Resting state fMRI analysis of pseudobulbar affect in Amyotrophic Lateral Sclerosis (ALS): motor dysfunction of emotional expression.

Pseudobulbar affect (PBA), referring to exaggerated or inappropriate episodes of laughing and/or crying without an apparent motivating stimulus, has been mainly attributed to bilateral degeneration of corticobulbar tracts. We aimed at exploring brain functional connectivity (FC) correlates of PBA in patients with amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, frequently associated with PBA. Resting state functional MRI (RS-fMRI) independent component (ICA) and seed-based analyses and voxel-based morphometry (VBM) whole-brain analysis were performed on 27 ALS patients (13 with PBA; 14 without PBA) and 26 healthy controls (HC), for investigating functional and structural abnormalities in ALS patients compared to HC and in patients with PBA compared to patients without PBA. Between-patient analysis revealed different FC patterns, especially regarding decreased FC in several areas of cognitive (default mode, frontoparietal, salience) and sensory-motor networks in patients with PBA compared to those without PBA. However, no significant differences were found in gray matter atrophy. Seed-based analysis showed increased FC between middle cerebellar peduncles and posterior cingulate cortex and decreased FC between middle cerebellar peduncles and left middle frontal gyrus in patients with PBA compared to patients without PBA. Our findings suggest that some alterations of fronto-tempo-parietal-cerebellar circuits could be related to PBA in ALS. In particular, the abnormal FC between cerebellum and posterior cingulate cortex and left middle frontal gyrus in patients with PBA compared to patients without PBA highlights a crucial role of the cerebellum in regulating emotion expression in patients with ALS.

Involuntary Emotional Expression Disorder in a Patient With Toluene Leukoencephalopathy.

OBJECTIVE: Inhalant users may develop toluene leukoencephalopathy, a devastating neuropsychiatric disorder. We present a case of toluene-induced damage to the corticospinal and the corticonuclear tracts, which presented with involuntary emotional expression disorder. METHODS: Case study of a 20-year-old man with a 3-year history of frequent solvent abuse was admitted to the Neuropsychiatry Unit of the National Institute of Neurology and Neurosurgery because "he could not speak or walk" but would keep "laughing and crying without reason". RESULTS: Neuropsychiatric examination revealed pathological laughter and crying, facial and speech apraxia, a bilateral pyramidal syndrome, and lack of control of urinary sphincter. Magnetic resonance imaging revealed a highly selective bilateral damage to the pyramidal system and the somatosensory pathway. SPECT imaging showed left fronto-parietal hypoperfusion. CONCLUSIONS: This document provides support for the understanding of involuntary emotional expression disorders as a differential diagnosis in the clinical practice of psychiatrists, as well as the functional anatomy of these conditions.

Involuntary Emotional Expression Disorder in a Patient With Toluene Leukoencephalopathy / Trastorno de expresión emocional involuntaria en un paciente con leucoencefalopatía por tolueno

ABSTRACT Objective: Inhalant users may develop toluene leukoencephalopathy, a devastating neuropsychiatric disorder. We present a case of toluene-induced damage to the corticospinal and the corticonuclear tracts, which presented with involuntary emotional expression dis-order. Methods: Case study of a 20-year-old man with a 3-year history of frequent solvent abuse was admitted to the Neuropsychiatry Unit of the National Institute of Neurology and Neurosurgery because "he could not speak or walk" but would keep "laughing and crying without reason". Results: Neuropsychiatric examination revealed pathological laughter and crying, facial and speech apraxia, a bilateral pyramidal syndrome, and lack of control of urinary sphincter. Magnetic resonance imaging revealed a highly selective bilateral damage to the pyramidal system and the somatosensory pathway. SPECT imaging showed left fronto-parietal hypoperfusion. Conclusions: This document provides support for the understanding of involuntary emotional expression disorders as a differential diagnosis in the clinical practice of psychiatrists, as well as the functional anatomy of these conditions.

RESUMEN Objetivo: Los usuarios de inhalantes pueden contraer leucoencefalopatía por tolueno, un trastorno neuropsiquiátrico devastador. Se presenta un caso de daño inducido por tolueno en el tracto corticoespinal y corticonuclear, que se manifestó con un trastorno involuntario de la expresión emocional. Métodos: Un varón de 20 años con antecedente de 3 años de abuso de solventes ingresó en la Unidad de Neuropsiquiatría del Instituto Nacional de Neurología y Neurocirugía porque «no podía hablar ni caminar¼ y presentaba episodios súbitos de risa y llanto sin razón aparente. Resultados: La valoración neuropsiquiátrica reveló risa y llanto patológicos, apraxia facial y fonatoria, síndrome piramidal bilateral y ausencia de control del esfínter urinario. La resonancia magnética cerebral mostró un daño bilateral muy selectivo del sistema piramidal y la vía somatosensorial. La imagen de tomografía computarizada por emisión monofotónica mostró hipoperfusión frontoparietal izquierda. Conclusiones: Este documento proporciona apoyo para la comprensión de los trastornos de la expresión emocional involuntaria como diagnóstico diferencial en la práctica clínica de los psiquiatras, así como de la anatomía funcional de estas condiciones.

Emotional Lability at Disease Onset Is an Independent Prognostic Factor of Faster Disease Progression in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fast progressing neurodegenerative disease leading to quadriplegia, anarthria and respiratory insufficiency. A large variety of phenotypes and disability progression requires individually tailored management. Identification of predictors of poor prognosis may not only improve management, but also allow for more precise patients' stratification for clinical trials or research studies. The aim of the study was to investigate the influence of emotional lability present at disease onset on ALS progression by exploring its direct impact on the decay of the ALS Functional Rating Scale-Revised (ALSFRS-R). The study was performed in a group of 1145 patients from Germany, Poland, Portugal and Turkey between 2014 and 2018. The analysis showed that the presence of emotional lability at ALS onset was linked to a faster decline of ALSFRS-R (0.70 vs 0.50, p<0.0001), in case of either bulbar (0.80 vs 0.65, p<0.05) or limb disease onset (0.59 vs 0.46, p <0.01). It was most prominent in the bulbar subscore of ALSFRS-R. A multiple regression analysis showed a direct influence of emotional lability at ALS onset on disease progression, regardless of age, gender, site of onset, weight loss, cognitive impairment and diagnosis delay (ß=0.071; p=0.019). It can therefore be concluded that the presence of emotional lability at the disease onset is an independent factor of faster disease progression in ALS.

Involuntary Emotional Expression Disorder in a Patient With Toluene Leukoencephalopathy.

OBJECTIVE: Inhalant users may develop toluene leukoencephalopathy, a devastating neuropsychiatric disorder. We present a case of toluene-induced damage to the corticospinal and the corticonuclear tracts, which presented with involuntary emotional expression disorder. METHODS: Case study of a 20-year-old man with a 3-year history of frequent solvent abuse was admitted to the Neuropsychiatry Unit of the National Institute of Neurology and Neurosurgery because "he could not speak or walk" but would keep "laughing and crying without reason". RESULTS: Neuropsychiatric examination revealed pathological laughter and crying, facial and speech apraxia, a bilateral pyramidal syndrome, and lack of control of urinary sphincter. Magnetic resonance imaging revealed a highly selective bilateral damage to the pyramidal system and the somatosensory pathway. SPECT imaging showed left fronto-parietal hypoperfusion. CONCLUSIONS: This document provides support for the understanding of involuntary emotional expression disorders as a differential diagnosis in the clinical practice of psychiatrists, as well as the functional anatomy of these conditions.

Posterior Fossa Lesion Load and Pathological Laughing and Crying in Multiple Sclerosis.

BACKGROUND: Pathological laughing and crying (PLC) encompasses episodes of involuntary laughing, crying, or both that are contextually incongruous with the individual's subjective mood. Despite a 10% to 46% prevalence in people with multiple sclerosis (MS) and reduced quality of life, localization of neuroanatomical lesions associated with PLC remains poorly delineated. METHODS: The relationship between posterior fossa lesions and PLC in people with MS was examined using a retrospective medical record review of people with MS (2012-2016) who had completed the Center for Neurologic Study-Liability Scale (CNS-LS) and had undergone 1.5-T magnetic resonance imaging within 6 months of each other. RESULTS: Medical record review identified 80 potential cases, with 77 included. Brainstem and cerebellar lesions were counted, measured, and compared between people with MS who had positive results on the CNS-LS (scores ≥17, n = 22) with those who had negative results on the CNS-LS (scores ≤16, n = 55). Initial χ2 analysis showed no significant difference in lesion numbers in people with MS without (CNS-LS score ≤16) versus with (CNS-LS score ≥17) PLC. When analyzing only people with MS without evidence of depression, a significant inverse relationship was identified such that fewer posterior fossa lesions on automated magnetic resonance imaging was associated with the presence of PLC. CONCLUSIONS: Posterior fossa lesion load is not indicative of which individuals could develop PLC. Further investigations to delineate the primary source of PLC symptoms would aid in diagnosis and treatment of this condition.

Investigating the neuroanatomical substrate of pathological laughing and crying in amyotrophic lateral sclerosis with multimodal neuroimaging techniques.

OBJECTIVE: Pathological laughing and crying (PLC) is common in several neurological and psychiatric diseases and is associated with a distributed network involving the frontal cortex, the brainstem and cortico-pontine-cerebellar circuits. By applying multimodal neuroimaging approach, we examined the neuroanatomical substrate of PLC in a sample of patients with amyotrophic lateral sclerosis (ALS). METHODS: We studied 56 non-demented ALS patients and 25 healthy controls (HC). PLC was measured in ALS using the Center of Neurologic Study Lability Scale (CNS-LS; cutoff score: 13). All participants underwent 3D-T1-weighted and 30-directional diffusion-weighted imaging at 3T. Voxel-based morphometry and tract-based spatial-statistics analysis was used to examine gray matter (GM) and white matter (WM) differences between ALS patients with and without PLC (ALS-PLC and ALS-nonPLC, respectively). Comparisons were restricted to regions with detected differences between ALS and HC, controlling for age, gender, total intracranial volume and depressive symptoms. RESULTS: In regions with significant differences between ALS and HC, ALS-PLC patients showed decreased GM volume in left orbitofrontal cortex, frontal operculum, and putamen and bilateral frontal poles, compared to ALS-nonPLC. They also had decreased fractional anisotropy in left cingulum bundle and posterior corona radiata. WM abnormalities were additionally detected in WM associative and ponto-cerebellar tracts (using a more liberal threshold). CONCLUSIONS: PLC in ALS is driven by both GM and WM abnormalities which highlight the role of circuits rather than isolated centers in the emergence of this condition. ALS is suggested as a useful natural experimental model to study PLC.

Altered resting-state functional activity in isolated pontine infarction patients with pathological laughing and crying.

We used resting-state functional magnetic resonance imaging to investigate the global spontaneous neural activity involved in pathological laughing and crying after stroke. Twelve pathological laughing and crying patients with isolated pontine infarction were included, along with 12 age- and gender-matched acute isolated pontine infarction patients without pathological laughing and crying, and 12 age- and gender-matched healthy controls. We examined both the amplitude of low-frequency fluctuation and the regional homogeneity in order to comprehensively evaluate the intrinsic activity in patients with post-stroke pathological laughing and crying. In the post-stroke pathological laughing and crying group, changes in these measures were observed mainly in components of the default mode network (medial prefrontal cortex/anterior cingulate cortex, middle temporal gyrus, inferior temporal gyrus, superior frontal gyrus, middle frontal gyrus and inferior parietal lobule), sensorimotor network (supplementary motor area, precentral gyrus and paracentral lobule), affective network (medial prefrontal cortex/anterior cingulate cortex, parahippocampal gyrus, middle temporal gyrus and inferior temporal gyrus) and cerebellar lobes (cerebellum posterior lobe). We therefore speculate that when disinhibition of the volitional system is lost, increased activation of the emotional system causes pathological laughing and crying.

Pathological laughing and crying in amyotrophic lateral sclerosis is related to frontal cortex function.

The syndrome of pathological laughing and crying (PLC) is characterized by episodes of involuntary outbursts of emotional expression. Although this phenomenon has been referred to for over a century, a clear-cut clinical definition is still lacking, and underlying pathophysiological mechanisms are not well understood. In particular, it remains ill-defined which kind of stimuli-contextually appropriate or inappropriate-elicit episodes of PLC, and if the phenomenon is a result of a lack of inhibition from the frontal cortex ("top-down-theory") or due to an altered processing of sensory inputs at the brainstem level ("bottom-up-theory"). To address these questions, we studied ten amyotrophic lateral sclerosis (ALS) patients with PLC and ten controls matched for age, sex and education. Subjects were simultaneously exposed to either emotionally congruent or incongruent visual and auditory stimuli and were asked to rate pictures according to their emotional quality. Changes in physiological parameters (heart rate, galvanic skin response, activity of facial muscles) were recorded, and a standardized self-assessment lability score (CNS-LS) was determined. Patients were influenced in their rating behaviour in a negative direction by mood-incongruent music. Compared to controls, they were influenced by negative stimuli, i.e. they rated neutral pictures more negatively when listening to sad music. Patients rated significantly higher on the CNS-LS. In patients, changes of electromyographic activity of mimic muscles during different emotion-eliciting conditions were explained by frontal cortex dysfunction. We conclude that PLC is associated with altered emotional suggestibility and that it is preferentially elicited by mood-incongruent stimuli. In addition, physiological reactions as well as behavioural changes suggest that this phenomenon is primarily an expression of reduced inhibitory activity of the frontal cortex, since frontal dysfunction could explain changes in physiological parameters in the patient group. We consider these findings being important for the clinical interpretation of emotional reactions of ALS patients.

The association of pathological laughing and crying and cognitive impairment in multiple sclerosis.

BACKGROUND: Pathological laughing and crying (PLC) is common in multiple sclerosis (MS), defined as emotional expression that is exaggerated/incongruent with underlying mood. In other neurological disorders, PLC is associated with cognitive impairment (CI). Few studies have examined this relationship in MS. OBJECTIVE: To determine the association between PLC and CI in an MS population. METHODS: Retrospective chart review study of 153 MS subjects assessed in an outpatient clinic for CI. Data was collected on the minimal assessment of cognitive function in MS (MACFIMS), the Center for neurological study-lability scale (CNS-LS), a screening measure for PLC symptoms and the hospital anxiety and depression scale (HADS). Analyses of covariance compared performance on the MACFIMS between PLC (CNS-LS score ≥ 17, HADS-D ≤ 7) and non-PLC groups. RESULTS: MS subjects positive for PLC on the CNS-LS but without depression had lower scores on the controlled oral word association test, a measure of verbal fluency, and the California verbal learning test - 2 immediate recall score, a verbal memory measure. CONCLUSIONS: This study demonstrates a connection between CI, specifically verbal fluency and verbal learning, and PLC in MS subjects. Further studies are warranted to explore the causative relationship between CI and PLC.

Clinical Features and Related Factors of Poststroke Pathological Laughing and Crying: A Case-Control Study.

OBJECTIVES: The purpose of this study was to analyze clinical features and related factors of poststroke pathological laughing and crying (PSPLC) and to differentiate PSPLC patients with and without pseudobulbar signs. METHODS: We performed a case-control study in which 56 patients with PSPLC were matched to 56 control stroke patients by age and gender. The pathological laughing and crying scale was used to identify patients with PSPLC. Characteristics of PSPLC outbursts, presence of pseudobulbar signs and autonomic symptoms, lesion locations, and different clinical data were analyzed. Mild cognitive impairment (MCI) was evaluated by the Montreal Cognitive Assessment. Poststroke anger proneness (PSAP) was evaluated by comparison of the patients' premorbid states. RESULTS: Significantly more patients in the PSPLC group showed MCI, PSAP, and pseudobulbar signs than those in the control group. Most patients with PSPLC showed bilateral multiple lesions and the pons (especially the bilateral paramedian basal and basal-tegmental areas) stood out as the most important lesion location. Logistic regression analysis showed that pontine lesion, MCI, and PSAP were independently related to PSPLC; however, the presence of pseudobulbar signs was not related. PSPLC patients with pseudobulbar signs showed more recurrent strokes in the previous 2 years, more severe neurological deficits, as well as higher severity of PSPLC. In addition, more patients in the group with pseudobulbar signs showed concomitant autonomic symptoms. CONCLUSIONS: PSPLC, MCI, and PSAP could be manifestations of a more general disorder, in which pontine lesion plays an important role. PSPLC patients with pseudobulbar signs and those without show different features.

Crying and suicidal, but not depressed. Pseudobulbar affect in multiple sclerosis successfully treated with valproic acid: Case report and literature review.

OBJECTIVE: Pseudobulbar affect/emotional incontinence is a potentially disabling condition characterized by expressions of affect or emotions out of context from the normal emotional basis for those expressions. This condition can result in diagnostic confusion and unrelieved suffering when clinicians interpret the emotional expressions at face value. In addition, the nomenclature, etiology, and treatment for this condition remain unclear in the medical literature. METHOD: We report the case of a 60-year-old woman with multiple sclerosis who was referred to an inpatient psychiatry unit with complaints of worsening depression along with hopelessness, characterized by unrelenting crying. Our investigation showed that her symptoms were caused by pseudobulbar affect/emotional incontinence stemming from multiple sclerosis. RESULTS: The patient's history of multiple sclerosis and the fact that she identified herself as depressed only because of her incessant crying suggested that her symptoms might be due to the multiple sclerosis rather than to a depressive disorder. Magnetic resonance imaging demonstrated a new plaque consistent with multiple sclerosis lateral to her corpus callosum. Her symptoms resolved completely within three days on valproic acid but returned after she was cross-tapered to dextromethorphan plus quinidine, which is the FDA-approved treatment for this condition. SIGNIFICANCE OF RESULTS: This case provides important additional information to the current literature on pseudobulbar affect/emotional incontinence. The existing literature suggests a selective serotonin reuptake inhibitor (SSRI) and dextromethorphan/quinidine (Nuedexta) as first-line treatments; however, our patient was taking an SSRI at the time of presentation without appreciable benefit, and her symptoms responded to valproic acid but not to the dextromethorphan/quinidine. In addition, the case and the literature review suggest that the current nomenclature for this constellation of symptoms can be misleading.

Dextromethorphan/quinidine for the treatment of pseudobulbar affect.

OBJECTIVE: To evaluate the role of dextromethorphan/quinidine (DM/Q; Nuedexta™) in the treatment of pseudobulbar affect (PBA). DATA SOURCES: A literature search of MEDLINE/PubMed (January 1966-June 2013) was conducted using search terms pseudobulbar affect, pathological laughing and/or crying, emotional lability, dextromethorphan, and quinidine. STUDY SELECTION AND DATA EXTRACTION: English language clinical trials and case reports evaluating the safety and efficacy of DM/Q in PBA were included for review. Bibliographies of all relevant articles were reviewed for additional citations. DATA SYNTHESIS: PBA, a poorly understood disorder, is characterized by involuntary crying and/or laughing. In the past, antidepressants and antiepileptics have been used off-label with mixed results. Four clinical trials have evaluated the use of DM/Q for the treatment of PBA. Although the therapeutic outcomes with DM/Q have been positive, interpretation of the published evidence is limited by small sample size and short treatment duration. CONCLUSIONS: Based on the data available, DM/Q may be a viable, short-term treatment alternative for PBA. Long-term safety and efficacy data are lacking.

Emotional and behavioral dyscontrol after traumatic brain injury.

Emotional and behavioral dyscontrol are relatively common neuropsychiatric sequelae of traumatic brain injury and present substantial challenges to recovery and community participation. Among the most problematic and functionally disruptive of these types of behaviors are pathologic laughing and crying, affective lability, irritability, disinhibition, and aggression. Managing these problems effectively requires an understanding of their phenomenology, epidemiology, and clinical evaluation. This article reviews these issues and provides clinicians with brief and practical suggestions for the management of emotional and behavioral dyscontrol.

The epidemiology and pathophysiology of pseudobulbar affect and its association with neurodegeneration.

Pseudobulbar affect is a disorder resulting from neurologic damage manifesting as sudden, stereotyped affective outbursts that are not reflective of internal emotion. A literature review was completed to examine the current understanding of the epidemiology, characterization, diagnosis, pathophysiology, and treatment of pseudobulbar affect. This review revealed that it is common in neurodegenerative disorders but is poorly recognized, placing significant impacts on patients and their families. The disorder appears to result from a disruption of the cortico-limbic-subcortical-thalamic-pontocerebellar network involved in emotional expression and regulation with resulting disruptions of neurotransmitter systems. Effective treatment is available with agents such as selective serotonin reuptake inhibitors and dextromethorphan combined with quinidine, but further well-designed comparative studies are needed. Advances in technology such as neuroimaging may enhance knowledge about the pathophysiology of this disorder, and help guide future interventions.

Pathological Laughing and Crying: Pathophysiology and Treatment / 정신신체의학

Pathological laughing and crying(PLC) is a condition that is characterized by episodic, brief, contextually inappropriate, uncontrollable outbursts of laughing and/or crying. It can be observed in patients with various neurological disorders. PLC often causes distress in interpersonal functioning and activities for patients and their families. PLC can be recognized easily with proper understanding of the condition and its nature. Also it generally shows good response to various pharmacological treatments. This review aims to encourage the diagnosis and treatment of PLC by providing definition and clinical presentation of PLC, analysis of its pathophysiology and various current treatment options.

Relationship between Post-stroke Pathological Laughing and Crying and Depression / 中国康复理论与实践

@#Objective To investigate the relationship between post-stroke pathological laughing and crying and depression.Methods Among 276 stroke patients in hospital,28 patients with pathological laughing and crying were chosen as PLC group,and other 28 patients matched with gender and age but without PLC were choosen as the control group.All patients were investigated with Hamilton Depression Scale(HAMD),PLC scale and clinical features.Results There was no significantly difference(P>0.05)in total and factor scores of HAMD between these two groups.Conclusion The pathological laughing and crying and depression seem to result from different pathogenesis.