The double-hit effect of childhood maltreatment on drug relapse.

Three individualswith a substance use disorder enter an inpatient 12-step program in a communitymental health center and for the first month of the program, all 3 individuals are abstinent. They are then discharged from inpatient treatment and return for face-toface follow-up interviews at 14, 30, and 90 days postdischarge. At the latest postdischarge measure, it is observed that 1 individual didnot relapse,while the other 2 relapsed at day 35. The first relapsing individual tookdrugof choice fromday35 today42 (7-day relapse),while the second individual took drug of choice from day 35 to day 90 (55-day relapse), thus showing greater severity of drug relapse than the first individual. In this issue of JAMA Psychiatry, Van Dam and colleagues1 showed that what predicted relapse in the 2 individuals was exposure to childhood maltreatment, while what predicted the severity of drug relapse in these individuals were childhood maltreatment– related reductions in specific limbic regions of the brain. Tomy knowledge, the study by Van Dam and colleagues1 is the first to assess the unique and shared influence of childhood maltreatment and substance use disorder on gray matter volume (GMV) of the brain as assessed by voxel-based morphometry. In this study, they found that childhood maltreatment was specifically associated with lower GMV in the lefthippocampus,parahippocampus,andanterior fusiformgyrus,while substanceusedisorderwasuniquelyassociatedwith lower GMV in the thalamus, midcingulate gyrus, motor area, andcingulategyrus. Interestingly, childhoodmaltreatmentand substance use disorder did not interact to predict significant clusters in GMV, showing distinct effects of childhood maltreatment and substance use disorder on brain morphology. More importantly, it was shown that while childhood maltreatment prospectively predicted a shorter timeof relapse to any drug, GMV reductions associated with childhood maltreatment predicted the severity of drug relapse. This study showed that the first hit of childhoodmaltreatment is onbrainmorphology so that exposure tomaltreatment in early life leads to lowerGMV in thehippocampal regions and fusiformgyruswhenmeasuredduring adulthood. This finding confirms previous results on the effects of childhoodmaltreatment on adult brain regions, particularly the hippocampal regions,2 aneffect thathasbeenreferredtoas limbic scarsbythe group of Dannlowski and colleagues.3 Thus, exposure to childhoodmaltreatmentmay set intomotion a series of events that lead to a reorganization of synaptic development in the brain. However, the timingof these effects remains largelyunknown. In the present study, decreased GMV in limbic regions was observed in adults who retrospectively reported greater childhoodmaltreatmentasmeasuredbytheChildhoodTraumaQuestionnaire. In this regard, it is important to note that different effects of exposure to childhood maltreatment have been reportedonthevolumeofthehippocampusinchildrenandadults. Hence, smaller hippocampal volumes have been reported in adults retrospectively reporting childhood abuse (as in the present study),4,5 while no differences in hippocampal volumeswereobservedinchildrenexposedtomaltreatment.6-8The contrasting effects of early adversity on hippocampal volumes inchildrenandadultssuggest that theeffectsofadversityonthe hippocampusmaynotbe readily apparentuntil adolescenceor adulthood,9 reflecting the presence of an incubation period for the effects of childhoodmaltreatment on hippocampal/limbic regions in humans. Interestingly, it is during adolescence that initiationofdruguse/abuseoccurs.Thus, itcouldbepossiblethat the limbic regions shown to be responsive to childhood maltreatment also confer greater vulnerability to initiation of drug use/abuse during adolescence. Further studies assessing these brain regions in adolescentswho initiate drug use/abuse or not should provide important data on this issue. The results of this study also showed that the secondhit of childhood maltreatment is on drug relapse severity through childhoodmaltreatmentchanges inbrainmorphology.Here, the authorshaveshownthat thebrainregionsassociatedwithchildhoodmaltreatment are a significant predictor of relapse severityasassessedbydaysofuseduringtherelapseperiod.Thetemporality of these effects is very interesting. In a first phase, exposure to childhood maltreatment could lead to changes in brainmorphologyacrossdevelopment. Inasecondphase, these changes in brain morphology could confer greater vulnerability to drug relapse severity later in adulthood. Interestingly, the limbic regions associatedwith relapse severity in thestudybyVanDamandcolleagues1are thesamethat are involved in the physiological stress response. Stress activates thehypothalamic-pituitary-adrenalaxis, leading tosecretion of glucocorticoids. Various studies performed in both animals and humans have shown that chronic exposure to stress hormones from the prenatal period to aging impacts limbic regions(andparticularlythehippocampalregions) involvedincognitionandmentalhealth.10 Specific effectson thebrain,behavior, and cognition emerge as a function of the timing and the duration of exposure to stress, and some of these effects depend on interaction between genes and exposure to environmental adversity. Studies in human children exposed to severe deprivation(eg,orphanagesandinstitutions),neglect,andabuse Related article Opinion