Exploring the Impact of Amyotrophic Lateral Sclerosis on Otolaryngological Functions.

IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons at the spinal or bulbar level. OBJECTIVE: We aim to describe the most frequent otolaryngology (ORL) complaints and voice disturbances in patients with bulbar onset ALS. DESIGN: Retrospective cohort study. SETTING: Single-center study with combined ORL and ALS clinic evaluation. PARTICIPANTS: Patients with a confirmed diagnosis of ALS following an ORL visit and who underwent comprehensive voice assessments between January 2021 and January 2023. EXPOSURE: Objective voice assessments. MAIN OUTCOMES AND MEASURES: Glottal functional index (GFI), voice handicap index (VHI), reflux system index (RSI), and voice quality characteristics such as shimmer, jitter, maximum phonation time (MPT), and other essential parameters were assessed. RESULTS: One hundred and thirty-three patients (age 62.17 ± 10.79, 54.48% female) were included. Three patients were referred from the ORL department to the ALS clinic. The most frequent symptoms were; dysphagia, dysarthria, facial weakness, pseudobulbar affect, and sialorrhea. The mean of forced vital capacity was 59.85%, EAT-10 15.91 ± 11.66, RSI 25.84 ± 9.03, GFI 14.12 ± 5.58, VHI-10 42.81 ± 34.94, MPT 15.22 s ± 8.06. Many patients reported voice impairments mainly related to spastic dysarthria and the combination of lower and upper motor neuron dysarthria, hypernasality, reduced verbal expression, and articulatory accuracy. Shimmer was increased to 8.46% ± 7.20, and jitter to 2.26% ± 1.39. CONCLUSIONS AND RELEVANCE: Based on our cohort, this population with bulbar onset ALS has a higher frequency of voice disturbance characterized by hypernasality, spastic dysarthria, and reduced verbal expression. LEVEL OF EVIDENCE: Level 3.

Pseudobulbar Affect in an Elderly Female With Small Vessel Ischemic Disease and Alcohol Abuse Disorder: A Case Report.

Pseudobulbar affect (PBA) is a neurological condition characterized by recurrent, inappropriate, and involuntary outbursts of emotion, primarily crying and laughter, which are dissociated from the individual's emotional experience. The precise underlying cause of PBA remains unknown; however, existing evidence suggests the involvement of dopaminergic, serotonergic, and glutamatergic neurotransmission within the corticopontine-cerebellar pathways responsible for regulating the motor expression of emotions. Additionally, PBA has been observed to co-occur with other neurocognitive and psychiatric disorders. Therefore, it is crucial to consider the possibility of a PBA diagnosis in patients with underlying neurological damage and disorders.

Chinese Translation and Validation of the Center for Neurologic Study Lability Scale.

INTRODUCTION: Pseudobulbar palsy is a common symptom in patients with amyotrophic lateral sclerosis (ALS), but it is often underdiagnosed or misdiagnosed as other diseases. The Center for Neurologic Study Lability Scale (CNS-LS) is a self-report scale consisting of seven questions designed for evaluating pseudobulbar affect (PBA). The current study aimed to validate a Chinese version of the CNS-LS. METHODS: The Chinese version of the CNS-LS was obtained through a standardized forward-backward translation and cultural adaptation. A total of 105 patients with ALS were recruited from the ALS database of Peking University Third Hospital in Beijing, China, to complete the CNS-LS. The reliability of the Chinese version was determined by the test-retest method, and receiver operating characteristic (ROC) analysis was performed for criterion validity. RESULTS: Of 105 patients with ALS, 37 had symptoms of PBA and were diagnosed with that condition by neurologists. Forty-two patients completed the CNS-LS twice, and there was no statistically significant difference between the scores (Z = -0.896, p = 0.37). The Spearman correlation coefficient between the test and retest scores was 0.940 (p < 0.0005), and the Cronbach alpha coefficient was high (α = 0.905, n = 105). Scores of 12 or higher on the CNS-LS identified PBA with sensitivity of 0.919 and specificity of 0.882. The area under the ROC curve was 0.924. CONCLUSION: The Chinese version of the CNS-LS demonstrated good sensitivity and specificity in the group of patients with ALS enrolled in this study. The CNS-LS should be a useful instrument for clinical and research purposes for patients in this language group.

Emotional dysmetria after cerebellar-pontine stroke: a case report.

INTRODUCTION: Pseudobulbar affect, or emotional dysregulation, commonly occurs following stroke. However, it is frequently missed in cases involving the cerebellum, resulting in a lack of treatment, which can directly impact stroke rehabilitation. CASE PRESENTATION: A 63-year-old Caucasian female with no history of mood disorders presented with gait instability, dysarthria, and right sided hemiplegia, secondary to cerebellar and pontine ischemic stroke from a basilar occlusion. She underwent endovascular therapy and her deficits gradually improved. However during recovery she began to develop uncontrollable tearfulness while retaining insight that her emotional expression was contextually inappropriate. She was treated with a selective serotonin reuptake inhibitor with reported improvements in her emotional regulation at one year follow up. CONCLUSION: This case highlights cerebellar injury as a potential cause of poorly regulated emotions, or an emotional dysmetria. The recognition of this disorder in patients with cerebellar or pontine strokes is critical, as untreated pseudobulbar affect can impact future stroke rehabilitation.

Definitions, phenomenology, diagnosis, and management of the disorders of laughter and crying in amyotrophic lateral sclerosis (ALS): Consensus from ALS and Motor Neuron Disease Scientific Department of the Brazilian Academy of Neurology / Definições, fenomenologia, diagnóstico e manejo das desordens do riso e do choro em esclerose lateral amiotrófica (ELA): Consenso do Departamento Científico de ELA e Doença do Neurônio Motor da Academia Brasileira de Neurologia

Abstract The spectrum of neuropsychiatric phenomena observed in amyotrophic lateral sclerosis (ALS) is wide and not fully understood. Disorders of laughter and crying stand among the most common manifestations. The aim of this study is to report the results of an educational consensus organized by the Brazilian Academy of Neurology to evaluate the definitions, phenomenology, diagnosis, and management of the disorders of laughter and crying in ALS patients. Twelve members of the Brazilian Academy of Neurology - considered to be experts in the field - were recruited to answer 12 questions about the subject. After exchanging revisions, a first draft was prepared. A face-to-face meeting was held in Fortaleza, Brazil on 9.23.22 to discuss it. The revised version was subsequently emailed to all members of the ALS Scientific Department from the Brazilian Academy of Neurology and the final revised version submitted for publication. The prevalence of pseudobulbar affect/pathological laughter and crying (PBA/PLC) in ALS patients from 15 combined studies and 3906 patients was 27.4% (N = 1070), ranging from 11.4% to 71%. Bulbar onset is a risk factor but there are limited studies evaluating the differences in prevalence among the different motor neuron diseases subtypes, including patients with and without frontotemporal dementia. Antidepressants and a combination of dextromethorphan and quinidine (not available in Brazil) are possible therapeutic options. This group of panelists acknowledge the multiple gaps in the current literature and reinforces the need for further studies.

Resumo O espectro de fenômenos neuropsiquiátricos observados na ELA é amplo e não completamente entendido. Desordens do riso e do choro estão entre as manifestações mais comuns. O objetivo deste estudo é relatar os resultados de um Consenso organizado pela Academia Brasileira de Neurologia para avaliar definições, fenomenologia, diagnóstico, e manejo dos distúrbios do riso e do choro em pacientes com ELA. Doze membros da Academia Brasileira de Neurologia - considerados experts na área - foram recrutados para responder 12 questões na temática. Depois da verificação das revisões, um primeiro manuscrito foi preparado. Após, foi realizado um encontro presencial em Fortaleza, Brasil, em 23/09/2022, para discussão do conteúdo. A versão revisada foi posteriormente enviada por e-mail para todos os membros do Departamento Científico de DNM/ELA da Academia Brasileira de Neurologia e a versão final revisada foi submetida para publicação. A prevalência da síndrome pseudobulbar em pacientes com ELA em 15 estudos combinados com 3906 pacientes foi de 27,4% (n = 1070), variando entre 11,4% e 71%. Início bulbar é um fator de risco, mas há limitados estudos avaliando as diferenças em prevalência entre os diferentes subtipos de Doença do Neurônio Motor, incluindo pacientes com e sem Demência Frontotemporal. Antidepressivos e uma combinação de dextrometorfana e quinidina (indisponíveis no Brasil) são opções terapêuticas possíveis. Esse grupo de panelistas reconhece as múltiplas demandas não atendidas na literatura atual e reforça a necessidade de futuros estudos.

Radiological correlates of pseudobulbar affect: Corticobulbar and cerebellar components in primary lateral sclerosis.

INTRODUCTION: Pseudobulbar affect (PBA) is a distressing symptom of a multitude of neurological conditions affecting patients with a rage of neuroinflammatory, neurovascular and neurodegenerative conditions. It manifests in disproportionate emotional responses to minimal or no contextual stimulus. It has considerable quality of life implications and treatment can be challenging. METHODS: A prospective multimodal neuroimaging study was conducted to explore the neuroanatomical underpinnings of PBA in patients with primary lateral sclerosis (PLS). All participants underwent whole genome sequencing and screening for C9orf72 hexanucleotide repeat expansions, a comprehensive neurological assessment, neuropsychological screening (ECAS, HADS, FrSBe) and PBA was evaluated by the emotional lability questionnaire. Structural, diffusivity and functional MRI data were systematically evaluated in whole-brain (WB) data-driven and region of interest (ROI) hypothesis-driven analyses. In ROI analyses, functional and structural corticobulbar connectivity and cerebello-medullary connectivity alterations were evaluated separately. RESULTS: Our data-driven whole-brain analyses revealed associations between PBA and white matter degeneration in descending corticobulbar as well as in commissural tracts. In our hypothesis-driven analyses, PBA was associated with increased right corticobulbar tract RD (p = 0.006) and decreased FA (p = 0.026). The left-hemispheric corticobulbar tract, as well as functional connectivity, showed similar tendencies. While uncorrected p-maps revealed both voxelwise and ROI trends for associations between PBA and cerebellar measures, these did not reach significance to unequivocally support the "cerebellar hypothesis". CONCLUSIONS: Our data confirm associations between cortex-brainstem disconnection and the clinical severity of PBA. While our findings may be disease-specific, they are consistent with the classical cortico-medullary model of pseudobulbar affect.

Classics in Chemical Neuroscience: Dextromethorphan (DXM).

Dextromethorphan (DXM) was introduced in 1958 as the first non-opioid cough suppressant and is indicated for multiple psychiatric disorders. It has been the most used over-the-counter cough suppressant since its emergence. However, individuals quickly noticed an intoxicating and psychedelic effect if they ingested large doses. DXM's antagonism at N-methyl-d-aspartate receptors (NMDAr) is thought to underly its efficacy in treating acute cough, but supratherapeutic doses mimic the activity of dissociative hallucinogens, such as phencyclidine and ketamine. In this Review we will discuss DXM's synthesis, manufacturing information, drug metabolism, pharmacology, adverse effects, recreational use, abuse potential, and its history and importance in therapy to present DXM as a true classic in chemical neuroscience.

Use of Escitalopram for pseudobulbar affect following severe traumatic.

Those who have suffered from traumatic brain injury (TBI) often develop behavioural, affective, and cognitive complications. Some might experience episodes of involuntary and/or exaggerated laughter and crying. This condition is commonly known as 'pseudobulbar affect'(PBA) and leads to anger, frustration, and social disability. This case report presents the use of low-dose Escitalopram in an individual suffering from agitation and PBA following severe TBI (sTBI). It emphasises the importance of adopting a holistic approach in the treatment of such individuals with appropriate attention paid to factors such as cognitive and behavioural impairment, and caregiver distress.

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.

Central Pontine Myelinolysis: A Case Report of Persistent Hyperglycemia With Normal Serum Sodium.

Rapid correction of hyponatremia is the most frequent predisposing factor for the development of central pontine myelinolysis (CPM). Alcoholism, cirrhosis, malnutrition, and severe burns are associated conditions that often present in combination with a rapid rise in serum sodium concentration. However, its association with hyperglycemia has not been as well established. There have been recent reports of acute to subacute presentation of CPM with hyperglycemia. We report an unusual case of a 48-year-old Caucasian male who presented with pseudobulbar palsy, ataxia, and quadriplegia with worsening pontine hyperintensities and was diagnosed with CPM in the setting of persistent hyperglycemia with normal serum sodium.

Pseudobulbar Affect Mimicking Depression: A Case Report.

Pseudobulbar affect (PBA) is a neurological condition that is associated with short periods of involuntary, sudden, and inappropriate emotions such as crying or laughing, which are mood incongruent. An accurate estimate of the prevalence of PBA is hard to obtain due to varying diagnostic criteria and variable patient populations. The cause of PBA is not known, but current evidence suggests dual etiology. A neural circuit dysfunction and an abnormality of neurotransmitters that regulate motor expression of emotions. PBA can easily be mistaken for a depressive disorder due to the overlap of symptoms. Moreover, patients with PBA may have a major depressive disorder (MDD) or other depressive disorders. Therefore, it is essential to recognize and treat PBA as well as possible psychiatric comorbidities. We present a case report of a 59-year-old man with no past psychiatric history who presents with paroxysms of episodes of crying for the past one year. He endorsed feelings of hopelessness and poor concentration. MRI of the brain revealed bilateral basal ganglia and a thalamic infarct. The patient was treated with citalopram. This case describes a unique presentation of pseudobulbar affect mimicking depression.

The relationship between stress, anxiety, and depression levels and pseudobulbar affect in patients with multiple sclerosis.

BACKGROUND: Pseudobulbar affect (PBA) has recently been added to the list of mental disorders commonly observed in patients with Multiple Sclerosis (MS). The emotional changes experienced by MS patients may be associated with other mental problems and adversely affect disease prognosis. However, there are limited studies in the international and national literature on this subject. AIM: This study aimed to evaluate the relationship between PBA and stress, anxiety, and depression levels in patients with MS. DESIGN: This is a descriptive, relational, and cross-sectional study. METHODS: A total of 442 MS patients followed in the neurology outpatient clinic of a hospital and registered with the MS Society in Turkey participated in this study. Data were collected using a personal information form, the Turkish version of the Center for Neurologic Study-Lability Scale (CNS-LS), and the Depression Anxiety Stress Scale (DASS). RESULTS: In this study, 63.3% of the patients had PBA, 21% had extremely severe depression, 41.6% had extremely severe anxiety, and 24.9% had severe stress. Correlation analysis revealed weak positive correlations between CNS-LS total score and DASS subscale and total scores. Depression, anxiety, and stress levels accounted for 22.5% of the variation in CNS-LS total score. CONCLUSION: The results of this study indicate that a majority of MS patients in Turkey experience PBA, depression, anxiety, and stress, and that PBA is positively associated with depression, anxiety, and stress. IMPACT STATEMENT: This study, indicates that should be increased consultation-liaison psychiatry services in Turkey, and MS patients should benefit from comprehensive psychiatric services.

A missing link in affect regulation: the cerebellum.

The cerebellum is one-third the size of the cerebrum yet holds twice the number of neurons. Historically, its sole function was thought to be in the calibration of smooth movements through the creation and ongoing modification of motor programs. This traditional viewpoint has been challenged by findings showing that cerebellar damage can lead to striking changes in non-motor behavior, including emotional changes. In this manuscript, we review the literature on clinical and subclinical affective disturbances observed in individuals with lesions to the cerebellum. Disorders include pathological laughing and crying, bipolar disorder, depression and mixed mood changes. We propose a theoretical model based on cerebellar connectivity to explain how the cerebellum calibrates affect. We conclude with actionable steps for future researchers to test this model and improve upon the limitations of past literature.

Cerebellar pathology in motor neuron disease: neuroplasticity and neurodegeneration.

Amyotrophic lateral sclerosis is a relentlessly progressive multi-system condition. The clinical picture is dominated by upper and lower motor neuron degeneration, but extra-motor pathology is increasingly recognized, including cerebellar pathology. Post-mortem and neuroimaging studies primarily focus on the characterization of supratentorial disease, despite emerging evidence of cerebellar degeneration in amyotrophic lateral sclerosis. Cardinal clinical features of amyotrophic lateral sclerosis, such as dysarthria, dysphagia, cognitive and behavioral deficits, saccade abnormalities, gait impairment, respiratory weakness and pseudobulbar affect are likely to be exacerbated by co-existing cerebellar pathology. This review summarizes in vivo and post mortem evidence for cerebellar degeneration in amyotrophic lateral sclerosis. Structural imaging studies consistently capture cerebellar grey matter volume reductions, diffusivity studies readily detect both intra-cerebellar and cerebellar peduncle white matter alterations and functional imaging studies commonly report increased functional connectivity with supratentorial regions. Increased functional connectivity is commonly interpreted as evidence of neuroplasticity representing compensatory processes despite the lack of post-mortem validation. There is a scarcity of post-mortem studies focusing on cerebellar alterations, but these detect pTDP-43 in cerebellar nuclei. Cerebellar pathology is an overlooked facet of neurodegeneration in amyotrophic lateral sclerosis despite its contribution to a multitude of clinical symptoms, widespread connectivity to spinal and supratentorial regions and putative role in compensating for the degeneration of primary motor regions.

A Neuroanatomy of Positive Affect Display - Subcortical Fiber Pathways Relevant for Initiation and Modulation of Smiling and Laughing.

Background: We here report two cases of stimulation induced pathological laughter (PL) under thalamic deep brain stimulation (DBS) for essential tremor and interpret the effects based on a modified neuroanatomy of positive affect display (PAD). Objective/Hypothesis: The hitherto existing neuroanatomy of PAD can be augmented with recently described parts of the motor medial forebrain bundle (motorMFB). We speculate that a co-stimulation of parts of this fiber structure might lead to a non-volitional modulation of PAD resulting in PL. Methods: We describe the clinical and individual imaging workup and combine the interpretation with normative diffusion tensor imaging (DTI)-tractography descriptions of motor connections of the ventral tegmental area (VTA) (n = 200 subjects, HCP cohort), [[18F] fluorodeoxyglucose (18FDG)] positron emission tomography (PET), and volume of activated tissue simulations. We integrate these results with literature concerning PAD and the neuroanatomy of smiling and laughing. Results: DBS electrodes bilaterally co-localized with the MB-pathway ("limiter pathway"). The FDG PET activation pattern allowed to explain pathological PAD. A conceptual revised neuroanatomy of PAD is described. Conclusion: Eliciting pathological PAD through chronic thalamic DBS is a new finding and has previously not been reported. PAD is evolution driven, hard wired to the brain and realized over previously described branches of the motorMFB. A major relay region is the VTA/mammillary body complex. PAD physiologically undergoes conscious modulation mainly via the MB branch of the motorMFB (limiter). This limiter in our cases is bilaterally disturbed through DBS. The here described anatomy adds to a previously described framework of neuroanatomy of laughter and humor.

Pseudobulbar affect in neurodegenerative diseases: A systematic review and meta-analysis.

BACKGROUND: Pseudobulbar affect (PBA) is characterized by uncontrolled episodes of crying and laughing which is associated with a variety of neurological diseases including traumatic brain injury, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), brain tumors, stroke, Parkinson's disease (PD), Alzheimer's disease (AD) and other dementias. However, there is a lack of exact estimated prevalence of PBA among neurological disorders. AIM: In this systematic review and meta-analysis study we aimed to assess the prevalence of PBA in four neurodegenerative diseases including ALS, MS, AD, and PD. METHODS: PubMed, Scopus, and Web of Science were searched in July 2021 for studies that reported the prevalence of PBA in ALS, MS, AD, and PD patients. The mean point of PBA prevalence and odds ratios were calculated as effect size (ES) using the random-effect model with a 95% confidence interval (CI). RESULTS: The summarized prevalence of PBA was of PBA in PD patients were ranged between 1% and 31% with an overall meta-analysis prevalence of 16.5% and high heterogeneity (I2: 98.7%, p: 0.000). Patients with ALS showed a PBA prevalence of 38.5%, which is higher than other neurodegenerative diseases (CI 95%: 31%-45%, I2: 61.4%, p: 0.034). Moreover, the prevalence of PBA in MS patients in the analysis was 23.3% ranging between 11% and 35% with high-level heterogeneity according to the I2 value (I2: 98.9%, p: 0.000). Also, our meta-analysis showed that the PBA prevalence in AD was 16.4% (CI 95%: 7%-25%) with high heterogeneity (I2: 97.8%, p: 0.000). CONCLUSION: This review showed that PBA is common in patients with neurodegenerative diseases including PD, AD, MS, and especially ALS. Due to the lack of proper recognition, medication and treatment would not be effective and sufficient. Therefore, it can dramatically lower the quality of life in PBA patients and decrease their social interactions.

Prevalence of Pseudobulbar Affect (PBA) in Parkinson's Disease: An Underrecognized Patient Burden.

Objective Pseudobulbar affect (PBA) is a neurological condition characterized by emotional lability and a discrepancy between the patient's emotional expression and emotional experience. These uncontrollable episodes cause distress in social situations resulting in embarrassment and social withdrawal. The most comprehensive study to date estimated that 26% of Parkinson's disease (PD) patients screened positive for PBA symptoms via the validated Center for Neurologic Study-Lability Scale (CNS-LS) screening tool. We hypothesize that the prevalence of this disabling syndrome is higher than reported, often being labeled as depression. Methods One hundred patients were enrolled in the study and screened with a CNS-LS tool, all of whom were diagnosed with PD by a fellowship-trained movement disorder specialist. Patients were also asked about previous diagnosis of depression, current antidepressant medication use, and history of PBA diagnosis and treatment. Results The percentage of PD patients (n = 100) with PBA symptoms as defined by a CNS-LS score ≥13 was 41% (n = 41) and by a CNS-LS score ≥17 was 21.0% (n = 21). In our sample, 38.0% of patients (n = 38) had a previous clinical diagnosis of depression and 25.0% (n = 25) were currently undergoing treatment for their depression. There was a significant association between previous depression diagnosis, current antidepressant use, and higher CNS-LS scores (p < 0.001). Conclusion Using either of the CNS-LS score cutoffs, a significant proportion of the PD population in our sample displayed symptoms of PBA. We also found an association between previous diagnosis of depression and higher CNS-LS scores as well as between antidepressant use and higher CNS-LS scores. This suggests both a higher prevalence than prior studies showed as well as frequent misdiagnosis or co-diagnosis with depression.

Treatment of disorders of emotional comprehension, expression, and emotional semantics.

Neurological disease can impair emotional communication by several means: damaging the networks important in understanding the meaning of emotional stimuli (emotional semantics); damaging networks important in the perceptual recognition and production of emotional stimuli, and damaging the connections between networks supporting emotional semantics and recognition/production networks. Disorders of emotional expression, comprehension, and emotional semantics may improve with pharmacological or behavioral treatments. Pharmacological treatments can be used to redress naturally occurring or disease-related alterations in the computational properties of target neural systems. No drug treatment can replace a loss of cerebral knowledge related to the pathological loss of neural connectivity. Behavioral treatments that benefit either comprehension or expression of specific emotions may be of value if these emotions are particularly important in enabling human social interaction. However, behavioral treatments that achieve generalization, that is, improve performance with untrained exemplars and in daily life, are much to be preferred, even as they pose the greatest methodological challenges. This chapter will discuss possible mechanisms of generalization and then review what is known about the treatment of expressive and receptive affective aprosodia, deficits in recognition of facial emotions, and pseudobulbar affect. The final section of the chapter is devoted to a discussion of three disorders of emotional semantics, apathy, alexithymia, and impaired empathy.

Brainstem Correlates of Pathological Laughter and Crying Frequency in ALS.

Pseudobulbar affect is a disorder of emotional expression commonly observed in amyotrophic lateral sclerosis (ALS), presenting as episodes of involuntary laughter, or crying. The objective of the current study was to determine the association between frequency of pathological laughter and crying (PLC) episodes with clinical features, cognitive impairment, and brainstem pathology. Thirty-five sporadic ALS patients underwent neuropsychological assessment, with a subset also undergoing brain imaging. The Center for Neurological Study Lability Scale (CNS-LS) was used to screen for presence and severity of pseudobulbar affect (CNS-LS ≥ 13) and frequency of PLC episodes. Presence of pseudobulbar affect was significantly higher in bulbar onset ALS (p = 0.02). Frequency of PLC episodes was differentially associated with cognitive performance and brainstem integrity. Notably pathological laughter frequency, but not crying, showed a significant positive association with executive dysfunction on the Trail Making Test B-A (R 2 = 0.14, p = 0.04). Similarly, only pathological laughter frequency demonstrated a significant negative correlation with gray matter volume of the brainstem (R 2 = 0.46, p < 0.01), and mean fractional anisotropy of the superior cerebellar peduncles (left: R 2 = 0.44, p < 0.01; right: R 2 = 0.44, p < 0.01). Hierarchical regression indicated brainstem imaging in combination with site of symptom onset explained 73% of the variance in pathological laughter frequency in ALS. The current findings suggest emotional lability is underpinned by degeneration across distinct neural circuits, with brainstem integrity critical in the emergence of pathological laughter.