The Ash Twins Blog

See previous posts on history, symptoms, neurophysiology, genetics, molecular biology, targets of UbE3A , and systems pathophysiology of Angelman Syndrome.

The laughing, happy demeanor with little or no verbalization is the most distinctive, unusual, and interesting aspect of Angelman syndrome. At the current state of the field, neuroscience has no good way to study the neural basis of this fascinating phenotype. Outside the AS field, some attempts have been made to study the happiness circuit. In one functional MRI study, for example, professional actors placed themselves into a happy or sad affect while in the scanner (Pelletier et al 2003). Nonoverlapping loci within the same regions (orbitofrontal, left medial prefrontal, left ventrolateral prefrontal, left uncus, and right pons) were identified for each emotion.

Addiction researchers have identified hedonic circuits in the midbrain and striatum and circuits for negative affect in the extended amygdala and insula (Koob & Volkow 2010). In humans, primates, and rodents, similar behaviors are predictably associated with hedonic experience (Berridge & Kringelbach 2008). Although many brain regions demonstrate activity associated with reward, stimulation of only a few small hotspots by themselves increase the probability of these hedonic behaviors.  From stimulation experiments, it appears that only the nucleus accumbens shell, the ventral pallidum, and the pontine parabrachial nucleus are causative areas for pleasure (Berridge & Kringelbach 2008). Humans report that stimulation of the nucleus accumbens causes pleasurable sensations, and rodents will voluntarily stimulate the nucleus accumbens until they die. Infusion of opioids or cannabinoids into these hotspots prior to stimulation multiplies the hedonic reaction. The ventral pallidum may be the most important node in the pleasure circuit, as it is only by lesion to this region that hedonic reactions to pleasurable stimuli can be abolished.  An interesting hypothesis is that in AS, circuit malfunction leads to hyperactivity in these areas. Measuring the fMRI BOLD activity in AS patients or recording electrical activity in the AS mouse model in these pleasure-linked areas would test this hypothesis.

Otherwise, we can philosophize: Do these patients behave this way because they are locked into a perpetual state of joy, or are their behavioral circuits so degraded that the only one that is intact is happy laughter? The subjective feeling of pleasure (mood) and the behavioral signs of pleasure (affect) are dissociable, and it is possible that in AS the latter occurs without the former. Circumstantial evidence that AS patients do experience authentic joy comes from the fact that their laughter and happy affect are not random, but tied to things that a child may find humorous; slap-stick humor, for example, is especially popular among AS patients (Clayton-Smith & Laan 2003). Given the mild neuropathological findings of AS and the rescue of neurological deficits in the AS mouse by a single-amino acid CaMKII mutation, one may be sanguine that drugs targeting these pathways or gene therapy restoring maternally-imprinted UbE3A could significantly ameliorate the symptoms of AS. In this scenario, we would be able to ask cured AS patients about their internal state and determine if they really had been in a permanent state of gaiety. And if that were the case, would a cure be ethical?

Berredge K, Kringelbach M (2008) “Affective neuroscience of pleasure: reward in humans and animals.” Psychopharmacology 199:457–480

Clayton-Smith J, Laan L. (2003) “Angelman syndrome: a review of the clinical and genetic aspects.” J Med Genet. 40(2):87-95. Review.

Koob GF, Volkow ND. (2010) “Neurocircuitry of addiction.” Neuropsychopharmacology. 35(1):217-38.

Pelletier M, Bouthillier A, Lévesque J, Carrier S, Breault C, Paquette V, Mensour B, Leroux JM, Beaudoin G, Bourgouin P, Beauregard M. (2003) “Separate neural circuits for primary emotions? Brain activity during self-induced sadness and happiness in professional actors.” Neuroreport. 14(8):1111-6.