Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis.

OBJECTIVE: The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. METHODS: Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. RESULTS: Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. INTERPRETATION: This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024.

Breakdown of utilitarian moral judgement after basolateral amygdala damage.

Most of us would regard killing another person as morally wrong, but when the death of one saves multiple others, it can be morally permitted. According to a prominent computational dual-systems framework, in these life-and-death dilemmas, deontological (nonsacrificial) moral judgments stem from a model-free algorithm that emphasizes the intrinsic value of the sacrificial action, while utilitarian (sacrificial) moral judgments are derived from a model-based algorithm that emphasizes the outcome of the sacrificial action. Rodent decision-making research suggests that the model-based algorithm depends on the basolateral amygdala (BLA), but these findings have not yet been translated to human moral decision-making. Here, in five humans with selective, bilateral BLA damage, we show a breakdown of utilitarian sacrificial moral judgments, pointing at deficient model-based moral decision-making. Across an established set of moral dilemmas, healthy controls frequently sacrifice one person to save numerous others, but BLA-damaged humans withhold such sacrificial judgments even at the cost of thousands of lives. Our translational research confirms a neurocomputational hypothesis drawn from rodent decision-making research by indicating that the model-based algorithm which underlies outcome-based, utilitarian moral judgements in humans critically depends on the BLA.

Large-scale lesion symptom mapping of depression identifies brain regions for risk and resilience.

Understanding neural circuits that support mood is a central goal of affective neuroscience, and improved understanding of the anatomy could inform more targeted interventions in mood disorders. Lesion studies provide a method of inferring the anatomical sites causally related to specific functions, including mood. Here, we performed a large-scale study evaluating the location of acquired, focal brain lesions in relation to symptoms of depression. Five hundred and twenty-six individuals participated in the study across two sites (356 male, average age 52.4 ± 14.5 years). Each subject had a focal brain lesion identified on structural imaging and an assessment of depression using the Beck Depression Inventory-II, both obtained in the chronic period post-lesion (>3 months). Multivariate lesion-symptom mapping was performed to identify lesion sites associated with higher or lower depression symptom burden, which we refer to as 'risk' versus 'resilience' regions. The brain networks and white matter tracts associated with peak regional findings were identified using functional and structural lesion network mapping, respectively. Lesion-symptom mapping identified brain regions significantly associated with both higher and lower depression severity (r = 0.11; P = 0.01). Peak 'risk' regions include the bilateral anterior insula, bilateral dorsolateral prefrontal cortex and left dorsomedial prefrontal cortex. Functional lesion network mapping demonstrated that these 'risk' regions localized to nodes of the salience network. Peak 'resilience' regions include the right orbitofrontal cortex, right medial prefrontal cortex and right inferolateral temporal cortex, nodes of the default mode network. Structural lesion network mapping implicated dorsal prefrontal white matter tracts as 'risk' tracts and ventral prefrontal white matter tracts as 'resilience' tracts, although the structural lesion network mapping findings did not survive correction for multiple comparisons. Taken together, these results demonstrate that lesions to specific nodes of the salience network and default mode network are associated with greater risk versus resiliency for depression symptoms in the setting of focal brain lesions.

Sleep and dream disturbances associated with dissociative experiences.

Some dissociative experiences may be related, in part, to REM intrusion into waking consciousness. If so, some aspects of dream content may be associated with daytime dissociative experiences. We tested the hypothesis that some types of dream content would predict daytime dissociative symptomology. As part of a longitudinal study of the impact of dreams on everyday behavior we administered a battery of survey instruments to 219 volunteers. Assessments included the Dissociative Experiences Scale (DES), along with other measures known to be related to either REM intrusion effects or dissociative experiences. We also collected dream reports and sleep measures across a two-week period from a subgroup of the individuals in the baseline group. Of this subgroup we analyzed two different subsamples; 24 individuals with dream recall for at least half the nights in the two-week period; and 30 individuals who wore the DREEM Headband which captured measures of sleep architecture. In addition to using multiple regression analyses to quantify associations between DES and REM intrusion and dream content variables we used a split half procedure to create high vs low DES groups and then compared groups across all measures. Participants in the high DES group evidenced significantly greater nightmare distress scores, REM Behavior Disorder scores, paranormal beliefs, lucid dreams, and sleep onset times. Validated measures of dreamed first person perspective and overall dream coherence in a time series significantly predicted overall DES score accounting for 26% of the variance in dissociation. Dream phenomenology and coherence of the dreamed self significantly predicts dissociative symptomology as an individual trait. REM intrusion may be one source of dissociative experiences. Attempts to ameliorate dissociative symptoms or to treat nightmare distress should consider the stability of dream content as a viable indicator of dissociative tendencies.

The place of Free Will: the freedom of the prisoner.

Debates about the concept of Free Will date back to ancient times. About 40 years ago, Benjamin Libet designed an experiment showing that the conscious intention to move is preceded by a specific pattern of brain activation. His finding suggested that unconscious processes determine our decisions. Libet-style experiments have continued to dominate the debate about Free Will, pushing some authors to argue that the existence of Free Will is a mere illusion. We believe that this dispute is because we often measure Free Will using arbitrary human decisions rather than deliberate actions. After reviewing the definition of Free Will and the related literature, we conclude that the scientific evidence does not disprove the existence of Free Will. However, our will encounters several constraints and limitations that should be considered when evaluating our deeds' personal responsibility.

Demographic and Symptom Correlates of Initial Idiopathic Psychiatric Diagnosis in Frontotemporal Dementia.

INTRODUCTION: This study aims to measure frequency and correlates of initial idiopathic psychiatric diagnosis in a cohort of 147 patients with Frontotemporal Dementia (FTD)-spectrum disorders. METHODS: Participants were evaluated at the National Institutes of Health in Bethesda, Maryland. Initial participant diagnoses were determined by chart review and patient and informant interviews. Logistic regression was used to assess the relationships between diagnosis and age of symptom onset, gender, education, family history of psychiatric illness, and family history of dementia. Additional exploratory analyses investigated patients' first symptom type. RESULTS: 25% (n=43) of all the patients reviewed were initially misdiagnosed with an idiopathic psychiatric illness, which is less than half the commonly cited 50% rate.3 Depression was the most common misdiagnosis (46.5%). Family history of dementia, family history of mental illness and an exploratory analysis of behavioral first symptoms suggested significant association with a greater likelihood of initial idiopathic psychiatric diagnosis in FTD patients. DISCUSSION: This data confirms patterns of initial idiopathic psychiatric diagnosis in FTD and elucidates potential factors underlying misdiagnosis. Potential implications for patient outcomes, caregiver burden and healthcare costs are discussed.

Alternation in functional connectivity within default mode network after psychodynamic psychotherapy in borderline personality disorder.

BACKGROUND: Borderline personality disorder (BPD) is characterized by impairments in emotion regulation, impulse control, and interpersonal and social functioning along with a deficit in emotional awareness and empathy. In this study, we investigated whether functional connectivity (FC) within the default mode network (DMN) is affected by 1-year psychodynamic psychotherapy in patients with BPD. METHODS: Nine BPD patients filled out the demography, Interpersonal Reactive Index (IRI), Toronto Alexithymia Scale 20 (TAS 20), the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), and the Borderline Evaluation Severity over Time (BEST) questionnaire. The BPD group (9F) and the control group (9F) had a mean ± SD age of 28.2 ± 5.3 years and 30.4 ± 6.1 years, respectively. BPD subjects underwent longitudinal resting-state fMRI before psychodynamic psychotherapy and then every 4 months for a year after initiating psychotherapy. FC in DMN was characterized by calculating the nodal degree, a measure of centrality in the graph theory. RESULTS: The results indicated that patients with BPD present with aberrant DMN connectivity compared to healthy controls. Over a year of psychotherapy, the patients with BPD showed both FC changes (decreasing nodal degree in the dorsal anterior cingulate cortex and increasing in other cingulate cortex regions) and behavioral improvement in their symptoms and substance use. There was also a significant positive association between the decreased nodal degree in regions of the dorsal cingulate cortex and a decrease in the score of the TAS-20 indicating difficulty in identifying feelings after psychotherapy. CONCLUSION: In BPD, there is altered FC within the DMN and disruption in self-processing and emotion regulation. Psychotherapy may modify the DMN connectivity and that modification is associated with positive changes in BPD emotional symptoms.

The shifting role of the cerebellum in executive, emotional and social processing across the lifespan.

The cerebellum's anatomical and functional organization and network interactions between the cerebellum and the cerebral cortex and subcortical structures are dynamic across the lifespan. Executive, emotional and social (EES) functions have likewise evolved during human development from contributing to primitive behaviors during infancy and childhood to being able to modulate complex actions in adults. In this review, we address how the importance of the cerebellum in the processing of EES functions might change across development. This evolution is driven by the macroscopic and microscopic modifications of the cerebellum that are occurring during development including its increasing connectivity with distant supra-tentorial cortical and sub-cortical regions. As a result of anatomical and functional changes, neuroimaging and clinical data indicate that the importance of the role of the cerebellum in human EES-related networks shifts from being crucial in newborns and young children to being only supportive later in life. In early life, given the immaturity of cortically mediated EES functions, EES functions and motor control and perception are more closely interrelated. At that time, the cerebellum due to its important role in motor control and sequencing makes EES functions more reliant on these computational properties that compute spatial distance, motor intent, and assist in the execution of sequences of behavior related to their developing EES expression. As the cortical brain matures, EES functions and decisions become less dependent upon these aspects of motor behavior and more dependent upon high-order cognitive and social conceptual processes. At that time, the cerebellum assumes a supportive role in these EES-related behaviors by computing their motor and sequential features. We suspect that this evolving role of the cerebellum has complicated the interpretation of its contribution to EES computational demands.

Limits on using the clock drawing test as a measure to evaluate patients with neurological disorders.

BACKGROUND: The Clock Drawing Test (CDT) is used as a quick-to-conduct test for the diagnosis of dementia and a screening tool for cognitive impairments in neurological disorders. However, the association between the pattern of CDT impairments and the location of brain lesions has been controversial. We examined whether there is an association between the CDT scores and the location of brain lesions using the two available scoring systems. METHOD: One hundred five patients with brain lesions identified by CT scanning were recruited for this study. The Montreal Cognitive Assessment (MoCA) battery including the CDT were administered to all partcipants. To score the CDT, we used a qualitative scoring system devised by Rouleau et al. (1992). For the quantitative scoring system, we adapted the algorithm method used by Mendes-Santos et al. (2015) based on an earlier study by Sunderland et al. (1989). For analyses, a machine learning algorithm was used. RESULTS: Remarkably, 30% of the patients were not detected by the CDT. Quantitative and qualitative errors were categorized into different clusters. The classification algorithm did not differentiate the patients with traumatic brain injury 'TBI' from non-TBI, or the laterality of the lesion. In addition, the classification accuracy for identifying patients with specific lobe lesions was low, except for the parietal lobe with an accuracy of 63%. CONCLUSION: The CDT is not an accurate tool for detecting focal brain lesions. While the CDT still is beneficial for use with patients suspected of having a neurodegenerative disorder, it should be cautiously used with patients with focal neurological disorders.

Postoperative but not preoperative depression is associated with cognitive impairment after cardiac surgery: exploratory analysis of data from a randomized trial.

BACKGROUND: In this study we hypothesize that depression is associated with perioperative neurocognitive dysfunction and altered quality of life one month after surgery. METHODS: Data were obtained as part of a study evaluating cerebral autoregulation monitoring for targeting arterial pressure during cardiopulmonary bypass. Neuropsychological testing was performed before surgery and one month postoperatively. Testing included the Beck Depression Inventory, a depression symptoms questionnaire (0-63 scale), as well as anxiety and quality of life assessments. Depression was defined as a Beck Depression Inventory score > 13. RESULTS: Beck Depression data were available from 320 patients of whom cognitive domain endpoints were available from 88-98% at baseline and 69-79% after surgery. This range in end-points data was due to variability in the availability of each neuropsychological test results between patients. Depression was present in 50 (15.6%) patients before surgery and in 43 (13.4%) after surgery. Baseline depression was not associated with postoperative domain-specific neurocognitive function compared with non-depressed patients. Those with depression one month after surgery, though, had poorer performance on tests of attention (p = 0.017), memory (p = 0.049), verbal fluency (p = 0.010), processing speed (p = 0.017), and fine motor speed (p = 0.014). Postoperative neurocognitive dysfunction as a composite outcome occurred in 33.3% versus 14.5% of patients with and without postoperative depression (p = 0.040). Baseline depression was associated with higher anxiety and lower self-ratings on several quality of life domains, these measures were generally more adversely affected by depression one month after surgery. CONCLUSIONS: The results of this exploratory analysis suggests that preoperative depression is not associated with perioperative neurocognitive dysfunction, but depression after cardiac surgery may be associated with impairment in in several cognitive domains, a higher frequency of the composite neurocognitive outcome, and altered quality of life. TRIAL REGISTRATION: www. CLINICALTRIALS: gov, NCT00981474 (parent study).

Preoperative Anemia and Risk for Perioperative Neurocognitive Dysfunction in Cardiac Surgery Patients: A Retrospective Analysis.

OBJECTIVES: To evaluate whether there is a relationship between preoperative anemia and domain-specific cognitive performance in patients undergoing cardiac surgery. DESIGN: Retrospective analysis of data collected from a randomized study. SETTING: Tertiary care university hospital. PARTICIPANTS: A total of 436 patients age ≥55 years undergoing cardiac surgery. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Neuropsychological testing was performed before and one month after surgery, using a standard battery. Individual Z-scores calculated from the mean and standard deviation of tests at baseline were combined into domain-specific scores. Anemia (hemoglobin <130 g/L for men, <120 g/L for women) was present in 41% of patients. Preoperative anemia had little impact on preoperative cognition. There were no differences in the change in cognitive performance one month after surgery from baseline between patients with and without preoperative anemia. However, in a sensitivity analysis using multiple imputation for missing cognitive test scores, significant associations were observed between preoperative anemia and change in postoperative processing speed (p = 0.016), change in executive function (p = 0.049), and change in fine motor speed (p = 0.016). Nadir hemoglobin during cardiopulmonary bypass, which was lower in anemic than nonanemic patients, was associated with decrements in performance on tests of verbal fluency (p = 0.007), processing speed (p = 0.042), and executive function (p = 0.10) one month after surgery but not delayed neurocognitive recovery (p = 0.06). CONCLUSIONS: Preoperative anemia may be associated with impairment of selective cognitive domains after surgery. Any effect of preoperative anemia may have on cognition after surgery might be related to lower nadir hemoglobin during cardiopulmonary bypass.

Traumatic brain injury and post-traumatic stress disorder are not associated with Alzheimer's disease pathology measured with biomarkers.

INTRODUCTION: Epidemiological studies report an association between traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) and clinically diagnosed Alzheimer's disease (AD). We examined the association between TBI/PTSD and biomarker-defined AD. METHODS: We identified 289 non-demented veterans with TBI and/or PTSD and controls who underwent clinical evaluation, cerebrospinal fluid (CSF) collection, magnetic resonance imaging (MRI), amyloid beta (Aß) and tau positron emission tomography, and apolipoprotein E testing. Participants were followed for up to 5.2 years. RESULTS: Exposure groups (TBI, PTSD, and TBI + PTSD) had higher prevalence of mild cognitive impairment (MCI: P < .0001) and worse Mini-Mental State Examination scores (PTSD: P = .008; TBI & PTSD: P = .009) than controls. There were no significant differences in other cognitive scores, MRI volumes, Aß or tau accumulation, or in most longitudinal measures. DISCUSSION: TBI and/or PTSD were not associated with elevated AD biomarkers. The poorer cognitive status of exposed veterans may be due to other comorbid pathologies.

The neural basis for mental state attribution: A voxel-based lesion mapping study.

The ability to infer other persons' mental states, "Theory of Mind" (ToM), is a key function of social cognition and is needed when interpreting the intention of others. ToM is associated with a network of functionally related regions, with reportedly key prominent hubs located in the dorsolateral prefrontal cortex (dlPFC) and the temporoparietal junction (TPJ). The involvement of (mainly the right) TPJ in ToM is based primarily on functional imaging studies that provide correlational evidence for brain-behavior associations. In this lesion study, we test whether certain brain areas are necessary for intact ToM performance. We investigated individuals with penetrating traumatic brain injury (n = 170) and healthy matched controls (n = 30) using voxel-based lesion-symptom mapping (VLSM) and by measuring the impact of a given lesion on white matter disconnections. ToM performance was compared between five patient groups based on lesion location: right TPJ, left TPJ, right dlPFC, left dlPFC, and other lesion, as well as healthy controls. The only group to present with lower ToM abilities was the one with lesions in the right dlPFC. Similarly, VLSM analysis revealed a main cluster in the right frontal middle gyrus and a secondary cluster in the left inferior parietal gyrus. Last, we found that disconnection of the left inferior longitudinal fasciculus and right superior longitudinal fasciculus were associated with poor ToM performance. This study highlights the importance of lesion studies in complementing functional neuroimaging findings and supports the assertion that the right dlPFC is a key region mediating mental state attribution.

Determinants of caregiver burden in male patients with epilepsy following penetrating traumatic brain injury.

PURPOSE: We determined burden of caring for patients with post-traumatic epilepsy (PTE) following penetrating traumatic brain injury (TBI) and identified factors predicting higher burden. METHOD: We assessed 331 caregiver-veteran dyads in Phase 2 (136 PTE, 136 non-PTE, and 59 HC dyads), 133 in Phase 4 (47 PTE, 56 non-PTE, and 30 HC dyads) - 30 years later, and 46 dyads in the follow-up study (18 PTE, 19 non-PTE, and 9 HC). Caregiver's burden was measured by Zarit Burden Index and a questionnaire. Veterans completed demographic, mental and physical well-being, quality-of-life, and medical-related information. Caregivers provided information about burden and their assessments of cognitive decline and neuropsychiatric status of the veterans. RESULTS: PTE caregivers perceived significantly more burden than comparison groups at all phases. Bivariate analyses revealed that caregiver distress due to the veteran's neuropsychiatric state including cognitive decline, apathy, and disinhibition and the veteran's characteristics including older age at epilepsy onset and role limitation due to physical problems were associated with higher burden. Finally, we revealed disinhibition distress, and role imitation due to physical problems as the predictors in a model of caregiver burden. CONCLUSION: Elevated PTE caregiver burden is persistent across the life span suggesting that caregivers could benefit from counseling and targeted psychosocial interventions to reduce their burden.

Neurocognitive, Quality of Life, and Behavioral Outcomes for Patients With Covert Stroke After Cardiac Surgery: Exploratory Analysis of Data From a Prospectively Randomized Trial.

BACKGROUND: Asymptomatic brain ischemic injury detected with diffusion-weighted magnetic resonance imaging (DWI) is reported in more than one-half of patients after cardiac surgery. There are conflicting findings on whether DWI-detected covert stroke is associated with neurocognitive dysfunction after surgery, and it is unclear whether such ischemic injury affects quality of life or behavioral outcomes. The purpose of this study was to perform exploratory analysis on whether covert stroke after cardiac surgery is associated with delayed neurocognitive recovery 1 month after surgery, impaired quality of life, anxiety, or depression. METHODS: Analysis of data collected in a prospectively randomized study in patients undergoing cardiac surgery testing whether basing mean arterial pressure (MAP) targets during cardiopulmonary bypass to be above the lower limit of cerebral autoregulation versus usual practices reduces the frequency of adverse neurological outcomes. A neuropsychological testing battery was administered before surgery and then 1 month later. Patients underwent brain magnetic resonance imaging (MRI) between postoperative days 3 and 5. The primary outcome was DWI-detected ischemic lesion; the primary end point was change from baseline in domain-specific neurocognitive Z scores 1 month after surgery. Secondary outcomes included a composite indicator of delayed neurocognitive recovery, quality of life measures, state and trait anxiety, and Beck Depression Inventory scores. RESULTS: Of the 164 patients with postoperative MRI data, clinical stroke occurred in 10 patients. Of the remaining 154 patients, 85 (55.2%) had a covert stroke. There were no statistically significant differences for patients with or without covert stroke in the change from baseline in Z scores in any of the cognitive domains tested adjusted for sex, baseline cognitive score, and randomization treatment arm. The frequency of delayed neurocognitive recovery (no covert stroke, 15.1%; covert stroke, 17.6%; P = .392), self-reported quality of life measurements, anxiety rating, or depression scores were not different between those with or without DWI ischemic injury. CONCLUSIONS: More than one-half of patients undergoing cardiac surgery demonstrated covert stroke. In this exploratory analysis, covert stroke was not found to be significantly associated with neurocognitive dysfunction 1 month after surgery; evidence of impaired quality of life, anxiety, or depression, albeit a type II error, cannot be excluded.

Oculometric signature of switch into awareness? Pupil size predicts sudden insight whereas microsaccades predict problem-solving via analysis.

According to the Gestalt theorists, restructuring is an essential component of insight problem-solving, contributes to the "Aha!" experience, and is similar to the perceptual switch experienced when reinterpreting ambiguous figures. Previous research has demonstrated that pupil diameter increases during the perceptual switch of ambiguous figures, and indexes norepeinephrine functioning mediated by the locus coeruleus. In this study, we investigated if pupil diameter similarly predicts the switch into awareness people experience when solving a problem via insight. Additionally, we explored eye movement dynamics during the same task to investigate if the problem-solving strategies used are linked to specific oculomotor behaviors. In 38 participants, pupil diameter increased about 500 msec prior to solution only in trials for which subjects report having an insight. In contrast, participants increased their microsaccade rate only prior to non-insight solutions. Pupil dilation and microsaccades were not reliably related, but both appear to be robust markers of how people solve problems (with or without insight). The pupil size change seen when people have an "Aha!" moment represents an indicator of the switch into awareness of unconscious processes humans depend upon for insight, and suggests important involvement of norepinephrine, via the locus coeruleus, in sudden insight.

Cortical lesions causing loss of consciousness are anticorrelated with the dorsal brainstem.

Brain lesions can provide unique insight into the neuroanatomical substrate of human consciousness. For example, brainstem lesions causing coma map to a specific region of the tegmentum. Whether specific lesion locations outside the brainstem are associated with loss of consciousness (LOC) remains unclear. Here, we investigate the topography of cortical lesions causing prolonged LOC (N = 16), transient LOC (N = 91), or no LOC (N = 64). Using standard voxel lesion symptom mapping, no focus of brain damage was associated with LOC. Next, we computed the network of brain regions functionally connected to each lesion location using a large normative connectome dataset (N = 1,000). This technique, termed lesion network mapping, can test whether lesions causing LOC map to a connected brain circuit rather than one brain region. Connectivity between cortical lesion locations and an a priori coma-specific region of brainstem tegmentum was an independent predictor of LOC (B = 1.2, p = .004). Connectivity to the dorsal brainstem was the only predictor of LOC in a whole-brain voxel-wise analysis. This relationship was driven by anticorrelation (negative correlation) between lesion locations and the dorsal brainstem. The map of regions anticorrelated to the dorsal brainstem thus defines a distributed brain circuit that, when damaged, is most likely to cause LOC. This circuit showed a slight posterior predominance and had peaks in the bilateral claustrum. Our results suggest that cortical lesions causing LOC map to a connected brain circuit, linking cortical lesions that disrupt consciousness to brainstem sites that maintain arousal.

Neural underpinning of a personal relationship with God and sense of control: A lesion-mapping study.

A strong personal relationship with God is theoretically and empirically associated with an enhanced sense of control. While a growing body of research is focused on understanding the neural mechanisms underlying religious belief, little is known about the brain basis of the link between a personal relationship with God and sense of control. Here, we used a sample of patients with focal brain lesions (N = 84) and matched healthy controls (N = 22) to determine whether damage to the ventromedial prefrontal cortex (vmPFC)-a region associated with emotionally meaningful religious experiences and with sense of control-will modulate self-reports of a personal relationship with God and sense of control. We also examined potential mediators for these associations. Voxel-based lesion symptom mapping revealed that damage to the right vmPFC resulted in a stronger personal relationship with God, and patients with damage to this region demonstrated an increased sense of control relative to patients with damage to posterior cortex and healthy controls. Moreover, the association between vmPFC damage and greater perceived sense of control was mediated by a stronger personal relationship with God. Collectively, these results suggest that a strong personal relationship with God can serve an important psychological function by affecting sense of control, with both enhanced following damage to the right vmPFC.

Effect of Functional BDNF and COMT Polymorphisms on Symptoms and Regional Brain Volume in Frontotemporal Dementia and Corticobasal Syndrome.

OBJECTIVE: The authors examined the effects of two common functional polymorphisms-brain-derived neurotrophic factor (BDNF) Val66Met and catechol-O-methyltransferase (COMT) Val158Met-on cognitive, neuropsychiatric, and motor symptoms and MRI findings in persons with frontotemporal lobar degeneration (FTLD) syndromes. METHODS: The BDNF Val66Met and COMT Val158Met polymorphisms were genotyped in 174 participants with FTLD syndromes, including behavioral variant frontotemporal dementia, primary progressive aphasia, and corticobasal syndrome. Gray matter volumes and scores on the Delis-Kaplan Executive Function System, Mattis Dementia Rating Scale, Wechsler Memory Scale, and Neuropsychiatric Inventory were compared between allele groups. RESULTS: The BDNF Met allele at position 66 was associated with a decrease in depressive symptoms (F=9.50, df=1, 136, p=0.002). The COMT Val allele at position 158 was associated with impairment of executive function (F=6.14, df=1, 76, p=0.015) and decreased bilateral volume of the head of the caudate in patients with FTLD (uncorrected voxel-level threshold of p<0.001). Neither polymorphism had a significant effect on motor function. CONCLUSIONS: These findings suggest that common functional polymorphisms likely contribute to the phenotypic variability seen in patients with FTLD syndromes. This is the first study to implicate BDNF polymorphisms in depressive symptoms in FTLD. These results also support an association between COMT polymorphisms and degeneration patterns and cognition in FTLD.