Pathological laughter and crying: insights from lesion network-symptom-mapping

Abstract

The study of pathological laughter and crying (PLC) allows insights into the neural basis of laughter and crying, two hallmarks of human nature. PLC is defined by brief, intense and frequent episodes of uncontrollable laughter or crying provoked by trivial stimuli. It occurs secondary to CNS disorders such as stroke, tumours or neurodegenerative diseases. Based on case studies reporting various lesions locations, PLC has been conceptualized as dysfunction in a cortico-limbic-subcortico-thalamo-ponto-cerebellar network. To test whether the heterogeneous lesion locations are indeed linked in a common network, we applied ‘lesion network-symptom-mapping’ (LNSM) to 70 focal lesions identified in a systematic literature search for case reports of PLC. In LNSM normative connectome data (resting state functional MRI, n = 100) is used to identify the brain regions which are likely affected by diaschisis based on the lesion locations. With LNSM we were able to identify a common network specific for PLC when compared with a control cohort (n = 270). This bilateral network is characterized by positive connectivity to the cingulate and temporomesial cortices, striatum, hypothalamus, mesencephalon and pons and negative connectivity to the primary motor and sensory cortices. In the most influential pathophysiological model of PLC, a center for the control and coordination of facial expressions, respiration and vocalization in the periaqueductal grey is assumed which is controlled via two pathways: an emotional system that exerts excitatory control of the periaqueductal grey descending from the temporal and frontal lobes, basal ganglia and hypothalamus and a volitional system descending from the lateral premotor cortices which can suppress laughter or crying. To test whether the positive and negative PLC subnetworks identified in our analyses can indeed be related to an emotional system and a volitional system, we identified lesions causing emotional (n = 15) or volitional facial paresis (n = 46) in a second literature search. Patients with emotional facial paresis show preserved volitional movements but cannot trigger emotional movements in the affected hemiface, while the reverse is true for volitional facial paresis. Importantly, these lesions map differentially onto the PLC subnetworks: the ‘positive PLC subnetwork’ is part of the emotional system and the ‘negative PLC subnetwork’ overlaps with the volitional system for the control of facial movements. Based on this network analysis we propose a two-hit model of PLC: a combination of direct lesion and indirect diaschisis effects cause PLC through the loss of inhibitory cortical control of a dysfunctional emotional system.

Non-motor Adverse Effects Avoided by Directional Stimulation in Parkinson's Disease: A Case Report

“…In contrast, pathological laughter consists of uncontrollable outbursts of laughter that are inappropriate for the external circumstances and emotional state of the patient (42). There has been a wide variety of case reports in the last century showing that pathological laughter can appear in many neurological diseases.…”

“…It has been described as the prodromal of a stroke (43), pseudobulbar palsy (44), strategic cerebral lesions or diffuse cerebral disease (45), and epileptic disorders such as temporal lobe epilepsy or hypothalamic hamartomas (46). Due to the huge variety of possible regions reported, it has been postulated that this symptom is the consequence of a dysfunctional "corticolimbic-subcortical-thalamo-ponto-cerebellar network" (42). Recently, it has been hypothesized that two circuits might interact: an "emotional" system that exerts excitatory control (temporal and frontal lobes, basal ganglia, thalamus, and hypothalamus) and a "volitional" system that generates inhibitory control (lateral premotor cortices).…”

“…Recently, it has been hypothesized that two circuits might interact: an "emotional" system that exerts excitatory control (temporal and frontal lobes, basal ganglia, thalamus, and hypothalamus) and a "volitional" system that generates inhibitory control (lateral premotor cortices). Both systems project to the periaqueductal gray matter for the final coordination of the facial, respiratory, and vocal components of laughter (42).…”

Lesion network mapping for symptom localization: recent developments and future directions

“…In each of these conditions, prior neuroimaging studies have provided heterogeneous results and causal lesions are scattered throughout many different regions in the brain, leaving the neural substrate unknown. Using LNM, lesions causing tics mapped to a common circuit with the anterior putamen as the most sensitive and specific hub of the circuit [5 ▪ ], lesions causing blindsight were associated with connectivity to the medial pulvinar nucleus of the thalamus [22 ▪ ], and lesions causing pathological laughter and crying were characterized by connectivity to a complex network with positive connectivity to subcortical and medial cortical regions involved in emotional processing, and negative connectivity to sensorimotor cortex [13]. The identified circuits provide insight into the neural mechanisms of these symptoms and help to evaluate the link between patients’ symptoms and brain lesions.…”

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

“…Tu et al (2021) recently emphasized the importance of WM and GM brainstem integrity in the development of pathological laughter. In addition, Klingbeil et al (2021), applying a "lesion networksymptom-mapping" to focal lesions identi ed in a systematic literature search for case reports of pathological laughter and crying (PLC), identi ed an emotional system that exerts excitatory control of the periaqueductal grey (descending from the temporal and frontal lobes, basal ganglia, and hypothalamus), and a volitional system (descending from the lateral premotor cortices) that can suppress laughter or cry. However, no investigation of functional connectivity (FC) abnormalities has been performed in ALS patients with or without PBA to explore resting state functional MRI (RS-fMRI) networks (RSNs) alterations underlying this syndrome.…”