it has been a working assumption of chronobiologists that the harms of shift - worker dysrhythmia would be most effectively mitigated if , instead of altering activity rhythms volitionally or pharmacologically , the phase of the circadian pacemaker and its outputs could be reset to correspond with the desired schedule . in other words ,
the timing of subjective day and night would be directly shifted , eliminating the dysrhythmia .
the phase - shift is thus the most commonly attempted circadian manipulation , and typically involves the timed application of bright light , the principal environmental cue for resetting all mammalian clocks ( duffy et al . , 1996 ; danilenko et al . , 2000
; crowley et al . , 2003 ; roenneberg and merrow , 2007 ) . under laboratory conditions , humans and non - human animals can phase - shift successfully in either direction ( earlier or later ) . in the real world
too , humans rapidly crossing several time zones eventually adopt a phase aligned with the new location , though it may take several days .
this sluggish rate underscores a significant barrier to effective phase - resetting in the work context : many shift - workers are on rotating shifts , requiring that the pacemaker be shifted both rapidly and repeatedly .
likewise , when a shift - worker is given time off , as on a weekend , the new schedule competes with the old ( smith et al . , 2009 ) .
in fact , it has been advised for night shift - workers with weekends off to adapt a 
compromise phase position ,  entraining to a phase between the two conflicting schedules , without being well - matched to either ( lee et al .
, 2006 ; smith and eastman , 2008 ) . a further complication of phase manipulations is that effective phase - shifting may require complex schedules of light ( revell and eastman , 2005 ; dumont et al . , 2009 ) .
in humans and other animals , the phase - resetting actions of light are greatest during subjective night : light at the beginning and end of subjective night delays and advances the pacemaker , respectively ( aschoff , 1999 ) .
inappropriately timed light can therefore not only undo an achieved phase - shift , but actually move an individual s clock further from the desired schedule . in particular , bright morning light at the end of a night shift has strong phase - advancing effects that counteract the desired shift ( crowley et al . ,
2003 ) . empirically , even in individuals with permanent schedules , for whom a stably altered phase may be reasonably expected , the clock generally remains entrained to a phase typical of day workers .
only one in four shift - workers with a permanent schedule outside of the regular nine to five workday are able to even partially shift circadian phase as measured by melatonin , while only 3% fully shift ( folkard , 2008 ) .
thus , despite a solid understanding of how the human circadian rhythm responds to light , the lack of practically implemented strategies for shift - workers underscores the need for an alternative target of circadian manipulation that may be more responsive and more tractable than phase .
the waveform of a circadian rhythm is simply its shape across the 24  h cycle .
compared to phase ( or period ) , waveform has received scant attention in the circadian literature ( e.g. , in pubmed ,  circadian  and  waveform  yield under 2% of the hits generated by  circadian  and  phase  ) . the novel thesis of this  perspective  paper is that the waveform of the mammalian pacemaker itself is flexible and thus may offer a superior entrainment alternative for shift - workers compared to shifting the phase of the pacemaker or superficially altering the waveform of individual outputs such as sleep / wake .
the impetus for a focus on circadian waveform is a recent series of studies in rodents demonstrating a surprising degree of pacemaker plasticity that can be easily manipulated experimentally ( gorman and elliott , 2003 , 2004 ) .
briefly , when maintained on a permissive 24  h light : dark : light : dark ( ldld ) cycle , nocturnal rodents can be induced to re - organize their circadian timing systems such that they show night - typical levels of activity in each of the two daily dark periods ( figure 2 ) .
likewise , they exhibit daytime patterns of inactivity during each of the two daily light periods . called rhythm 
bifurcation ,  this entrainment paradigm allows animals to express in each 24  h cycle two subjective days each lasting 78  h and beginning 12  h apart and two subjective nights of  45  h each , also 12  h apart .
considerable evidence establishes that this is a bona fide bifurcation of subjective day and night , not a superimposition of an additional activity bout in the middle of subjective day : classic markers of subjective night 
melatonin secretion and circadian sensitivity to light pulses  are present during both intervals of activity ( raiewski , under review ; gorman et al . , 2001 ) .
thus , in this paradigm , activity rhythms can be temporally reorganized via a change in the waveform of the circadian pacemaker .
mechanistically , bifurcation derives from a temporal dissociation of component oscillators in the core and shell of the scn that appear to correspond to the alternating bouts of activity ( gorman et al . , 2001
; watanabe et al . , 2007 ; yan et al . , 2010 ) .
this distinguishes it from the splitting paradigm seen in constant light ( de la iglesia et al . , 2000 ) .
actual wheel running activity of bifurcated syrian hamsters in various ldld cycles with and without perturbations .
each line represents a 24  h day ( x axis ) with 11  days of activity plotted below one another in each panel .
( a ) nocturnal wheel running is stably divided between two 5  h nights with intervening 5 and 9  h intervals of light .
when one light phase is replaced with darkness ( arrow ) , the subsequent activity bout is advanced , but the bifurcated pattern is quickly restored . the analogous human exposure would be a shift - worker sleeping through the environmental night on a day off or having a long sleep during the day .
note that scotophases do not have to be evenly spaced within 24  h. ( b ) removal of a photophase ( a )  analogous to a shift - worker sleeping in on a day off  or a scotophase ( b )  analogous to a shift - worker staying up all day on a day off  does not compromise the stability of the bifurcated state of entrainment .
( c ) scotophases do not have to be of equal length , and bifurcation remains stable even when the bouts are asymmetrical and greatly reduced in length .
( d ) bifurcated animals can revert to a normal , diurnal rhythm within one cycle .
it remains to be determined whether and how a similar bifurcation of pacemaker waveform might be accomplished in humans , but the implications for shift - workers are nevertheless worth considering .
as with any circadian generalization from nocturnal rodents to diurnal humans , this exercise necessitates the transposition of rest / activity relative to subjective day / night . applying this paradigm to a worker on a stable night shift ( figure 1c ) , we envision entraining a person to begin one of their two mini - subjective days around midnight coinciding with the beginning of the work shift . after work , a mini - subjective night would allow a 4  h sleep interval . waking in the afternoon
, the worker would have a second subjective day during daylight hours , and could sleep again during the second mini - subjective night before work .
of course , shift - workers commonly adopt some version of this sleep / wake cycle ( akerstedt and wright , 2009 ) , as do some who take naps or siestas , but presumably do so without the benefit of a shift in the pacemaker s programming of subjective day and night .
first , because it would align the pacemaker with the behaviorally modified output of the sleep / wake cycle ( figure 1c ) , there is the strong expectation that alertness would be optimized both during the nighttime work shift and the active - time away from work , despite these times falling 12  h apart at opposite phases of the natural day .
correspondingly , the programming of sleep during intervals of subjective night would plausibly enhance sleep efficiency .
the non - pharmacological enhancement of worker alertness and sleep efficiency has obvious benefits related to optimization of productivity and minimization of accidents , and perhaps the physiological and behavioral problems commonly seen in the shift - working population .
as discussed , phase - shifts are generally achieved very slowly in humans , requiring successive timed bright light exposures to generate a controlled shift in entrainment .
bifurcation , in contrast , can be reliably elicited in rodents within a single cycle in nearly every individual without transient entrainment states ( yan et al . , 2010 ) . moreover , the paradigm takes advantage of morning light , which typically impedes entrainment of the shift - worker , but actually reinforces the bifurcated entrainment pattern ( gorman and steele , 2006 ) . when light between bouts , which includes morning light , is removed ,
the subsequent activity bout is advanced (  pulled  ) toward the preceding ( figure 2a ) .
thus , the light surrounding the subjective night serves to hold the system in place . for a bifurcated entrainment protocol to be useful to human shift - workers it must be robust to schedule variation .
while days off tend to undo shifts of non - bifurcated rhythms ( smith and eastman , 2008 ) , bifurcation is immediately re - established after perturbations in the lighting cycle , including replacement of light with darkness ( gorman and steele , 2006 ) or darkness with light ( figures 2a , b ) .
if desired , the bifurcated state can , however , be instantly reverted to the unbifurcated state upon exposure to a unimodal ld cycle ( figure 2d ) . additionally , the ldld schedule described above is only one of many that support bifurcated entrainment .
the two intervals of darkness in each 24  h can range anywhere from 1 to 6  h ; the two dark periods need not be of equal duration ( figure 2c ; unpublished observations ) , nor occur 12  h apart ( gorman and steele , 2006 ) .
an asymmetrical bifurcated entrainment schedule provides a good model for a night shift - worker who might commute for an hour before and after an 8  h work shift to necessitate one 10  h subjective day .
the remaining portion of the 24  h cycle might be entrained to yield two 4  h sleep bouts bracketing another 6  h subjective day for business and family .
if the waveform of mammals is fundamentally plastic , why , then , are there no reports of bifurcated humans in the literature ? specific and surprising environmental conditions , such as dim nocturnal illumination , have been shown to facilitate bifurcation in rodents ( gorman et al . , 2003 ) .
so we expect that catalytic conditions may also be necessary for bifurcation in humans . moreover , as in the case of photoperiodism ( see below ) , competing zeitgebers (  time - givers  ) , such as bright light at night , may make it difficult for such a reorganization to occur spontaneously .
finally , entrainable pacemaker bifurcation has been described only recently in animal models and to our knowledge has not yet been systematically sought in humans .
although examinations of bifurcated work schedules might inform the feasibility of human circadian bifurcation , such studies are relatively few and most do not assess melatonin for a definitive determination of subjective night .
unfortunately , they typically focus on the sleep / wake rhythm even though this output is often forced to disassociate and underlies the symptoms of dysrhythmia ( eriksen et al . , 2006 ; jay et al . , 2006 ; gander et al . ,
as discussed , shift - workers commonly split their sleep / wake schedule in an attempt to adjust to the challenges of working odd hours ( akerstedt , 1998a , b ) .
prophylactic napping is advised as a coping mechanism for shift - work ( akerstedt , 1998a ; sack et al .
, 2007 ; caldwell et al . , 2008 ) and coupled with dark exposure may even promote pacemaker shifting ( weibel et al .
, 1997 ) . likewise , polyphasic sleep ( including napping and  siestas  ) is common in many cultures ( webb and dinges , 1989 ) .
these schedules , however , differ from rodent bifurcation in that the waveform of the pacemaker itself is not altered . in the one known study of a split work schedule wherein
both sleep and melatonin were measured , the subjects rest / activity cycle was forced to split while the light schedule remained a natural solar day , and the melatonin waveform remained unimodal ( arendt , 2006 ) . the absence of pacemaker bifurcation under these conditions , while informative ,
should not be interpreted as indicating that pacemaker bifurcation is impossible . in these early days of understanding bifurcation requirements , mechanisms , and sequelae ,
feasibility of rhythm bifurcation in humans is more reasonably evaluated with respect to fundamentals of circadian organization .
one context in which circadian waveform has been studied is the entrainment to seasonally varying daylengths ( i.e. , photoperiodism ) .
pacemaker waveform has been commonly conceptualized as a simple alternation ( e.g. , square - wave ) between biological night and day , and both humans and non - human animals share a capacity for waveform adjustment to seasonal changes in relative length of night . in rodents ,
the waveform of a given photoperiod is encoded in the scn itself ( schwartz et al .
2010 ) with parallel patterns in such downstream outputs as melatonin and behavior ( illnerova et al . , 1984 ; elliott and tamarkin , 1994 ; figure 2c ) .
humans retain this fundamental photoperiodic capacity : the duration of human nocturnal melatonin secretion can expand in both natural and artificial daylength manipulations ( beck - friis et al .
, 1984 ; kauppila et al . , 1987 ; makkison and arendt , 1991 ; wehr , 1991 , 1998 ; stokkan and reiter , 1994 ; vondrasova et al . , 1997 ) . the waveform of human melatonin can be considered an index of the waveform of the underlying pacemaker ( lewy , 1999 ) .
moreover , that the extension of melatonin persists in constant conditions ( wehr , 1991 ; wehr et al . , 1993 ) indicates a change in the underlying pacemaker and provides evidence that humans retain the machinery required to alter circadian waveform in response to environment .
parenthetically , it is not commonly seen in urban populations , likely because most individuals substitute artificial for bright , natural sunlight ( savides et al . , 1986 ;
1998 ) , and artificially extend their days with indoor lighting ( wehr et al . ,
although direct measures of scn function are not possible in humans , all indications are that circadian system organization is conserved : cross - species commonalities exist in fundamental properties of circadian systems , such as molecular basis of cellular rhythmicity , scn cell types and neuroanatomy , circadian control of organ systems , and phase - resetting actions of light ( hofman et al . ,
further indications of multi - oscillator circadian function in humans include bimodality in rhythms of alertness , performance , and errors across 24  h ; ( campbell and zulley , 1985 ; mitler et al . , 1988 ; bes et al . , 2009
, 1995b ) , and dissociable rhythmic components seen under internal desynchrony protocols ( aschoff and wever , 1976 ; folkard and wever , 1983 ) .
given these commonalities the presumption should be that the human pacemaker , like those of other mammals , will be dissociable under permissive conditions .
although application of a bifurcated entrainment pattern to humans has been motivated by attractive features of having two alertness intervals per 24  h cycle , a necessary consequence is that the human nocturnal sleep pattern would likewise be bifurcated .
this may cause some concern among sleep experts as , in general , consolidated sleep is considered preferable to fragmented sleep ( bonnet , 1986 ; stepanski , 2002 ) and daytime sleep is poorer in quality than nighttime sleep ( dijk et al .
however , such principles consider daytime sleep in the context of a normal , diurnal , and unimodal waveform .
the incidence of two subjective nights in which to sleep might circumvent these issues , which are likely a result of sleep occurring during subjective day .
in fact , assessments of vigilance in monophasic versus polyphasic sleep schedules indicate that performance is comparable given equivalent time in bed ( nicholson et al . , 1985 ; mollicone et al . , 2007 ; mollicone , 2008 ) .
moreover , polyphasic sleep can be more effective than monophasic sleep in combating the buildup of fatigue in sleep - deprived subjects ( hartley , 1974 ) .
therefore , performance may improve under bifurcation , though any effects on sleep and other physiological outcomes are yet unknown .
photoperiodic responses in human melatonin that persist in constant conditions suggest that the human pacemaker itself is responsive to experimental manipulations of waveform .
the bimodality of output rhythms suggests that there are potentially dissociable components in the human pacemaker and thus results from animal studies of rhythm waveform manipulation may generalize to humans .
taken together , these findings allude to the potential for a more complete adjustment to challenging schedules given appropriate zeitgebers .
experimental manipulation of the waveform of the human pacemaker , a largely neglected circadian parameter , may therefore have the potential to vastly improve upon current methodologies for treating dysrhythmia , thereby reducing the health , safety , and performance costs of shift - work .
future research should focus on characterizing the optimal and minimal protocols to induce such plasticity in animal models , while simultaneous inquiries into the feasibility of introducing such protocols into human research are explored .
the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
 circadian disruption in shift - work is common and has deleterious effects on health and performance . 
 current efforts to mitigate these harms reasonably focus on the phase of the circadian pacemaker , which unfortunately in humans , shifts slowly and often incompletely . 
 temporal reorganization of rhythmic waveform ( i.e. , the shape of its 24  h oscillation ) , rather than phase , however , may better match performance demands of shift - workers and can be quickly and feasibly implemented in animals . 
 in fact , a bifurcated pacemaker waveform may permit stable entrainment of a bimodal sleep / wake rhythm promoting alertness in both night and daylight hours . 
 although bifurcation has yet to be formally assessed in humans , evidence of conserved properties of circadian organization and plasticity predict its occurrence : humans respond to conventional manipulations of waveform ( e.g. , photoperiodism ) ; behaviorally , the sleep / wake rhythm is adaptable ; and finally , the human circadian system likely derives from the same multiple cellular oscillators that permit waveform flexibility in the rodent pacemaker . in short , investigation into untried manipulations of waveform in humans to facilitate adjustment to challenging schedules is justified . 
Current Treatments Target Circadian Phase with Limited Success
Circadian Waveform is a Promising Target of Circadian Manipulation
Pacemaker Bifurcation Potentially Addresses Problems Posed by Shift-Work
There is Precedent for Plasticity in Pacemaker Waveform in Rodents and Humans
The Human Sleep/Wake Cycle is Flexible and may Not Hinder Bifurcation
Summary
Conflict of Interest Statement