Frontal-subcortical Circuits Research Articles

The spectrum of behavioral disorders in amyotrophic lateral sclerosis: current view.

Behavioral disorders, with an average prevalence of 30-60% are important non-motor symptoms in amyotrophic lateral sclerosis (ALS) that have a negative impact on prognosis, management and quality of life, yet the underlying neurobiology is poorly understood. Among people with ALS, apathy, fatigue, anxiety, irritability and other behavioral symptoms are the most prominent, although less frequent than cognitive impairment. The present review explores the current understanding of behavioral changes in ALS with particular emphasis on our current knowledge about their structural and functional brain correlates, substantiating a multisystem degeneration with particular dysfunction of frontal-subcortical circuits and dysfunction of fronto-striatal, frontotemporal and other essential brain systems. The natural history of behavioral dysfunctions in ALS and their relationship to frontotemporal lobe degeneration (FTLD) are not fully understood, although they form a clinical continuum, suggesting a differential vulnerability of non-motor brain networks, ALS being considered a brain network disorder. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of behavioral impairment in ALS. Treatment of both ALS and co-morbid behavioral disorders is a multidisciplinary task, but whereas no causal or disease-modifying therapies for ALS are available, symptomatic treatment of a variety of behavioral symptoms plays a pivotal role in patient care, although the management of behavioral symptoms in clinical care still remains limited.

A Literature Review of Language Characteristics in Patients with Vascular Dementia

Vascular dementia may present with language disorders due to damage to frontal subcortical circuits. This study aimed to review recent studies of language abilities in patients with vascular dementia. Sixty-nine studies were classified according to language modalities (spontaneous speech, auditory comprehension, repetition and naming). First, spontaneous speech was impaired in the ability to describe pictures, objects and in the ability to convey information in discourse. Second, the auditory comprehension was impaired in word comprehension, sentence comprehension, paragraph comprehension, and speech act comprehension tasks. Third, repetition was preserved in word-level tasks but impaired at the sentence level. Fourth, the naming performance was impaired in a generative naming task (phonemic fluency) rather than in a confrontational naming task. Therefore, when summarizing the results between patient groups, in spontaneous speech, to convey information through highly informative utterances was relatively good in vascular dementia (VaD), but the number of utterances was lower than dementia of Alzheimer’s type (DAT). In auditory comprehension, VaD’s performance was good in the task of word comprehension and speech act comprehension tasks. It is organized as in repetition, VaD’s performance was relatively good in the sentence-level task, and in naming, VaD’s performance was reported to be better than DAT in the oppositional naming and generative naming semantic category tasks. In the generative naming phoneme category, opposite result was reported. Further studies on the language abilities of patients with vascular dementia needs to consider factors such as subtype and language modality. Future studies should be evenly distributed across all language domains.

Exploring Cognitive Dysfunction in Long COVID Patients: Eye Movement Abnormalities and Frontal-Subcortical Circuits Implications via Eye-Tracking and Machine Learning

BackgroundCognitive dysfunction is regarded as one of the most severe aftereffects following coronavirus disease 2019 (COVID-19). Eye movements, controlled by several brain areas, such as the dorsolateral prefrontal cortex and frontal-thalamic circuits, provide a potential metric for assessing cortical networks and cognitive status. We aimed to examine the utility of eye movement measurements in identifying cognitive impairments in long COVID patients. MethodsWe recruited 40 long COVID patients experiencing subjective cognitive complaints and 40 healthy controls and used a certified eye-tracking medical device to record saccades and antisaccades. Machine learning was applied to enhance the analysis of eye movement data. ResultsPatients did not differ from the healthy controls regarding age, sex, and years of education. However, the patients' Montreal Cognitive Assessment total score was significantly lower than healthy controls. Most eye movement parameters were significantly worse in patients. These included the latencies, gain (computed as the ratio between stimulus amplitude and gaze amplitude), velocities, and accuracy (evaluated by the presence of hypermetric or hypometria dysmetria) of both visually and memory-guided saccades; the number of correct memory saccades; the latencies and duration of reflexive saccades; and the number of errors in the antisaccade test. Machine learning permitted distinguishing between long COVID patients experiencing subjective cognitive complaints and healthy controls. ConclusionOur findings suggest impairments in frontal subcortical circuits among long COVID patients who report subjective cognitive complaints. Eye-tracking, combined with machine learning, offers a novel, efficient way to assess and monitor long COVID patients' cognitive dysfunctions, suggesting its utility in clinical settings for early detection and personalized treatment strategies. Further research is needed to determine the long-term implications of these findings and the reversibility of cognitive dysfunctions.

Neuropsychiatric symptoms associated multimodal brain networks in Alzheimer's disease.

Concomitant neuropsychiatric symptoms (NPS) are associated with accelerated Alzheimer's disease (AD) progression. Identifying multimodal brain imaging patterns associated with NPS may help understand pathophysiology correlates AD. Based on the AD continuum, a supervised learning strategy was used to guide four-way multimodal neuroimaging fusion (Amyloid, Tau, gray matter volume, brain function) by using NPS total score as the reference. Loadings of the identified multimodal patterns were compared across the AD continuum. Then, regression analyses were performed to investigate its predictability of longitudinal cognition performance. Furthermore, the fusion analysis was repeated in the four NPS subsyndromes. Here, an NPS-associated pathological-structural-functional covaried pattern was observed in the frontal-subcortical limbic circuit, occipital, and sensor-motor region. Loading of this multimodal pattern showed a progressive increase with the development of AD. The pattern significantly correlates with multiple cognitive domains and could also predict longitudinal cognitive decline. Notably, repeated fusion analysis using subsyndromes as references identified similar patterns with some unique variations associated with different syndromes. Conclusively, NPS was associated with a multimodal imaging pattern involving complex neuropathologies, which could effectively predict longitudinal cognitive decline. These results highlight the possible neural substrate of NPS in AD, which may provide guidance for clinical management.

Neuropsychological Profile of Early Cognitive Impairment in Cerebral Small Vessel Disease

Introduction: The neuropsychological feature of vascular mild cognitive impairment is a deficit of the frontal-subcortical circuit; however, the features in the early stage are not consistent. In the present study, we aimed to investigate the neuropsychological features of the very early stage of cognitive impairment with cerebral small vessel disease (CSVD) and to elucidate the cognitive differences among CSVD subtypes. Methods: A comprehensive neuropsychological test battery was applied to nondemented subjects scoring below the cutoff point 26 of the Japanese version of the Montreal Cognitive Assessment. After factor analysis was conducted to identify covert cognitive factors in the battery, correlation analyses were performed between the factors and CSVD subtypes: white matter hyperintensity (WMH), lacunar infarcts (LIs), cerebral microbleeds (CMBs), perivascular spaces, and cortical atrophy. Results: Among the 465 recruited patients, 139 underwent a full neuropsychological test battery. Through factor analysis, the following three factors were extracted: executive function, memory, and attention. Of the CSVD features, total WMH was correlated with executive function and memory, whereas deep WMH was correlated with memory alone. Of the CSVD subtypes, LIs and CMBs were correlated only with executive function. Frontal and posterior atrophy were correlated with memory and attention, whereas medial temporal atrophy was correlated with memory alone. Conclusions: Executive dysfunction accompanied by subtle impairment of memory and processing speed was the main feature of neuropsychological profiles in the subjects with CSVD, even in the very early stage. Furthermore, each CSVD feature and focal cerebral atrophy are associated with cognitive impairment.

Progressive Supranuclear Palsy Following as Major Depressive Disorder: A Case Report

Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disease that is classified among Parkinson plus syndromes, manifesting itself with behavioral, cognitive and emotional symptoms as well as parkinsonian symptoms such as postural instability, ophthalmoplegia, bradykinesia, rigidity affecting the brain stem, basal ganglia and cerebellum. Although there is sufficient information about the pathological process and clinical presentation of PSP, there is no valid biomarker for diagnosis, clinical findings and neuroimaging are very important in diagnosis, patients often get misdiagnosis at their first application. It has been reported that psychiatric symptoms are common in these individuals due to the involvement of the frontal-subcortical circuits, and therefore patients can get psychiatric diagnoses in the early period. We aimed to present a 72-year-old female patient who was followed up with the diagnosis of major depressive disorder in various centers for about 4 years, who did not benefit from psychiatric treatment, and diagnosed with PSP eventually. We also aimed to emphasize that importance of considering neurodegenerative diseases in differential diagnosis in patients whose depressive symptoms begin at an advanced age, are resistant to treatment and have atypical symptoms such as the presence of accompanying neurological findings, and psychiatric symptoms may be the first symptom of neurodegenerative diseases.

The Correlation of Reduced Fractional Anisotropy in the Cingulum With Suicide Risk in Bipolar Disorder.

Objective: This study aims to investigate the significant alterations in brain white matter integrity in individuals with bipolar disorder (BD) who had attempted suicide by applying a tract-based spatial statistics (TBSS) approach with tensor-based spatial normalization.Methods: A TBSS approach with novel tensor-based registration was used to compare the white matter fractional anisotropy (FA) between 51 individuals with BD, of whom 19 had attempted suicide, and 43 healthy controls (HC). The suicide attempt was assessed with the Columbia-Suicide Severity Rating Scale (C-SSRS). In addition, we also investigated the correlations of FA values with clinical measures in BD, including illness duration, and the severity of depression and anxiety measured by the Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Rating Scale (HAMA), respectively.Results: A significant reduction of FA value in the hippocampal cingulum was observed in BD individuals who had attempted suicide compared with those who had not. For the genu/body of the corpus callosum, inferior fronto-occipital fasciculus, uncinate fasciculus, and anterior thalamic radiation, the reductions in FA values were significantly greater in both BD subgroups who attempted suicide and who did not, compared to HC. The correlation analysis showed that the illness duration of attempters was correlated to the FA value of the genu of the corpus callosum, while the HAMD and HAMA scores of non-attempters were relevant to the FA of the superior longitudinal fasciculus.Conclusion: The observation that white matter integrity was altered in the hippocampal cingulum in BD individuals who attempted suicide suggested that this brain area may be the neurobiological basis of suicide attempts. Our findings also support the involvement of white matter (WM) microstructure of frontal–subcortical circuits in the neurobiological mechanism of BD. In addition, the illness duration of patients with attempted suicide may have an effect on the altered integrity of the corpus callosum.

Distinct Patterns of Brain Atrophy associated with Mild Behavioral Impairment in Cognitively Normal Elderly Adults.

A cross-sectional study was conducted to evaluate patterns of gray matter changes in cognitively normal elderly adults with mild behavioral impairment (MBI). Sixteen MBI patients and 18 healthy controls were selected. All the participants underwent a neuropsychological assessment battery, including the Mini-mental State Examination (MMSE), Geriatric Depression Scale (GDS), Self-rating Anxiety Scale (SAS), and Chinese version of the mild behavioral impairment-checklist scale (MBI-C), and magnetic resonance imaging (MRI) scans. Imaging data was analyzed based on voxel-based morphometry (VBM). There was no significant difference in age, gender, MMSE score, total intracranial volume, white matter hyperdensity, gray matter volume, white matter volume between the two groups (p > 0.05). MBI group had shorter education years and higher MBI-C score, GDS and SAS scores than the normal control group (p < 0.05). For neuroimaging analysis, compared to the normal control group, the MBI group showed decreased volume in the left brainstem, right temporal transverse gyrus, left superior temporal gyrus, left inferior temporal gyrus, left middle temporal gyrus, right occipital pole, right thalamus, left precentral gyrus and left middle frontal gyrus(uncorrected p < 0.001). The grey matter regions correlated with the MBI-C score included the left postcentral gyrus, right exterior cerebellum, and left superior frontal gyrus. This suggests a link between MBI and decreased grey matter volume in cognitively normal elderly adults. Atrophy in the left frontal cortex and right thalamus in MBI patients is in line with frontal-subcortical circuit deficits, which have been linked to neuropsychiatric symptoms (NPS) in dementia. These initial results imply that MBI might be an early harbinger for subsequent cognitive decline and dementia.

DEPRESSION AS THE FIRST SYMPTOM OF FRONTAL LOBE GRADE 2 MALIGNANT GLIOMA

DEPRESSION AS THE FIRST SYMPTOM OF FRONTAL LOBE GRADE 2 MALIGNANT GLIOMA

White matter structural network disturbances in first-episode, drug-naïve adolescents with generalized anxiety disorder

BackgroundPrevious studies have suggested that individuals with generalized anxiety disorder (GAD) would show inefficient whole-brain communication and dysconnectivity in the fronto-parietal-subcortical sub-networks in the white matter (WM) structural network. However, these hypotheses have yet to be tested. MethodsIndividual WM structural networks were constructed based on diffusion MRI data and deterministic tractography in 34 first-episode, medication-naïve adolescents with GAD and 27 healthy controls (HCs). Graph theory was applied to investigate the topological organization alterations of the structural network. ResultsGAD patients showed disrupted small-world configurations (i.e., increased path length and decreased clustering coefficient) and hub organization (i.e., less connection strength in the feeder and local connections). A decreased connection strength was found in a GAD-related sub-network (mainly involving the frontal-subcortical circuits), which was able to distinguish GAD patients from HCs with higher accuracy (area under the curve of 0.96, sensitivity of 94%, specificity of 89%) than clinical scores and other topological alternations. LimitationsThe current study just compared GAD patients with HCs based on a small sample, leaving whether the alternations found here are specific to GAD still an open question. Future studies are recommended to recruit patients with other anxiety disorders (e.g., social anxiety disorder) and/or comorbid mood disorders to identify the GAD-specific WM alterations using a larger sample. ConclusionsOur findings highlight the disruption of the topological organization of the whole-brain WM structural network (especially the frontal-subcortical circuits) in GAD, and suggest the potential of using structural connectivity of the GAD-related sub-network as a biomarker for GAD patients.

Value of the Frontal Assessment Battery Tool for Assessing the Frontal Lobe Function in Stroke Patients.

ObjectiveTo examine the correlation between the Frontal Assessment Battery (FAB) test, which is used to assess the frontal lobe function, and anatomical lesions as well as the ability of the test to detect frontal lobe dysfunction.MethodsRecords of stroke patients undergoing a FAB test and Mini-Mental State Examination (MMSE) were retrospectively reviewed. The patients were divided into three groups according to the lesions determined by an imaging study: frontal lobe cortex lesions, frontal subcortical circuit lesions, and other lesions. The FAB scores of the three groups were compared using the Kruskal-Wallis test. The validity of the FAB test to detect frontal lobe dysfunction was assessed by a comparison with the Computerized Neuropsychological Function Test (CNT) using the Spearman correlation coefficient. The correlation coefficients between the FAB test and MMSE were analyzed further based on the MMSE cutoff score.ResultsPatients with frontal cortex lesions had significantly lower total and subtest scores according to the FAB test than the other patients. The FAB test correlated better with the CNT than the MMSE, particularly in the executive function and memory domains. A high MMSE score (r=0.435) indicated a lower correlation with the FAB test score than a low MMSE score (r=0.714).ConclusionThe FAB test could differentiate frontal lobe lesions from others in stroke patients and showed a good correlation with the CNT. Moreover, the FAB test can be used in patients with high MMSE scores to detect frontal lobe dysfunction and determine the treatment strategies for stroke patients.

Correlation Between High Sensitivity C-Reactive Protein Level and Executive Function Disorders in Elderly Patients

C-Reactive Protein is a marker of inflammation and vascular disease. The high serum of high-sensitivity C-Reactive Protein (hs-CRP) concentration was associated with interruption the integrity of the frontal-subcortical circuit. To determine the correlation between high serum concentration of hs-CRP and executive function disorder in elderly patients. Thirty six elderly patients was examined by using a case control study. The subjects were enrolled from the out-patient at Neurology Department Dr. Soetomo General Hospital, Surabaya, Indonesia. The time period was 4 months (April to July 2015). Executive function was measured with the Trail Making Test B (TMT B) and divided into two groups, case and control. Complete blood count and serum hs-CRP concentration were measured from nonfasting blood samples. Chi-square test was used for data analysis. Eighteen subjects were enrolled in the case group (3 men, 15 women) and the other 18 subjects were enrolled in the control group (4 men, 14 women). Executive function disorder was found in 17 (94,4%) subjects of case group and 11 (61,1%) subjects of control group. High levels of hs-CRP was not associated with executive function, withp= 0,149 and adjusted OR 5,629 (CI 95% 0, 538-58, 860). These data suggested that high levels of hs-CRP was not associated with executive function in elderly patients.

Hippocampal α-synuclein pathology correlates with memory impairment in multiple system atrophy.

Recent post-mortem studies reported 22-37% of patients with multiple system atrophy can develop cognitive impairment. With the aim of identifying associations between cognitive impairment including memory impairment and α-synuclein pathology, 148 consecutive patients with pathologically proven multiple system atrophy were reviewed. Among them, 118 (79.7%) were reported to have had normal cognition in life, whereas the remaining 30 (20.3%) developed cognitive impairment. Twelve of them had pure frontal-subcortical dysfunction, defined as the presence of executive dysfunction, impaired processing speed, personality change, disinhibition or stereotypy; six had pure memory impairment; and 12 had both types of impairment. Semi-quantitative analysis of neuronal cytoplasmic inclusions in the hippocampus and parahippocampus revealed a disease duration-related increase in neuronal cytoplasmic inclusions in the dentate gyrus and cornu ammonis regions 1 and 2 of patients with normal cognition. In contrast, such a correlation with disease duration was not found in patients with cognitive impairment. Compared to the patients with normal cognition, patients with memory impairment (pure memory impairment: n = 6; memory impairment + frontal-subcortical dysfunction: n = 12) had more neuronal cytoplasmic inclusions in the dentate gyrus, cornu ammonis regions 1-4 and entorhinal cortex. In the multiple system atrophy mixed pathological subgroup, which equally affects the striatonigral and olivopontocerebellar systems, patients with the same combination of memory impairment developed more neuronal inclusions in the dentate gyrus, cornu ammonis regions 1, 2 and 4, and the subiculum compared to patients with normal cognition. Using patients with normal cognition (n = 18), frontal-subcortical dysfunction (n = 12) and memory impairment + frontal-subcortical dysfunction (n = 18), we further investigated whether neuronal or glial cytoplasmic inclusions in the prefrontal, temporal and cingulate cortices or the underlying white matter might affect cognitive impairment in patients with multiple system atrophy. We also examined topographic correlates of frontal-subcortical dysfunction with other clinical symptoms. Although no differences in neuronal or glial cytoplasmic inclusions were identified between the groups in the regions examined, frontal release signs were found more commonly when patients developed frontal-subcortical dysfunction, indicating the involvement of the frontal-subcortical circuit in the pathogenesis of frontal-subcortical dysfunction. Here, investigating cognitive impairment in the largest number of pathologically proven multiple system atrophy cases described to date, we provide evidence that neuronal cytoplasmic inclusion burden in the hippocampus and parahippocampus is associated with the occurrence of memory impairment in multiple system atrophy. Further investigation is necessary to identify the underlying pathological basis of frontal-subcortical dysfunction in multiple system atrophy.

Pragmatic language dysfunction in systemic lupus erythematosus patients: Results from a single center Italian study.

BackgroundCognitive impairment (CI) in systemic lupus erythematosus (SLE) is a frequent neuropsychiatric manifestation affecting several domains, even in apparently asymptomatic patients. Current research revealed that the typical CI pattern affects frontal-subcortical circuit and thus executive functions. The impairment of non-literal language or pragmatic language (PL), including metaphors, idioms, inferences or irony has been well described in several conditions such as autism disorders, Parkinson’s disease, brain injury and even in earlier phases of neurodegenerative processes. Even if PL neuro-anatomy remains controversial, correlation between executive dysfunctions and non-literal language involvement has been reported both in traumatic injury and mild cognitive impairment patients. Nonetheless, no specific study has been performed to evaluate PL impairment in SLE patients so far.ObjectivesWe aimed at assessing the PL domain in a Italian monocentric SLE cohort in comparison to healthy controls, matched to age and education, through a specific battery, the batteria sul linguaggio dell'emisfero destro (BLED). Secondly, we focused attention on possible correlations between CI and clinical and laboratory SLE-related features.MethodsForty adult patients affected by SLE, according to the American College of Rheumatology (ACR) criteria, and thirty healthy subjects were enrolled consecutively in this cross-sectional study. The protocol included complete physical examination, extensive clinical and laboratory data collection (comprehensive of demographics, past medical history, co-morbidities, disease activity, chronic damage evaluation, previous and concomitant treatments) and cognitive assessment for five different domains: memory, attention, pragmatic language, executive and visuospatial functions. Self-reported scale for anxiety and depression were performed to exclude the influence of mood disorders on cognitive dysfunction.ResultsWe studied 40 Caucasian SLE patients [male (M)/ female (F) 3/37; mean±standard deviation (SD) age 45.9±10.1 years, mean±SD disease duration 120.8±81.2 months] and 30 healthy subjects (M/F 9/21; mean±SD age 41.3±13 years). According to the low level of disease activity and damage (mean±SD Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) of 1.3±2.3, mean±SD Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI) of 0.2±0.5), only 30% of patients was on glucocorticoid treatment at the study entry. PL was the most compromised domain in terms of Mean Domain Z scores. As for the Domain Cognitive Dysfunction score, a deficit of PL was observed in 45% of patients and was significantly more prevalent than memory, executive and visuospatial functions impairment (P = 0.0002, P = 0.0002 and P<0.000001, respectively). According to Global Cognitive Dysfunction score, 25% of patients experienced a mild impairment and 7.5% a moderate one. Anti-phospholipid antibodies positivity was significantly associated with memory impairment (P<0.0005), whereas the presence of other neuropsychiatric events was associated with executive dysfunctions (P<0.05); no further significant association nor correlation were identified.ConclusionIn this study we evaluated for the first time PL in SLE patients finding a dysfunction in almost half of patients. The dysfunction of PL was significantly more frequent than the other domains assessed.

Fahr syndrome: A case series analysis

Fahr disease or Fahr syndrome is a rare neurological disorder characterized by abnormal calcified deposits in basal ganglia and cerebral cortex. As the disease progresses, it was found that lateral thalamus, dentate nucleus of cerebellum and the frontal cortex get affected as well. Aim of the study was to analyze 5 cases of Fahr syndrome highlighting any possible correlation between the progressive nature of the disease, clinical spectrum and neuroimaging data. Methods Five patients aged 19, 31, 43 and 53 and 56 were studied in Albania. They were hospitalized in the Neurology service, each showing a different clinical spectrum. One patient presented with seizures, another one with headache and two patients developed neuropsychiatric and cognitive disorders. Another patient was hospitalized for an acute stroke. After a thorough evaluation, brain computed tomography scans revealed calcifications in basal ganglia, with one case revealing calcifications in basal ganglia, globus pallidus, cerebellar white matter and frontal subcortical white matter. Results Although the progressive nature of the disease is estimated, different neurological manifestations account for different cases. Family history and comorbidities should always be kept in mind when analyzing the neurological signs and symptoms. Conclusion No clear cut correlation is found between the progressive nature of the disease, neurological manifestations and neuroimaging data. The concept of frontal subcortical circuits, a system of loops linking the basal ganglia and frontal brain regions, and functional neuroimaging may give additional data regarding the pathophysiology and clinical signs of the disease.

Frontal-subcortical behaviors during Alzheimer's disease in individuals with Down syndrome

There is evidence that frontal-subcortical circuits play an important role in the initial presentation of dementia in Down syndrome (DS), including changes in behavior, a decline in working memory and executive dysfunction. We evaluated 92 individuals with DS (≥30 years of age), divided into 3 groups by diagnosis—stable cognition, prodromal dementia, and Alzheimer's disease. Each individual was evaluated with an executive protocol developed for people with intellectual disabilities and was rated for behaviors related to frontal lobe dysfunction (disinhibition, executive dysfunction, and apathy) by an informant using the Frontal Systems Behavior Scale. Informant-reported behaviors related to frontal lobe dysfunction were found to correlate negatively with executive function performance. Disinhibition and executive dysfunction were associated with the clinical stage of dementia. The odds of having Alzheimer's disease increased in parallel with increases in the domain and total Frontal Systems Behavior Scale scores (p ≤ 0.5). Disinhibition, executive dysfunction and apathy should be taken into consideration during the clinical evaluation of adults with DS, and future studies should consider the intersection of neuropathology, brain connectivity, and behavior.

Genome-Wide Association Studies of Impulsive Personality Traits (BIS-11 and UPPS-P) and Drug Experimentation in up to 22,861 Adult Research Participants Identify Loci in the CACNA1I and CADM2 genes.

Impulsive personality traits are complex heritable traits that are governed by frontal-subcortical circuits and are associated with numerous neuropsychiatric disorders, particularly drug abuse and attention-deficit/hyperactivity disorder (ADHD). In collaboration with the genetics company 23andMe, we performed 10 genome-wide association studies on measures of impulsive personality traits [the short version of the UPPS-P Impulsive Behavior Scale, and the Barratt Impulsiveness Scale (BIS-11)] and drug experimentation (the number of drug classes an individual had tried in their lifetime) in up to 22,861 male and female adult human research participants of European ancestry. Impulsive personality traits and drug experimentation showed single nucleotide polymorphism heritabilities that ranged from 5 to 11%. Genetic variants in the CADM2 locus were significantly associated with UPPS-P Sensation Seeking (p = 8.3 × 10-9, rs139528938) and showed a suggestive association with Drug Experimentation (p = 3.0 × 10-7, rs2163971; r2 = 0.68 with rs139528938). Furthermore, genetic variants in the CACNA1I locus were significantly associated with UPPS-P Negative Urgency (p = 3.8 × 10-8; rs199694726). The role of these genes was supported by single variant, gene- and transcriptome-based analyses. Multiple subscales from both UPPS-P and BIS showed strong genetic correlations (>0.5) with Drug Experimentation and other substance use traits measured in independent cohorts, including smoking initiation, and lifetime cannabis use. Several UPPS-P and BIS subscales were genetically correlated with ADHD (rg = 0.30-0.51), supporting their validity as endophenotypes. Our findings demonstrate a role for common genetic contributions to individual differences in impulsivity. Furthermore, our study is the first to provide a genetic dissection of the relationship between different types of impulsive personality traits and various psychiatric disorders.SIGNIFICANCE STATEMENT Impulsive personality traits (IPTs) are heritable traits that are governed by frontal-subcortical circuits and are associated with neuropsychiatric disorders, particularly substance use disorders. We have performed genome-wide association studies of IPTs to identify regions and genes that account for this heritable variation. IPTs and drug experimentation were modestly heritable (5-11%). We identified an association between single nucleotide polymorphisms in CADM2 and both sensation seeking and drug experimentation; and between variants in CACNA1I and negative urgency. The role of these genes was supported by single variant, gene- and transcriptome-based analyses. This study provides evidence that impulsivity can be genetically separated into distinct components. We showed that IPT are genetically associated with substance use and ADHD, suggesting impulsivity is an endophenotype contributing to these psychiatric conditions.

Synaptic Connectivity in Medium Spiny Neurons of the Nucleus Accumbens: A Sex-Dependent Mechanism Underlying Apathy in the HIV-1 Transgenic Rat

Frontal-subcortical circuit dysfunction is commonly associated with apathy, a neuropsychiatric sequelae of human immunodeficiency virus type-1 (HIV-1). Behavioral and neurochemical indices of apathy in the nucleus accumbens (NAc), a key brain region involved in frontal-subcortical circuitry, are influenced by the factor of biological sex. Despite evidence of sex differences in HIV-1, the effect of biological sex on medium spiny neurons (MSNs), which are central integrators of frontal-subcortical input, has not been systematically evaluated. In the present study, a DiOlistic labeling technique was used to investigate the role of long-term HIV-1 viral protein exposure, the factor of biological sex, and their possible interaction, on synaptic dysfunction in MSNs of the NAc in the HIV-1 transgenic (Tg) rat. HIV-1 Tg rats, independent of biological sex, displayed profound alterations in synaptic connectivity, evidenced by a prominent shift in the distribution of dendritic spines. Female HIV-1 Tg rats, but not male HIV-1 Tg rats, exhibited alterations in dendritic branching and neuronal arbor complexity relative to control animals, supporting an alteration in glutamate neurotransmission. Morphologically, HIV-1 Tg male, but not female HIV-1 Tg rats, displayed a population shift towards decreased dendritic spine volume, suggesting decreased synaptic area, relative to control animals. Synaptic dysfunction accurately identified presence of the HIV-1 transgene, dependent upon biological sex, with at least 80% accuracy (i.e., Male: 80%; Female: 90%). Collectively, these results support a primary alteration in circuit connectivity, the mechanism of which is dependent upon biological sex. Understanding the effect of biological sex on the underlying neural mechanism for HIV-1 associated apathy is vital for the development of sex-based therapeutics and cure strategies.

Neuropsychological And Psychopathological Profile Of Anti-Nmdar Encephalitis: A Possible Pathophysiological Model For Pediatric Neuropsychiatric Disorders.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a severe, but treatable, autoimmune disorder, characterized by autoantibodies causing hypofunction of blocking NMDA receptors leading to a unique constellation of cognitive, motor, and psychiatric symptoms. Neuropsychological and psychopathological outcome has not been fully explored, particularly in children. Aim of this study was to investigate pediatric anti-NMDAR encephalitis as a model of impairment of the complex frontal-subcortical circuits who are implicated in several of the childhood neuropsychiatric disorders. Seven children diagnosed with anti-NMDAR encephalitis at our department underwent an evaluation of the global mental functioning before discharge, a neuropsychological and psychological/behavioral standardized examination within one month after discharge and subsequently were followed up longitudinally for mean 35 months (range 24-48 months). Collected neuropsychological data were evaluated retrospectively. Deficits in attention, executive functions and/or visual motor functions involving executive functions were seen in all children within one month after discharge. These deficits were long lasting in about a half of the patients. In addition, four patients developed persistent psychopathological dysfunctions: difficulties to regulate their own behavior, impulsivity, hyperactivity, irritability, apathy, and obsessive-compulsive symptoms. Our data are in line with research suggesting a crucial role of the executive functions impairments in cognitive outcome disturbance of anti-NMDAR encephalitis. We found also behavioral and psychological deficits pointing to a more comprehensive framework of frontal-subcortical dysfunction, in which the NMDA mediated transmission appear to have a role, as suggested by neurobiological, pharmacological, and neuroimaging studies.

Emotion-Specific Affective Theory of Mind Impairment in Parkinson\u2019s Disease

The neuropathology of Parkinson’s disease (PD) involves the frontal-subcortical circuit, an area responsible for processing affective theory of mind (ToM). Patients with PD are expected to experience deficits in the affective ToM. This study aims to investigate whether the ability to infer emotion in others is affected in either young-onset Parkinson’s disease (YOPD) or middle-onset PD (MOPD) patients and to test whether the impairments in affective ToM are associated with the motor symptoms. The affective ToM, global mental abilities, and clinical symptoms were assessed in a total of 107 MOPD, 30 YOPD, and 30 normal controls (NCs). The MOPD patients exhibited deficits in affective ToM to the negative and neutral valences, when compared to the participants in the NCs and YOPD group. By conducting gender-stratified analysis, the deficits in affective ToM was only found in female participants. After adjusting for demographic variables, the multiple linear regression model revealed that affective ToM predicted motor symptoms, especially in female MOPD patients. The present study may aid in the development of medical care programs by advocating for a more comprehensive therapeutic plan that includes continuous disease progression monitoring and social skills training for female MOPD patients or their caregivers.