Laughter is a social expression of happiness in humans and in monkeys. Neural correlates of laughter and humor, with results of clinical, pathological, and imaging studies reported in the literature since 1985, are reviewed from the Universities of Tubingen, Germany, and Zurich, Switzerland. Responsive smiling develops in infants by 5 weeks of age and laughter, by the fourth month. Smiling and laughing occur spontaneously or may be elicited on command, each determined by separate neural pathways. Pathological laughter may be symptomatic of mania, schizophrenia, mood disorders, Alzheimer’s disease, or Angelman syndrome. Pathological laughter arises; 1) in response to non-specific stimuli; 2) without change in affect; 3) without voluntary control of duration; and 4) without change in mood. Poeck’s classification (1969, 1985) of symptomatic laughter differentiates: 1) that originating from motor neuron disease, vascular pseudobulbar paralysis, and extrapyramidal disorders; 2) fou rire prodromique heralding stroke; and 3) epileptic “gelastic” seizures, usually associated with hypothalamic hamartomas, tuberous sclerosis, or pathology in the frontal or temporal poles. Other neurologic disorders associated with pathological laughter include multiple sclerosis, and Foix-Chavany-Marie syndrome (progressive supranuclear motor system degeneration). Frontal and temporal lobes are involved in the perception of humor, and especially the non-dominant hemisphere. Patients with right frontal lesions show the greatest deficits in the appreciation of humor, and patients with temporal lobe epilepsy have impaired ability to perceive humor. In Parkinson’s syndrome and basal ganglia lesions, spontaneous emotional expression is impaired but the perception of humor may be preserved.
Facial reactions and laughter invoked by humor are mediated by dorsal brainstem regions and inhibited by circuits in the ventral brainstem, via frontal motor/premotor networks. Pathological laughter is the result of damage to the inhibitory system located in premotor/motor cortex and connections. A pontine ‘coordination center’ for laughter is postulated. Fibers from the periaqueductal grey, transmitting the signal to laugh, are located dorsally/tegmentally, whereas fibers inhibiting facial emotional expressions run ventrally from frontal motor areas, and may also involve the cerebellum. Two partially independent neuronal pathways are involved in the expression of laughter: 1) an ‘involuntary’ or ‘emotionally driven’ system, involving amygdala, thalamus, hypothalamus, subthalamus, and dorsal/tegmental brainstem; and 2) a ‘voluntary’ system originating in the premotor/frontal opercular areas, and passing via the motor cortex and pyramidal tract to the ventral brainstem. 
COMMENT. In pediatric neurology practice, pathological laughter occurs in patients with Angelman syndrome, pseudobulbar palsy as in cerebral palsy and infantile hydrocephalus, hypothalamic hamartoma and gelastic epilepsy, infantile spasms (Lacy JR, Penry JK, 1976), and complex partial seizures. Gelastic seizures were controlled by removal of a cavernous hemangioma in the anterior cingulate gyrus in one child treated at Johns Hopkins Hospital, Baltimore, MD . Mirth and laughter were invoked by cortical stimulation of the parahippocampal and fusiform gyri in 2 additional children treated for complex partial seizures. (see Progress in Pediatric Neurology II, PNB Publ, 1994;pp41-42).