neuropsychiatric Inventory (NPI) anxiety scores, which supports these regions' role in regulating anxiety. In summary, using a semi-automated analysis tool, we detected an effect of focal brain damage on the presentation of anxiety. We also separated the effects of brain injury and war experience by including a control group of combat veterans without brain injury. We compared this control group against veterans with brain lesions in areas associated with anxiety, and against veterans with lesions only in other brain areas.

A voxel-based lesion study on facial emotion recognition after penetrating brain injury.

The ability to read emotions in the face of another person is an important social skill that can be impaired in subjects with traumatic brain injury (TBI). To determine the brain regions that modulate facial emotion recognition, we conducted a whole-brain analysis using a well-validated facial emotion recognition task and voxel-based lesion symptom mapping (VLSM) in a large sample of patients with focal penetrating TBIs (pTBIs). Our results revealed that individuals with pTBI performed significantly worse than normal controls in recognizing unpleasant emotions. VLSM mapping results showed that impairment in facial emotion recognition was due to damage in a bilateral fronto-temporo-limbic network, including medial prefrontal cortex (PFC), anterior cingulate cortex, left insula and temporal areas. Beside those common areas, damage to the bilateral and anterior regions of PFC led to impairment in recognizing unpleasant emotions, whereas bilateral posterior PFC and left temporal areas led to impairment in recognizing pleasant emotions. Our findings add empirical evidence that the ability to read pleasant and unpleasant emotions in other people's faces is a complex process involving not only a common network that includes bilateral fronto-temporo-limbic lobes, but also other regions depending on emotional valence.

Implicit attitudes in prosopagnosia.

We studied a male with acquired prosopagnosia using a battery of Implicit Association Tests (IATs) to investigate whether observing faces varying by social category would activate the patient's implicit social biases. We also asked him to categorize faces explicitly by race, gender, and political party. The patient, G.B., was marginally slower to categorize black compared to white faces. He showed congruency effects in the race and celebrity IATs, but not in the gender or political IATs. These results indicate that G.B. possesses an implicit social sensitivity to certain facial stimuli despite an inability to overtly recognize familiar faces. The results demonstrate that social biases can be retrieved based on facial stimuli via pathways bypassing the fusiform gyri. Thus the IAT effect can be added to the list of covert recognition effects found in prosopagnosia.

Developmental effects of aggressive behavior in male adolescents assessed with structural and functional brain imaging.

Aggressive behavior is common during adolescence. Although aggression-related functional changes in the ventromedial prefrontal cortex (vmPFC) and frontopolar cortex (FPC) have been reported in adults, the neural correlates of aggressive behavior in adolescents, particularly in the context of structural neurodevelopment, are obscure. We used functional and structural magnetic resonance imaging (MRI) to measure the blood oxygenation level-depended signal and cortical thickness. In a block-designed experiment, 14-17-year old adolescents imagined aggressive and non-aggressive interactions with a peer. We show reduced vmPFC activation associated with imagined aggressive behavior as well as enhanced aggression-related activation and cortical thinning in the FPC with increasing age. Changes in FPC activation were also associated with judgments of the severity of aggressive acts. Reduced vmPFC activation was associated with greater aggression indicating its normal function is to exert inhibitory control over aggressive impulses. Concurrent FPC activation likely reflects foresight of harmful consequences that result from aggressive acts. The correlation of age-dependent activation changes and cortical thinning demonstrates ongoing maturation of the FPC during adolescence towards a refinement of social and cognitive information processing that can potentially facilitate mature social behavior in aggressive contexts.

Behavioral norms for condensed moral vignettes.

Moral judgment is an evaluation of the actions and character of a person made with respect to societal norms. Although many types of vignettes have been used in previous studies on moral beliefs and judgment, what is missing is a set of standardized common vignettes based in real life. The goal of this study was to provide researchers with stimuli that have values on several dimensions pertaining to moral judgment and whose underlying components are known. These values will allow researchers to select stimuli based on standardized ratings rather than on the results of pilot studies, while avoiding the limitations of the classic, abstract moral scenarios. Our study was composed of three phases, (i) collecting and shortening the vignettes, (ii) obtaining ratings of the vignettes on several dimensions including emotional intensity, degree of social norm violation, and level of harm or benefit caused and (iii) determining the underlying components of the vignettes by performing a factor analysis. We found three components that accounted for most of the variance: norm violation, social affect and intention. The resulting vignettes can be used in future parametric studies on moral judgment in behavioral, neuropsychological and functional imaging experiments.

Observing social gestures: an fMRI study.

We investigated the effects of social content of gestures on brain activation patterns. We used a 3 x 3 x 3 factorial design in an event-related functional magnetic resonance imaging experiment with participants observing gestures varied by type (fascist salute, wave, or arm lift), number of images shown at a time, and face frequency. We sought to determine whether increasing the social content of the gesture spreads activation from traditional sensorimotor regions engaged in mirror neuron activity to prefrontal regions concerned with social behavior. Results indicate that viewing a highly provocative gesture (fascist salute) compared to a less provocative but still socially meaningful gesture (wave) reveals activation in prefrontal and limbic areas. In addition, as expected there was more inferior frontal gyrus activation when participants observed a greater number of gesturing actors. Additionally, the psychological characteristics of shame and defeat affected activation in the inferior parietal lobe, which is part of the mirror neuron system, for the fascist salute compared to the wave contrast. We conclude that observing social gestures activates social- and emotion-processing areas of the brain, and the activation varies depending on the observer's psychological characteristics.