Archive for June, 2010

I recently came across this post by Michelle Dawson that states the thesis that one of the abnormalities in Autism spectrum disorders is due to abnormal circadian clock functioning. More specifically, the clock is internally driven and has a greeter ‘free running’ period and does not entrain readily to environmental and social clues.

Autistics whose sleep-wake cycles carry on independently from environmental and social cues are said to be “freerunning.”
The usual response to freerunning in autism is to see this as an autism-related sleep disorder. There is very preliminary evidence that freerunning autistics can be successfully treated with melatonin. Bourgeron (2007) refers to a short case study about an autistic whose free-running was remediated by melatonin treatment.

If you feel a bit overwhelmed by all the circadian clock related terminologies, I wholeheartedly recommend BoraZ’s clock tutorial series , especially this one.

Dawson further says:

Glickman (2010) speculates that some autistics’ failure to chain our sleep-wake cycles to environmental cues may arise from our atypical perception. My totally wild guess might be that an extreme freerunning phenotype in autism may be contributed to in part by cognitive versatility in autism, which would result in perceived environmental cues affecting sleep-wake cycles in an optional rather than mandatory way.

I wont speculate about the reasons behind why autistics have a greater free-running period and less entrainment to social and environmental clue, but I woudl say that instead of giving them flexibility, I would presume that this locks them into their internal rhythms, while others are more responsive to environment and better adapted. That brings me to the opposite phenotype of ASD…the psychotic phenotype shown by Schizophrenics, depressives and Bipolars.

As per this PLOS Genetics article:

The contribution of the circadian regulatory system, arising from conflicts between internal biological clocks and environmental (solar) and social clocks, is evident in affective disorders. All major affective disorders (such as unipolar depression, OMIM #608516; bipolar disorder, and schizophrenia, OMIM #181500) include circadian phase disturbances in sleep, activity, temperature, and hormone levels (for reviews see [84]–[86]). Moreover, there is evidence that if rhythms can be altered/stabilised using relevant therapies, improvements in the primary symptoms can occur. For example, in some instances sleep deprivation has an antidepressant effect in patients [87]. Conversely, many disorders with a primary anomaly in the circadian system are associated with depressed mood. Seasonal affective disorder (SAD; OMIM #608516) is a common condition where depressive symptoms occur during shorter winter days [88]–[90]. Two inherited sleep phase disorders, familial advanced sleep phase syndrome (FASPS; OMIM #604348) and delayed sleep phase syndrome (DSPS), are both associated with abnormal affective states [91],[92]. Furthermore, individuals with a behavioural preference for “eveningness” have a greater tendency to develop depression [93].

The above to me seems hypersensitivity to social and environmental cues in affective/psychotic disorders. contrast this with ASD description by the same authors:

Other behavioural disorders with circadian and sleep-related disturbances include autism spectrum disorders (ASD) (OMIM %209850) [81]). Behavioural disturbances in ASD may arise in part from an inability of an individual’s circadian oscillator to entrain to environmental and social cues. One specific correlate of ASD is a low level of melatonin, and one of the enzymes critical in the synthesis of melatonin, acetylserotonin-O-methyltransferase (ASMT, OMIM *300015), is implicated as a susceptibility gene for ASD [82].

The role of melatonin seems to provide a clue. In autism, there seems to be low levels of melatonin and perhaps hypo-sensitivity to melatonin changes. In contrast Bipolar is marked by hypersensitivity of Melatonin receptors:

It has been suggested that a hypersensitivity of the melatonin receptors in the eye could be a reliable indicator of bipolar disorder, in studies called a trait marker, as it is not dependent on state (mood, time, etc.). In small studies, patients diagnosed as bipolar reliably showed a melatonin-receptor hypersensitivity to light during sleep, causing a rapid drop in sleeptime melatonin levels compared to controls.[58] Another study showed that drug-free, recovered, bipolar patients exhibited no hypersensitivity to light.[59] It has also been shown in humans that valproic acid, a mood stabilizer, increases transcription of melatonin receptors[60] and decreases eye melatonin-receptor sensitivity in healthy volunteers[61] while low-dose lithium, another mood stabilizer, in healthy volunteers, decreases sensitivity to light when sleeping, but doesn’t alter melatonin synthesis.[62] The extent to which melatonin alterations may be a cause or effect of bipolar disorder are not fully known.

The above is not the only source implicating Bipolar disorder and circadian clock dysfunction., See more here and here. The big question is not whether ASD and Affective disorders are both circadian rhythm disorders, but the big question is whether they show opposite phenotypes with respect to circadian clocks- one showing too little entrainment while the other too much?
Barnard, A., & Nolan, P. (2008). When Clocks Go Bad: Neurobehavioural Consequences of Disrupted Circadian Timing PLoS Genetics, 4 (5) DOI: 10.1371/journal.pgen.1000040

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