historically , research has focused on understanding the mechanisms that give rise to the unwanted choices expressed by chronic cocaine users ( ccus ) and treatment efforts have been aimed at stopping them altogether . as with many addictions ,
stimulant addiction is portrayed as the hijacking of natural valuation and learning signals in the brain , such as those in the dopamine - rich striatum .
indeed , much scientific evidence supports the hypothesis that the neural systems that balance immediate desires with long - term gains [ 35 ] function suboptimally in ccus [ 68 ] and the very mechanisms evolved to protect are compromised in ways that drive addicts to choose cocaine .
while this narrative organizes a wealth of experimental data , it also deemphasizes an important observation : not all decisions made by ccus are unhealthy choices for drugs .
for example , it has been demonstrated that cocaine users decrease cocaine self - administration when offered merchandise vouchers as an alternative to cocaine , with levels decreasing even further for direct money vouchers .
furthermore , when cocaine users are given the choice between a 10  mg unit dose of intranasal cocaine and increasing amounts of money , choices for cocaine decrease as the amount of money offered increases .
the preference for money , as opposed to cocaine , in cocaine users has been referred to as a difficult but  rational  choice in the sense that individuals must forgo their abused drug for the opportunity to obtain other desired commodities .
what if cocaine users are choosing money with the intent to obtain cocaine and/or other commodities later ?
 if so , then these individuals are planning for the future and executing an advantageous preference away from an available drug of abuse .
hence , a tension exists between the observations that neural valuation and decision - making systems are compromised in ccus ; yet these individuals execute choice preferences away from cocaine in many domains of their life and for variable periods of time .
this supports a complementary approach that seeks to understand the similarities and differences in the expression of sensible choice preferences of ccus and non - cocaine using control participants ( controls ) .
this will help inform therapeutic strategies that aim to increase the expression of healthier choices in ccus . as a first step , the current study uses single- and cross - commodity intertemporal choice tasks to examine the times when individuals choose money in the presence of the opportunity to choose cocaine . whereas single - commodity choice tasks ( i.e. , money now versus money later ( mm ) and cocaine now versus cocaine later ( cc ) ) have been used extensively , cross - commodity tasks ( i.e. , money now versus cocaine later ( mc ) and cocaine now versus money later ( cm ) )
have recently been introduced to examine the real - world trade - offs that ccus experience on a daily basis . in a simple depiction of the claim that reward - guided valuation and decision - making systems are compromised in ccus , choices in favor of money , as opposed to cocaine ,
are likely to involve neural responses in structures other than the striatum . hence , our working hypothesis was that choosing money instead of cocaine would not correlate with activity in the striatum but rather with other structures related to reward - guided choice
furthermore , compensatory mechanisms would differentiate between the preference for money in ccus and that in controls and be observed as functional differences outside of the striatum .
fifty right - handed participants were recruited from the virginia tech carilion research center ( vtcri ; roanoke , va , usa ) or the baylor college of medicine ( bcm ; houston , tx , usa ) .
twenty - five individuals were non - treatment seeking chronic cocaine users ( ccus ) who met dsm - iv criteria for cocaine dependence and 25 individuals were control participants ( controls ) .
individuals were recruited via local advertisements and word of mouth and provided informed consent in accordance with the institutional review board at virginia tech or baylor college of medicine .
the first laboratory visit was a screening and consenting visit and the second was a scanning visit . at the beginning of each visit urinalysis tests
urinalysis kits ( quicktox drug screen dip card by branan medical corporation ) tested for the use of cocaine ( benzoylecgonine ; 300  ng / ml ) , amphetamine ( 500  ng / ml ) , opiates ( 300  ng / ml ) , benzodiazepines ( 300  ng / ml ) , and marijuana ( delta-9-tetrahydrocannabinol ; 50  ng / ml ) . individuals who tested positive for any drug other than cocaine in individuals considered for the ccus group were excluded from participation . following initial urinalysis screening , individuals answered a series of questions related to demographic variables and were administered the structured clinical interview for the diagnostic and statistical manual of mental disorders ( dsm - iv ) .
individuals who presented with a history of substance abuse for substances other than cocaine or nicotine were excluded from the study .
in addition , individuals were excluded if they presented with systemic diseases of the central nervous system , head trauma , neurological disorders , or axis - i psychiatric disorders ( other than cocaine or nicotine dependence ) .
specifically , individuals were asked to reflect on their cocaine use over the past 12 months and answer a series of 7 questions that addressed tolerance ; withdrawal ; taking more drug than expected ; failed quit attempts ; time spent sequestering or thinking about cocaine ; time spent away from family , hobbies , and friends ; and mental health problems , respectively .
the questions read as follows : ( 1 )  have you found that you needed to use much more cocaine to get the same effect that you did when you first started taking it ?  ( 2 )  when you reduced or stopped using cocaine , did you have withdrawal symptoms such as aches , shaking , fever , weakness , diarrhea , nausea , sweating , heart beat irregularities ? 
( 3 )  have you found that when you used cocaine , you ended up taking more than you thought you would ? " ( 4 )  have you tried to reduce or stop taking cocaine but failed ?  ( 5 )  on the days that you used cocaine , did you spend substantial time ( > 2 hours ) , obtaining , using , or recovering from cocaine , or thinking about using it ?  ( 6 )  did you spend less time working , enjoying hobbies , or being with family or friends because of your cocaine use ?  ( 7 )  if cocaine caused you health or mental problems , did you still keep on using it ?  whereas individuals who responded positively ( e.g. ,  yes  ) to at least 3 of the 7 questions met criteria for cocaine dependence , individuals who responded positively to 5 or more questions were considered to be addicted to cocaine .
individuals who met criteria for cocaine addiction were included as participants in the ccus group .
all individuals who passed screening criteria on the first laboratory visit were invited back to the laboratory for the scanning visit .
participants in the ccus group were asked to abstain from using cocaine starting at midnight the night before the scheduled scanning visit . on the day of the scanning visit
, participants arrived at the laboratory approximately two hours before the fmri scanning session . upon arrival individuals
were administered a second urinalysis test . since it is feasible that a positive screen for cocaine could be obtained from individuals remaining abstinent since the previous midnight ( e.g. , the cocaine metabolite benzoylecgonine
can typically be detected in urine up to 3 - 4 days following use in chronic users ) , participants in the ccus group who tested positive for cocaine use ( 100% of participants ) were asked to provide the exact time since last use .
they were also visually monitored for overt symptoms of acute cocaine intoxication ( e.g. , anxiety and agitation , excessive and/or uncontrolled motor movements , jaw clinching and/or mouth gnawing , erratic behavior , dilated pupils , etc . ) .
participants in the ccus group who reported using cocaine after the previous midnight and/or were judged to be acutely intoxicated by a trained research assistant were excluded from participation ( 0% of participants ) .
participants in the controls group were required to test negative for all drugs screened by urinalysis .
the behavioral task parameters used for the current study have been described in detail elsewhere .
participants performed two single - commodity and two cross - commodity discounting tasks in which they chose between hypothetical amounts of money or cocaine available immediately or after some delay ( figure 1(a ) ) .
single - commodity tasks were tasks where participants chose between money available now or money in the future ( mm ) and cocaine available now or cocaine in the future ( cc ) .
cross - commodity tasks were tasks where participants chose between money available now or cocaine in the future ( mc ) and cocaine available now or money in the future ( cm ) . prior to
the task participants gave an estimate of the number of grams of cocaine that they equated with $ 1000 .
controls were asked to treat cocaine as a commodity that they had experience with . prior to performing behavioral tasks in the fmri scanner , participants completed two similar single - commodity and two similar cross - commodity adjusting amount discounting tasks outside of the scanner .
indifference points , representing the amounts at which individuals are equally likely to choose a presently available commodity versus a future commodity , were calculated from the tasks performed outside the scanner and used to parameterize the scanner tasks .
this was done to limit the sampling space while participants were in the scanner , maximizing the likelihood that indifference points could be calculated from data obtained from the scanner task .
, participants chose between immediate and delayed amounts six times for each of seven delays ( 1 day , 1 week , 1 month , 6 months , 1 year , 5 years , and 25 years ) .
the sixth choice for each delay was used as the estimated indifference point , or the value at which the participant would be indifferent between immediate and delayed options . specifically , the initial choice at each delay was between the full large delayed amount and 50% of that amount available immediately .
when participants chose one of the two options offered , the immediate amount offered in the next trial was first adjusted by 50% of the current offer , with adjustments on subsequent trials being half of the previous adjustment .
if the participant chose the immediate amount , the immediate amount decreased for the next trial ; if the participant chose the delayed amount , the immediate offer increased .
the indifference values obtained from 1 week , 1 month , 6 months , and 1 year were used to parameterize the offers given in the scanner tasks at 1 week , 4 weeks , 26 weeks , and 52 weeks , respectively . an example trial from the modified behavioral task performed inside the fmri scanner
can be seen in figure 1(b ) . a trial consisted of a viewing period lasting a maximum of 5 seconds . during this period
, a question appeared on the top of the screen that asked ,  would you rather have ?  and the immediate and future choice options appeared randomly on the left or right side of the screen below the question .
participants selected their preferred option by pressing buttons on boxes positioned in their right and left hands .
as soon as a participant selected an option a box appeared around the selected option for approximately 1 second followed by a fixation screen that jittered 1 second around and average presentation period of 5 seconds . at the end of the fixation period
for each future time point , the amount of the immediate commodity was varied six times .
images were acquired on siemens 3 t allegra scanners either at vtcri or at bcm .
structural t1-weighted images were first acquired ( 0.5  0.5  1  mm ) followed by functional images with a 2  s repetition time , 25  ms echo time , and 90 flip angle in 37 interleaved slices ( 3.4  3.4  4  mm ) .
slices were hyperangulated approximately 30 from the anterior commissure - posterior commissure line in an effort to avoid orbital frontal washout .
functional data were adjusted to correct slice timing , realigned , coregistered to t1 anatomical image , normalized to montreal neurological institute ( mni ) coordinates , resliced ( 4  4  4  mm ) , and smoothed using an 8  mm gaussian kernel .
these steps were conducted using statistical parametric mapping ( spm08 , institute of neurology , london , uk ) .
data were also high - pass - filtered at 128  s. comparisons of parametric ( i.e. , age , education , and monthly income ) and categorical ( i.e. , gender and collection site ) demographic variables were conducted with independent samples t - tests and chi - squared tests , respectively , with significant thresholds set to p < 0.05 . based on the choice behaviors exhibited by participants inside the fmri scanner ( figure 2 ) ,
we first examined temporal discounting behavior across the four experimental tasks in nonexclusive responders , those individuals for whom indifference points could be calculated based on behavioral choices .
the second stream examined behavior and brain activity for all immediate and delayed choices in each task for all individuals , allowing clear distinctions to be made between immediate and delayed money and cocaine choices .
we adopted this approach to maximize the validity of the discounting analysis ( e.g. , only including individuals who switched choice preferences between the immediate and future options allowing calculation of an indifference point ) and to maximize the number of individuals included in the imaging analysis ( e.g. , including individuals who did not switch between immediate and future options according to their exclusive choices ) .
only individuals who distributed choices between immediate and future options were included in the behavioral discounting analysis .
first , an indifference point at each future time point , in each task , and for each individual was calculated .
indifference points were calculated as the average of the two amounts flanking a switch in choice preference between immediate and delayed options .
next , indifference points for each future time point were averaged across individuals in each group to generate indifference curves for each group in each task .
next , the area under indifference curves was calculated for each group in each task .
if groups differed in the value placed on future commodities in single - commodity and cross - commodity tasks , 2  2 analyses of variance ( anovas ) were performed on the indifference magnitudes for both the single - commodity and the cross - commodity tasks .
post hoc analyses were performed with independent samples or paired samples t - tests according to bonferroni adjusted alphas .
all individuals were included in this behavioral analysis according to their immediate and delayed choices .
for each individual , the percentage of choices allocated to immediate and delayed options was calculated in each task .
independent samples or paired samples t - tests were used to examine if groups differed in the proportion of immediate ( now ) and delayed ( later ) choices in each task . to determine if controls and ccus differed in functional brain activity while viewing and submitting choices for immediate and future options , general linear models were created for each individual . for each individual ,
a multiple linear regression was performed with delta functions set to the onset times for the viewing and submission times for all immediate and delayed responses .
this was done to examine activity that preceded the behavioral expression of choice associated with immediate and delayed options .
activity for each stimulus type was convolved with a canonical hemodynamic response function . for each individual
, beta maps of activity associated with viewing and submitting both immediate and delayed options were directly compared between groups for each task .
to account for potential variance associated with undesired variables and consistent with previous methods , the parametric variables of age in years , education in years , and number of cigarettes smoked per day were entered as nuisance variables in all random - effects analyses .
comparisons were thresholded with a voxelwise p value of 0.005 ( familywise error corrected at the cluster level ) .
the average ( sd ) age of controls was 39.9 ( 22.2 ) years and did not significantly differ from 34.7 ( 20.9 ) years in ccus , t(48 ) = 0.369 , p > 0.05 .
the average ( sd ) length of education in controls was 14 ( 6.7 ) years and did not differ from 14 ( 6.3 ) years in ccus , t(48 ) = 0.678 , p > 0.05 .
the average ( sd ) number of cigarettes smoked by controls was 2.1 ( 3.6 ) per day and did not differ from 4.5 ( 4.2 ) cigarettes smoked by ccus , t(48 ) = 0.18 , p > 0.05 .
the average ( sd ) monthly income of controls was $ 888.29 ( 619.26 ) and did not differ from $ 857.65 ( 782.37 ) in ccus , t(48 ) = 0.127 , p > 0.05 .
the distribution of controls and ccus collected at the two experimental locations did not differ from expected values ( bcm : controls = 14 , ccus = 20 ; vtcri : controls = 11 , ccus = 5 ) ,  ( 1 , n = 50 ) = 3.309 , p > 0.05 .
the number of males and females in each experimental group significantly differed from expected values ( controls : males = 13 , females = 12 , ccus : males = 20 , females = 5 ) , (1 , n = 50 ) = 4.367 , p < 0.05 .
within- and between - group analyses of both behavioral and brain imaging data , however , yielded no significant differences related to gender .
participants in the ccus group reported an average ( sd ) of 14.58 ( 4.5 ) years of experience using cocaine and reported using cocaine for 24.14 ( 7 ) days out of the previous month .
fourteen participants in the ccus group reported smoking crack cocaine as their primary method of delivery .
all participants in the ccus group met criteria for cocaine addiction according to questions derived from the dsm - iv ( see materials and methods ) .
ten members of the controls group reported having previous experience with marijuana use , while twenty - five members of the ccus group reported having previous experience with marijuana use .
all participants reported having previous experience with alcohol use . at the time of the study , however , all participants tested negative for illicit drug use other than cocaine in ccus .
furthermore , participants did not reach criteria for substance dependence , with the exception of cocaine and nicotine dependence in ccus and nicotine dependence in controls .
nicotine use ( cigarettes smoked per day ) was treated as a nuisance variable in all imaging analyses ( see section 2 ) .
based on choice behaviors on the discounting tasks performed in the fmri scanner individuals were included in two analysis streams ( figure 2 ) .
for the single - commodity tasks , this resulted in 92% of ccus ( n = 23 ) and 88% of controls ( n = 22 ) included in the mm groups .
the cc groups consisted of 84% of ccus ( n = 21 ) and 52% of controls ( n = 13 ) . in the cross - commodity tasks , 92% of ccus ( n = 23 ) and 40% of controls
the cm groups consisted of 76% of ccus ( n = 19 ) and 24% of controls ( n = 06 ) . in the second analysis stream ,
all individuals ( exclusive and nonexclusive responders ) were included according to their choices for immediate and delayed commodities .
the numbers of participants included in behavioral and corresponding imaging analyses of the second analysis stream can be observed in tables 1 and 2 . in the first stream ,
average indifference magnitudes ( sem ) revealed the value each group placed on future commodities .
these results are shown in figure 3 . in the single - commodity tasks a main effect of group
was observed when examining indifference magnitudes ( f(1 , 75 ) = 39.871 , p < 0.001 ) .
post hoc analysis demonstrated that the indifference magnitudes ( mean  sem ) in the mm task were significantly less in ccus ( 837  146 ) , compared to controls ( 1896  152 ) ( t(43 ) = 5.170 , p < 0.001 ) .
similarly , indifference magnitudes in the cc task were significantly less in ccus ( 612  132 ) , compared to controls ( 1921  232 ) ( t(32 ) = 3.783 , p = 0.001 )
. within - group analysis of single - commodity tasks revealed that indifference magnitudes did not differ between mm and cc within controls ( t(31 ) = 0.92 , n.s ) .
similarly , indifference magnitudes did not differ between mm and cc within ccus ( t(31 ) = 0.92 , n.s . ) . in the cross - commodity tasks main effects
were observed for group ( f(1 , 54 ) = 5.98 , p = 0.018 ) and task type ( f(1 , 54 ) = 20.18 , p < 0.001 ) .
post hoc comparisons revealed that ccus ( 457  124 ) and controls ( 640  203 ) did not differ in indifference magnitudes during the mc task ( t(31 ) = 0.791 , n.s . ) .
however , during the cm task , indifference magnitudes in ccus ( 942  129 ) were significantly less than controls ( 1860  281 ) ( t(23 ) = 2.304 , p < 0.031 ) .
within - group analysis of cross - commodity task types revealed that indifference magnitudes for controls were significantly greater in cm , compared to mc ( t(14 ) = 3.59 , p < 0.003 ) .
similarly , indifference magnitudes in ccus were significantly greater in cm , compared to mc ( t(40 ) = 2.85 , p = 0.007 ) , suggesting that both controls and ccus value future money more than future cocaine .
the group percentages ( mean  sem ) for all immediate and delayed choices in each group are displayed in figure 4 . during the mm task ,
the percentage of delayed money choices made by ccus ( 40  4.9 ) was significantly less than controls ( 58  4.7 ) ( t(48 ) = 2.5 , p = 0.016 ) .
no difference was observed between groups during the cc task ( t(48 ) = 0.62 , n.s . ) . during the cross - commodity mc task ,
ccus made significantly more delayed cocaine responses ( 35  4.3 ) than controls ( 17  5.3 ) ( t(48 ) = 2.7 , p = 0.01 ) . during the cross - commodity cm task , ccus made significantly less delayed money responses ( 50  6.4 ) than controls ( 92  3.8 ) ( t(40 ) = 5.5 , p < 0.001 ) .
examining the proportion of choices within groups during the cross - commodity tasks revealed that behavioral choices followed the money commodity in both groups .
this can be seen as the proportion of delayed responses between mc and cm significantly differed , in favor of the money option , in both controls ( t(24 ) = 9.0 , p < .001 ) and ccus ( t(24 ) = 2.4 , p = 0.03 ) .
general linear models targeted brain activity while submitting immediate ( now ) or delayed ( later ) choices and retrogradely isolated activity while viewing options that became now or later choices .
very few differences between groups were observed in the single - commodity tasks ( table 1 ) . in the mm task , viewing choice options for what became money now choices resulted in greater precuneus activity in ccus , compared to controls .
on the other hand , viewing what became money later choices resulted in greater inferior frontal gyrus and inferior temporal lobe activity in controls , compared to ccus . in the cc task , submitting cocaine now choices produced greater temporal lobe and postcentral gyral activity in controls , compared to ccus .
cocaine later choices resulted in greater medial prefrontal activity in controls , compared to ccus .
imaging results during cross - commodity tasks are presented in figure 5 and table 2 . during cross - commodity tasks , signals in the striatum and left lateral prefrontal cortex differentiated ccus from controls . while viewing options for what became money now choices , ccus had significantly greater activity in bilateral putamen , globus pallidus , and the left caudate ( figure 5(a ) ) .
activity in the left putamen persisted as ccus executed money now choices ( figure 5(b ) ) .
groups did not differ while viewing options that became money later choices ( figure 5(c ) ) .
however , spatially coincident striatal responses , as well as a response in the left dorsal lateral prefrontal cortex , emerged when ccus executed money later choices ( figure 5(d ) ) .
we used single- and cross - commodity choice tasks and fmri to examine the neurofunctional events that distinguish non - cocaine choice preferences made by chronic cocaine users ( ccus ) from those of controls ( controls ) .
consistent with previous behavioral studies , we observed that ccus devalued the future more than controls , as measured by diminished indifference magnitudes in the single - commodity context . in the cross - commodity context , both ccus and controls executed several choices for money when cocaine was the available alternative .
compared to controls , choices for immediate money as opposed to future cocaine were associated with greater activity in the dorsal striatum of ccus .
in addition to greater dorsal striatal activity , choices for future money as opposed to immediate cocaine , were associated with greater left dorsal lateral prefrontal cortex ( dlpfc ) activity in ccus , compared to controls .
our behavioral analyses of the single - commodity tasks ( i.e. , money now versus money later ( mm ) and cocaine now versus cocaine later ( cc ) ) revealed that ccus devalued future money significantly more than controls .
this was observed in the first analysis as significantly smaller indifference magnitudes during the mm task in ccus , compared to controls , and was confirmed in the second analysis where ccus chose future money 18% less often than controls ( 40% versus 58% ) .
this is consistent with previous single - commodity studies demonstrating that , relative to non - cocaine using individuals , cocaine addicts devalue the future . in the cross - commodity context ( i.e. , money now versus cocaine later ( mc ) and cocaine now versus money later ( cm ) ) , we found further evidence that ccus devalue future money , relative to controls .
ccus had significantly smaller indifference magnitudes during the cm task , compared to controls , and chose future money 42% less often than controls ( 50% versus 92% ) .
perhaps not surprisingly , when given the choice between money and cocaine , the majority of choices in controls were for money ( 83% in mc and 92% in cm ) .
interestingly , a large portion of responses in ccus was also for money ( 65% in mc and 50% in cm ) .
this allowed direct comparisons to be made between groups for money choices in the cross - commodity context .
also of note , in the cross - commodity context offering money in the future resulted in a 15% increase in future choices made by ccus .
this is a clear demonstration that a desired commodity engenders the ability to shift choices in ccus away from their drug of abuse towards a nondrug alternative for the future and is consistent with previous studies demonstrating the ability of cocaine users to forgo cocaine for money [ 9 , 10 ] .
in addition to demonstrating that ccus retain the ability to shift choices away from cocaine , these behavioral results are interesting for another reason . using a single dataset , we present data with seemingly conflicting interpretations . on one hand
, we show that ccus devalue the future , a finding so prevalent in various disease states that it is considered a transdisease process . on the other hand ,
we confirm previous behavioral results that ccus will forgo available drug when an alternative commodity is incentivized appropriately .
this highlights the complexity in understanding real - world trade - offs in ccus and should motivate future studies to tease apart such complexities . in the current study ,
given that both controls and ccus executed choice preferences for money , as opposed to cocaine , we were able to probe the neurofunctional signals that differentiated ccus from controls .
imaging analysis of the single - commodity choices revealed that during the mm task , inferior frontal and temporal lobe activity was greater in controls , compared to ccus , while viewing future money choices . on the other hand , ccus exhibited greater precuneus activity while viewing immediate money choices , relative to controls . during the cc task , controls displayed greater temporal lobe and postcentral gyrus activity while choosing immediate cocaine , compared to ccus , and greater medial prefrontal activity ( mpfc ) for cocaine later choices .
these results suggest that controls place more value on future commodities , compared to ccus , regardless of the commodity type and this is associated with increased executive function - related activity in controls , as opposed to ccus . we found that when choosing money as opposed to cocaine , ccus relied on greater activity than controls in areas known to be involved in normal valuation and decision - making [ 4 , 1720 ] .
namely , activity in the caudate and putamen of the dorsal striatum was greater as ccus viewed and executed money choices .
in addition to the role it plays in the expression of habitual behaviors , the midbrain dopamine system , including the dorsal striatum , has been studied extensively for its specific role in the picoeconomics and neuroeconomics of gambling disorders .
furthermore , it is hypothesized that disruptions in the dorsal striatum underlie the cocaine seeking behaviors that accompany chronic cocaine exposure in both rodent [ 22 , 23 ] and primate [ 24 , 25 ] models of addiction .
in addition , ccus displayed greater activity in the left dlpfc when choosing future money over immediate cocaine , compared to controls .
the left dlpfc is well known for its executive functioning role in on - going decision - making , and our results are consistent with a recent meta - analysis demonstrating that this area is where temporal discounting processes related to the future and working memory processes related to the recent past overlap in the brain . therefore , it is feasible that greater activity in the left dlpfc of ccus is required when executing a difficult choice preference for a future commodity while forgoing immediate cocaine .
these results are consistent with a model where ccus exhibit brain function above the levels of controls when executing a choice preference for money as opposed to cocaine .
the results from the current study are novel and relevant in light of previous studies that have suggested inhibiting cue - induced striatal dopamine increases as a therapeutic strategy for cocaine addiction .
this suggestion logically follows the observation that dopamine levels in the dorsal striatum are positively associated with drug craving   and drug craving is known to contribute to relapse .
this approach is also supported by data from experiments in primates demonstrating that the transition from acute to chronic cocaine self - administration results in a progressive shift in dopamine receptor expression and glucose utilization from the ventral to the dorsal striatum [ 24 , 25 ] . the shift from acute cocaine effects in the ventral striatum , impairing
goal - directed choice , to chronic cocaine effects in the dorsal striatum , impairing habitual choice , has been hypothesized to underlie many addiction - related dysfunctions in cocaine abusing humans ( for review see ) .
our results suggest , however , that simply inhibiting activity in the dorsal striatum , while being potentially beneficial for treating some of the negative aspects of addiction , may inadvertently compromise the ability of cocaine addicts to execute choice preferences away from available cocaine .
the current data suggests that therapeutic approaches should consider the potential confound of compromising real - world relevant , cross - commodity choices .
we contend that successful strategies will benefit from more detailed understanding of the brain activity associated with nondrug choices in ccus .
activity in the left dlpfc was greater in ccus , compared to controls , while executing choices for future money as opposed to immediate cocaine .
the lateral pfc is known to be active during decision - making and is particularly active when considering the costs and benefits of alternatives .
recently , a transcranial magnetic stimulation ( tms ) study found that disrupting the left , but not the right , dlpfc increased choices of immediate rewards over delayed rewards , providing a causal link between activity in the left dlpfc and self - control mechanisms of future choice .
our data are consistent with these results and the competing neurobehavioral decision systems hypothesis , which suggests that the evolutionarily young executive system ( including the dlpfc ) works in concert with the older limbic system for optimal decision - making [ 31 , 32 ] .
for example , hypofrontal activity is also associated with compromised executive abilities in various disease states , including schizophrenia   and major depression .
consistent with rodent studies demonstrating that repeated self - administration of cocaine decreases basal levels of pfc activity , methamphetamine - abusing populations have been observed to have prefrontal hypoactivity during future choice tasks , compared to controls .
our data suggests that , compared to controls , increased dlpfc is needed in conjunction with increased dorsal striatal activity for ccus to execute choices for alternative future commodities when immediate cocaine is also an available commodity .
our results suggest that the left dlpfc is a unique therapeutic target for shifting choices in ccus towards healthier alternatives for the future .
although we relied on strict methodological standards for screening out current illicit drug use and dependence on substances other than cocaine ( our key experimental variable ) and nicotine ( not different between groups and controlled for in imaging analyses ) , results may be influenced by extraneous variables not under our explicit experimental control ( e.g. , gender , age , education , cocaine use patterns , and poly drug , and nontarget drug use ) . while analysis of these variables , with the exception of gender , revealed no significant difference between groups , it is possible that these variables contributed in some way to the observed results .
it should be noted , however , that dividing groups by gender reduced group sample sizes to numbers often deemed underpowered for neuroimaging studies .
future studies will explicitly test gender differences associated with nondrug choices in chronic cocaine users .
as such , they are less likely to evoke visceral responses understood to influence decision - making processes .
it is worth noting , however , that fictive and real money gains and losses have been demonstrated to produce similar behaviors and activate similar brain networks during intertemporal choice tasks , including activity in the striatum and lateral prefrontal cortices .
nonetheless , it is plausible that due to their inexperience with cocaine , controls need not exert self - control comparable to that of the ccus when choosing money over cocaine . it is a possibility that ccus , on the other hand , experience willpower or planning proficiency ( even in the hypothetical case ) not present in controls . to inform this possibility , and in search of additional neural signals associated with choosing money , we performed additional random - effects analyses in each experimental group comparing single- and cross - commodity tasks ( i.e. , mm versus cm and mm versus mc ) .
this may reflect a lack of statistical power due to the current design and the limited choice behaviors exhibited by participants .
finally , in the current study , addiction was operationalized as affirmative responses to five or more ( out of seven ) dsm - iv criteria used to establish cocaine dependence ( which requires a minimum of three of seven affirmative responses ; see materials and methods ) .
therefore , the definition of addiction in the current study is somewhat arbitrary and our results may be generalizable only to a subgroup of cocaine dependent individuals who meet a high number of dependence criteria as established by the dsm - iv . in light of these potential limitations , we encourage readers to treat these data as preliminary . notwithstanding , we hold that the significant results obtained from between - group comparisons of money choices in the cross - commodity context , when cocaine is the nonchosen commodity , are novel , valid , and informative . these data should be considered in future accounts of therapies aimed at shifting choice behaviors in chronic cocaine users .
in conclusion , the cross - commodity context can be used as an experimental paradigm to isolate times when ccus forgo their drug of abuse for a preferred alternative .
our hypothesis that money choices in ccus would not rely on brain activity in the striatum was rejected . updating this hypothesis
, we propose that the difficult choice to forgo cocaine in ccus relies on hyperactivity in the dorsal striatum and dlpfc , known valuation and decision - making brain areas .
specifically , hyperactivity in the dorsal striatum is needed for immediate and future choice preferences away from cocaine , and coincident hyperactivity in the left dlpfc is needed for future choice preferences away from cocaine .
activity in these areas represents therapeutic targets for shifting choices in ccus away from cocaine options .
 addiction is considered a disorder that drives individuals to choose drugs at the expense of healthier alternatives . 
 however , chronic cocaine users ( ccus ) 
 who meet addiction criteria retain the ability to choose money in the presence of the opportunity to choose cocaine . 
 the neural mechanisms that differentiate ccus from non - cocaine using controls ( controls ) while executing these preferred choices remain unknown . 
 thus , therapeutic strategies aimed at shifting preferences towards healthier alternatives remain somewhat uninformed . 
 this study used bold neuroimaging to examine brain activity as fifty ccus and controls performed single- and cross - commodity intertemporal choice tasks for money and/or cocaine . 
 behavioral analyses revealed preferences for each commodity type . 
 imaging analyses revealed the brain activity that differentiated ccus from controls while choosing money over cocaine . 
 we observed that 
 ccus devalued future commodities more than controls . 
 choices for money as opposed to cocaine correlated with greater activity in dorsal striatum of ccus , compared to controls . 
 in addition , choices for future money as opposed to immediate cocaine engaged the left dorsolateral prefrontal cortex ( dlpfc ) of ccus more than controls . 
 these data suggest that the ability of ccus to execute choices away from cocaine relies on activity in the dorsal striatum and left dlpfc . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion
5. Conclusion