A potential neuromodulation target for PTSD in Veterans derived from focal brain lesions.

Neuromodulation trials for PTSD have yielded mixed results, and the optimal neuroanatomical target remains unclear. We analyzed three datasets to study brain circuitry causally linked to PTSD in military Veterans. After penetrating traumatic brain injury (n=193), lesions that reduced probability of PTSD were preferentially connected to a circuit including the medial prefrontal cortex (mPFC), amygdala, and anterolateral temporal lobe (cross-validation p=0.01). In Veterans without lesions (n=180), PTSD was specifically associated with connectivity within this circuit (p<0.01). Connectivity change within this circuit correlated with PTSD improvement after transcranial magnetic stimulation (TMS) (n=20) (p<0.01), even though the circuit was not directly targeted. Finally, we directly targeted this circuit with fMRI-guided accelerated TMS, leading to rapid resolution of symptoms in a patient with severe lifelong PTSD. All results were independent of depression severity. This lesion-based PTSD circuit may serve as a neuromodulation target for Veterans with PTSD.

Causal network localization of brain stimulation targets for trait anxiety.

Transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) can treat some neuropsychiatric disorders, but there is no consensus approach for identifying new targets. We localized causal circuit-based targets for anxiety that converged across multiple natural experiments. Lesions (n=451) and TMS sites (n=111) that modify anxiety mapped to a common normative brain circuit (r=0.68, p=0.01). In an independent dataset (n=300), individualized TMS site connectivity to this circuit predicted anxiety change (p=0.02). Subthalamic DBS sites overlapping the circuit caused more anxiety (n=74, p=0.006), thus demonstrating a network-level effect, as the circuit was derived without any subthalamic sites. The circuit was specific to trait versus state anxiety in datasets that measured both (p=0.003). Broadly, this illustrates a pathway for discovering novel circuit-based targets across neuropsychiatric disorders.

Digital Media and Developing Brains: Concerns and Opportunities.

Purpose of Review: The incorporation of digital technologies and their use in youth's everyday lives has been increasing rapidly over the past several decades with possible impacts on youth development and mental health. This narrative review aimed to consider how the use of digital technologies may be influencing brain development underlying adaptive and maladaptive screen-related behaviors. Recent Findings: To explore and provide direction for further scientific inquiry, an international group of experts considered what is known, important gaps in knowledge, and how a research agenda might be pursued regarding relationships between screen media activity and neurodevelopment from infancy through childhood and adolescence. While an understanding of brain-behavior relationships involving screen media activity has been emerging, significant gaps exist that have important implications for the health of developing youth. Summary: Specific considerations regarding brain-behavior relationships involving screen media activity exist for infancy, toddlerhood, and early childhood; middle childhood; and adolescence. Transdiagnostic frameworks may provide a foundation for guiding future research efforts. Translating knowledge gained into better interventions and policy to promote healthy development is important in a rapidly changing digital technology environment.

Studying the social mind: An updated summary of findings from the Vietnam Head Injury Study.

Lesion mapping studies allow us to evaluate the potential causal contribution of specific brain areas to human cognition and complement other cognitive neuroscience methods, as several authors have recently pointed out. Here, we present an updated summary of the findings from the Vietnam Head Injury Study (VHIS) focusing on the studies conducted over the last decade, that examined the social mind and its intricate neural and cognitive underpinnings. The VHIS is a prospective, long-term follow-up study of Vietnam veterans with penetrating traumatic brain injury (pTBI) and healthy controls (HC). The scope of the work is to present the studies from the latest phases (3 and 4) of the VHIS, 70 studies since 2011, when the Raymont et al. paper was published (Raymont et al., 2011). These studies have contributed to our understanding of human social cognition, including political and religious beliefs, theory of mind, but also executive functions, intelligence, and personality. This work finally discusses the usefulness of lesion mapping as an approach to understanding the functions of the human brain from basic science and clinical perspectives.

The burden of traumatic brain injury on caregivers: exploring the predictive factors in a multi-centric study.

BACKGROUND: Traumatic brain injury (TBI) is a significant cause of mortality and morbidity worldwide. With survivors often exhibiting degrees of function loss, a significant burden is exerted on their caregivers. The purpose of this study was to explore the predictive factors of caregiver burden among caregivers of patients with TBI. METHODS: Sixty-eight family members of individuals with a TBI who had been admitted to three hospitals were assessed in terms of caregiver burden using the Zarit Burden Interview. The association of caregiver burden with patients' baseline cognitive function according to the Montreal Cognitive Assessment (MoCA) test, as well as caregivers' sociodemographic characteristics, were evaluated using multiple regression analysis. RESULTS: Based on the multiple regression model, the MoCA score of the patients (std ß=-0.442, p < 0.001), duration of caregiving (std ß = 0.228, p = 0.044), and higher education of the caregivers (std ß = 0.229, p = 0.038) were significant predictors of caregiver burden. CONCLUSION: Overall, our findings highlight the importance of taking caregivers' psychosocial needs into account. Long-term caregivers of TBI patients with cognitive impairment should be viewed as vulnerable individuals who could benefit from psychosocial intervention programs, to improve their well-being and enabling them to enrich their care of the TBI patient.

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.

Insight Problem Solving Ability Predicts Reduced Susceptibility to Fake News, Bullshit, and Overclaiming.

The information humans are exposed to has grown exponentially. This has placed increased demands upon our information selection strategies resulting in reduced fact-checking and critical-thinking time. Prior research shows that problem solving (traditionally measured using the Cognitive Reflection Test-CRT) negatively correlates with believing in false information. We argue that this result is specifically related to insight problem solving. Solutions via insight are the result of parallel processing, characterized by filtering external noise, and, unlike cognitively controlled thinking, it does not suffer from the cognitive overload associated with processing multiple sources of information. We administered the Compound Remote Associate Test (problems used to investigate insight problem solving) as well as the CRT, 20 fake and real news headlines, the bullshit, and overclaiming scales to a sample of 61 participants. Results show that insight problem solving predicts better identification of fake news and bullshit (over and above traditional measures i.e., the CRT), and is associated with reduced overclaiming. These results have implications for understanding individual differences in susceptibility to believing false information.

Right BA 10 lesions impair performance on real-world planning but are not sensitive to problem novelty or tower tasks.

The prefrontal cortex (PFC) is associated with many cognitive functions, including planning. In the neuropsychology literature planning is reduced to "look ahead" ability and most extensively studied with the "tower" tasks. The most influential theoretical explanation is that planning is required in the absence of a routine solution and PFC patients have difficulty coping with novelty. There is an alternate view of planning that emphasizes the distinction between real world tasks and laboratory tower tasks. This account focuses on the structure of problem spaces and why patients with lesions to right PFC have difficulty navigating ill-structured problem spaces. To further explore these issues we administered two real world travel planning tasks to 56 Vietnam War veterans with penetrating brain lesions and 14 matched normal controls. One planning task involved familiar knowledge while the other involved knowledge unfamiliar to our participants. Participants also completed the D-KEFS tower task. A subset of 18 patients-with lesions to right anterior prefrontal cortex (BA 10)-were impaired in the travel planning task compared to normal controls. The task familiarity/novelty dimension affected performance across participant groups (familiar-task scores were higher than unfamiliar-task scores), but it did not differentially affect any group. An examination of cognitive strategies utilized by participants revealed that the impaired patient group had difficulty maintaining a sufficient level of abstraction and engaged the task at a much more concrete level than other participants. Interestingly, patients impaired in the real-world planning tasks were not impaired in the tower tasks. We conclude that patients with lesions to right BA 10 have difficulty in real-world planning tasks that can be attributed to difficulties in engaging problems at the appropriate level of abstraction.

Multimodal nonlinear correlates of behavioural symptoms in frontotemporal dementia.

Background: Studies exploring the brain correlates of behavioural symptoms in the frontotemporal dementia spectrum (FTD) have mainly searched for linear correlations with single modality neuroimaging data, either structural magnetic resonance imaging (MRI) or fluoro-deoxy-D-glucose positron emission tomography (FDG-PET). We aimed at studying the two imaging modalities in combination to identify nonlinear co-occurring patterns of atrophy and hypometabolism related to behavioural symptoms. Methods: We analysed data from 93 FTD patients who underwent T1-weighted MRI, FDG-PET imaging, and neuropsychological assessment including the Neuropsychiatric Inventory, Frontal Systems Behaviour Scale, and Neurobehavioral Rating Scale. We used a data-driven approach to identify the principal components underlying behavioural variability, then related the identified components to brain variability using a newly developed method fusing maps of grey matter volume and FDG metabolism. Results: A component representing apathy, executive dysfunction, and emotional withdrawal was associated with atrophy in bilateral anterior insula and putamen, and with hypometabolism in the right prefrontal cortex. Another component representing the disinhibition versus depression/mutism continuum was associated with atrophy in the right striatum and ventromedial prefrontal cortex for disinhibition, and hypometabolism in the left fronto-opercular region and sensorimotor cortices for depression/mutism. A component representing psychosis was associated with hypometabolism in the prefrontal cortex and hypermetabolism in auditory and visual cortices. Discussion: Behavioural symptoms in FTD are associated with atrophy and altered metabolism of specific brain regions, especially located in the frontal lobes, in a hierarchical way: apathy and disinhibition are mostly associated with grey matter atrophy, whereas psychotic symptoms are mostly associated with hyper-/hypo-metabolism.

Understanding altruistic behavior: The joint role of prefrontal damage and OXTR genotype.

Altruism is a type of prosocial behavior that is carried out in the absence of personal benefit or even at an expense to self. Trait altruism varies greatly across individuals, and the reasons for this variability are still not fully understood. Growing evidence suggests that altruism may be partly determined by the oxytocin receptor (OXTR) gene, which regulates the emotions underlying altruistic attitudes, such as empathy and trust. Neuroimaging and lesion studies have also implied several higher-order brain regions, including the prefrontal cortex, in altruistic behaviors. Yet the existing reports are contradictory and suggest that the top-down control exercised by the prefrontal cortex may promote both altruistic and self-interested behaviors and, thus, could obscure one's natural proclivity towards altruism encoded by OXTR. Here, we hypothesized that extensive prefrontal damage would result in an increased influence of the OXTR genotype on one's altruistic attitudes and actions. To test this hypothesis, we recruited 115 male combat veterans with penetrating traumatic brain injury to the prefrontal cortex and other brain regions, as well as 35 demographically matched control subjects without brain injury. Participants completed a self-report altruism questionnaire and were genotyped for four OXTR single nucleotide polymorphisms implicated in prosocial behavior, including rs53576, rs1042778, rs2254298 and rs7632287. Consistent with the previous studies, we found that individuals homozygotic for the G allele of rs53576 and rs7632287 were significantly more altruistic than carriers of at least one "vulnerable" A allele. Remarkably, in patients with prefrontal cortex damage, greater lesion extent was associated with significantly lower altruism scores in carriers of the A allele of rs7632287, but not in G-homozygotes, suggesting that significant disruption of the prefrontal cortex increased the influence of genetic polymorphisms on prosocial behavior. This study presents the first account of an interaction effect between the OXTR genotype and the location and extent of brain damage.

Mapping Lesion-Related Epilepsy to a Human Brain Network.

Importance: It remains unclear why lesions in some locations cause epilepsy while others do not. Identifying the brain regions or networks associated with epilepsy by mapping these lesions could inform prognosis and guide interventions. Objective: To assess whether lesion locations associated with epilepsy map to specific brain regions and networks. Design, Setting, and Participants: This case-control study used lesion location and lesion network mapping to identify the brain regions and networks associated with epilepsy in a discovery data set of patients with poststroke epilepsy and control patients with stroke. Patients with stroke lesions and epilepsy (n = 76) or no epilepsy (n = 625) were included. Generalizability to other lesion types was assessed using 4 independent cohorts as validation data sets. The total numbers of patients across all datasets (both discovery and validation datasets) were 347 with epilepsy and 1126 without. Therapeutic relevance was assessed using deep brain stimulation sites that improve seizure control. Data were analyzed from September 2018 through December 2022. All shared patient data were analyzed and included; no patients were excluded. Main Outcomes and Measures: Epilepsy or no epilepsy. Results: Lesion locations from 76 patients with poststroke epilepsy (39 [51%] male; mean [SD] age, 61.0 [14.6] years; mean [SD] follow-up, 6.7 [2.0] years) and 625 control patients with stroke (366 [59%] male; mean [SD] age, 62.0 [14.1] years; follow-up range, 3-12 months) were included in the discovery data set. Lesions associated with epilepsy occurred in multiple heterogenous locations spanning different lobes and vascular territories. However, these same lesion locations were part of a specific brain network defined by functional connectivity to the basal ganglia and cerebellum. Findings were validated in 4 independent cohorts including 772 patients with brain lesions (271 [35%] with epilepsy; 515 [67%] male; median [IQR] age, 60 [50-70] years; follow-up range, 3-35 years). Lesion connectivity to this brain network was associated with increased risk of epilepsy after stroke (odds ratio [OR], 2.82; 95% CI, 2.02-4.10; P < .001) and across different lesion types (OR, 2.85; 95% CI, 2.23-3.69; P < .001). Deep brain stimulation site connectivity to this same network was associated with improved seizure control (r, 0.63; P < .001) in 30 patients with drug-resistant epilepsy (21 [70%] male; median [IQR] age, 39 [32-46] years; median [IQR] follow-up, 24 [16-30] months). Conclusions and Relevance: The findings in this study indicate that lesion-related epilepsy mapped to a human brain network, which could help identify patients at risk of epilepsy after a brain lesion and guide brain stimulation therapies.

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.

A Lesion-Derived Brain Network for Emotion Regulation.

BACKGROUND: Emotion regulation has been linked to specific brain networks based on functional neuroimaging, but networks causally involved in emotion regulation remain unknown. METHODS: We studied patients with focal brain damage (N = 167) who completed the managing emotion subscale of the Mayer-Salovey-Caruso Emotional Intelligence Test, a measure of emotion regulation. First, we tested whether patients with lesions to an a priori network derived from functional neuroimaging showed impaired emotion regulation. Next, we leveraged lesion network mapping to derive a de novo brain network for emotion regulation. Finally, we used an independent lesion database (N = 629) to test whether damage to this lesion-derived network would increase the risk of neuropsychiatric conditions associated with emotion regulation impairment. RESULTS: First, patients with lesions intersecting the a priori emotion regulation network derived from functional neuroimaging showed impairments in the managing emotion subscale of the Mayer-Salovey-Caruso Emotional Intelligence Test. Next, our de novo brain network for emotion regulation derived from lesion data was defined by functional connectivity to the left ventrolateral prefrontal cortex. Finally, in the independent database, lesions associated with mania, criminality, and depression intersected this de novo brain network more than lesions associated with other disorders. CONCLUSIONS: The findings suggest that emotion regulation maps to a connected brain network centered on the left ventrolateral prefrontal cortex. Lesion damage to part of this network is associated with reported difficulties in managing emotions and is related to increased likelihood of having one of several neuropsychiatric disorders.

Death Anxiety in Huntington Disease: Longitudinal Heath-Related Quality-of-Life Outcomes.

Objective: Death anxiety, represented by the HDQLIFE™ Concern with Death and Dying (CwDD) patient-reported outcome (PRO) questionnaire, captures a person's worry about the death and dying process. Previous work suggests that death anxiety remains an unremitting burden throughout all stages of Huntington disease (HD). Although palliative interventions have lessened death anxiety among people with advanced cancer, none has yet to undergo testing in the HD population. An account of how death anxiety is associated with longitudinal changes to aspects of health-related quality of life (HRQoL) would help optimize neuropalliative interventions for people with HD. Methods: HDQLIFE collected PROs concerning physical, mental, social, and cognitive HRQoL domains and clinician-rated assessments from people with HD at baseline and 12 and 24 months. Linear mixed-effects models were created to determine how baseline death anxiety was associated with follow-up changes in HRQoL PROs after controlling for baseline death anxiety and other disease and sociodemographic covariates. Results: Higher baseline HDQLIFE CwDD is associated with 12- and 24-month declines in HDQLIFE Speech Difficulties, neurology quality of life (NeuroQoL) Depression, Suicidality, HDQLIFE Meaning and Purpose, and NeuroQoL Positive Affect and Well-being. Interpretation: Death anxiety may be a risk factor for worsening mental health and speech difficulty. A further prospective study is required to evaluate whether interventions on death anxiety or mental health generally can reduce declines in HRQoL for people with HD over time.

A transdiagnostic network for psychiatric illness derived from atrophy and lesions.

Psychiatric disorders share neurobiology and frequently co-occur. This neurobiological and clinical overlap highlights opportunities for transdiagnostic treatments. In this study, we used coordinate and lesion network mapping to test for a shared brain network across psychiatric disorders. In our meta-analysis of 193 studies, atrophy coordinates across six psychiatric disorders mapped to a common brain network defined by positive connectivity to anterior cingulate and insula, and by negative connectivity to posterior parietal and lateral occipital cortex. This network was robust to leave-one-diagnosis-out cross-validation and specific to atrophy coordinates from psychiatric versus neurodegenerative disorders (72 studies). In 194 patients with penetrating head trauma, lesion damage to this network correlated with the number of post-lesion psychiatric diagnoses. Neurosurgical ablation targets for psychiatric illness (four targets) also aligned with the network. This convergent brain network for psychiatric illness may partially explain high rates of psychiatric comorbidity and could highlight neuromodulation targets for patients with more than one psychiatric disorder.

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.

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.

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.