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Original Investigation |

Childhood Maltreatment, Altered Limbic Neurobiology, and Substance Use Relapse Severity via Trauma-Specific Reductions in Limbic Gray Matter Volume

Nicholas T. Van Dam, PhD1; Kenneth Rando, BS2; Marc N. Potenza, PhD, MD2; Keri Tuit, PsyD2; Rajita Sinha, PhD2
[+] Author Affiliations
1Department of Psychiatry, New York University School of Medicine, New York
2Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
JAMA Psychiatry. 2014;71(8):917-925. doi:10.1001/jamapsychiatry.2014.680.
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Importance  Substance use disorders (SUDs) are among the most common sequelae of childhood maltreatment, yet the independent contributions of SUDs and childhood maltreatment to neurobiological changes and the effect of the latter on relapse risk (a critical variable in addiction treatment) are relatively unknown.

Objectives  To identify structural neural characteristics independently associated with childhood maltreatment (CM; a common type of childhood adversity), comparing a sample with SUD with a demographically comparable control sample, and to examine the relationship between CM-related structural brain changes and subsequent relapse.

Design, Setting, and Participants  Structural magnetic resonance imaging study comparing 79 treatment-engaged participants with SUD in acute remission in inpatient treatment at a community mental health center vs 98 healthy control participants at an outpatient research center at an academic medical center. Both groups included individuals with a range of CM experiences. Participants with SUD were followed up prospectively for 90 days to assess relapse and relapse severity.

Intervention  Standard 12-step, recovery-based, inpatient addiction treatment for all participants with SUD.

Main Outcomes and Measures  Gray matter volume (GMV), subsequent substance use relapse, days to relapse, and severity of relapse.

Results  Controlling for SUD and psychiatric comorbidity, CM (dichotomously classified) was uniquely associated with lower GMV across all participants in the left hippocampus (cornu ammonis 1-3, dentate gyrus), parahippocampus (presubiculum, parasubiculum, prosubiculum, subiculum, and entorhinal cortex), and anterior fusiform gyrus (corrected P < .05; uncorrected P = .001). Among the sample with SUD, CM prospectively predicted a shorter relapse to use of any drug (P = .048), while CM-related GMV reductions predicted severity of substance use relapse (P = .04).

Conclusions and Relevance  Findings indicate that CM was related to decreased GMV in limbic regions, which in turn predicted increased risk of relapse in SUD. These results suggest that CM may significantly affect the course of SUD treatment outcomes and that SUD treatment planning may benefit from identifying and addressing CM.

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Figure 1.
Gray Matter Volume Differences Related to Childhood Maltreatment

Using whole-brain voxel-based morphometry, childhood maltreatment was associated with lower mean gray matter volume, after controlling for substance use disorder, psychiatric history, age, sex, total intracranial volume, and substance dependence by age, in the left medial temporal lobe (1087 voxels; maximum: x = −20, y = −16, z = −26). A, The gray matter volume cluster predominantly includes regions of the hippocampus and parahippocampal and fusiform gyri. Statistical parametric maps have been height thresholded at P < .005 (t ≥ 2.61) and cluster thresholded using topological false discovery rate to set the overall error rate to P < .05. B, Box-and-whisker plot of estimated, standardized region-of-interest (ROI) cluster volumes by group (no trauma vs trauma). The shaded boxes indicate the 75th (top) and 25th (bottom) percentiles; horizontal lines in the middle of the boxes, the median (50th percentile); and whiskers, the minimum and maximum volumes.aA t test revealed significant differences in the estimated volumes for the ROI between the 2 groups at P < .001.

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Figure 2.
Gray Matter Volume Differences Related to Substance Use Disorders

Using whole-brain voxel-based morphometry, substance use disorder was associated with lower mean gray matter volume, after controlling for childhood maltreatment, psychiatric history, age, sex, total intracranial volume, and substance use disorders by age, across 4 clusters. Gray matter volume differences are depicted as statistical parametric maps on rendered surfaces in the bilateral thalamus (1337 voxels; maximum: x = 6, y = −4, z = 10), left midcingulate gyrus and bilateral supplementary motor area (3899 voxels; maximum: x = −6, y = −31, z = 48), bilateral posterior cingulate gyrus and right cuneus and precuneus (2166 voxels; maximum: x = −5, y = −61, z = 7), and right fusiform gyrus (1157 voxels; maximum: x = 35, y = −73, z = −15). Statistical parametric maps have been height thresholded at P < .005 (t ≥ 2.61) and cluster thresholded using topological false discovery rate to set the overall error rate to P < .05.

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Figure 3.
Relapse Rate and Severity by Trauma Group and Childhood Maltreatment–Related Gray Matter Volume Differences

Among the subset of the substance-dependent sample for whom additional data were available (n = 72 [91.1%]), relapse time course was examined as a function of childhood maltreatment (A), and severity of relapse (defined as maximum number of days of drug use [alcohol, cocaine, and cannabis] during the 90-day follow-up) was examined as a function of childhood maltreatment–predicted gray matter volume differences in a whole-brain identified region of interest (ROI) (B and C). A, Significantly faster rate of drug relapse for participants with childhood maltreatment compared with those without childhood maltreatment (P value reflects the generalized Wilcoxon χ2 test). B, Correlation between ROI gray matter volume and severity of relapse in the entire subsample (n = 72). C, Relationship between ROI gray matter volume and severity of relapse among those individuals for whom severity of relapse was greater than 0 days (n = 52 [72.2% of subsample]).

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Maladaptive behavior as compensation for left hemispheric freeze response following childhood trauma
Posted on June 17, 2014
Sung Lee, Lee Gerdes
Brain State Technologies
Conflict of Interest: Dr. Lee and Mr. Gerdes are employees and shareholders of Brain State Technologies.
Van Dam and colleagues have made an important contribution to advanced understanding of the risks associated with childhood trauma,1 and their study may support a more general model of traumatic stress effects on health and behavior. The authors found that a history of childhood maltreatment was associated with volume reduction in the left medial temporal lobe, that a history of maltreatment predicted time to relapse among individuals with substance use disorders, and that the degree of volume reduction predicted severity of relapse. Childhood trauma likely has a priming role in the neurobiology of maladaptive behaviors other than substance abuse, and indeed left temporal lobe structural and metabolic abnormalities have been reported in association with violence.2 As to mechanisms, the authors proposed that altered functionality in the region of the hippocampal complex may create “vulnerability… around the processing of and response to stress.” That interpretation is undoubtedly correct, and we wish to extend their discussion with two comments. First, the stress response is not unitary. Whereas most studies of traumatic stress focus on high arousal (fight or flight) responses mediated through the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system, less attention has been paid to the more primitive parasympathetic immobilization (freeze) response. These different response systems appear to be organized in a hierarchical way reflecting their roots in evolutionary phylogeny, with severe or abandonment traumas being especially likely to produce freeze-state physiology.3 Second, data from behavioral science, neurology, and neurocardiology converge on a model of hemispheric lateralization in management of autonomic functioning, with sympathetic high arousal being produced principally by right-hemispheric structures, and parasympathetic freeze responses by the left hemisphere.4 Left temporal lobe abnormality (including limbic volume reduction) observed in individuals with a history of childhood maltreatment may reflect developmental perturbations associated with the left-hemispheric parasympathetic freeze state. This state may entail higher risk to enact adverse compensatory behaviors, including substance abuse, to depart the experience of emotional numbness.4 If limbic volume asymmetry in adults with history of childhood maltreatment trauma relates to hemispheric asymmetry in cortically-directed arousal tendencies, then a history of early life trauma may predict both high-risk behaviors and physiological hypo-arousal. If a bihemispheric autonomic model does accurately explain and predict behavioral sequelae of traumatic stress, then individuals with early life trauma may be good candidates to benefit from interventions designed to support brain activity to self-calibrate in the direction of greater hemispheric symmetry.5References1Van Dam NT, Rando K, Potenza MN, Tuit K, Sinha R. Childhood maltreatment, altered limbic neurobiology, and substance use relapse severity via trauma-specific reductions in limbic gray matter volume. JAMA Psychiatry. 2014; online June 11.2Volkow ND, Tancredi L. Neural substrates of violent behaviour. A preliminary study with positron emission tomography. Br J Psychiatry. 1987; 151:668-73.3Porges SW. The Polyvagal Theory. New York, NY: W.W. Norton and Company, Inc.; 2011.4Lee SW, Gerdes L, Tegeler CL, Shaltout HA, Tegeler CH. A bihemispheric autonomic model for traumatic stress effects on health and behavior through auto-calibration of arousal. Front Psychol. (Under Review.)5Gerdes L, Gerdes P, Lee SW, Tegeler CH. HIRREM: a noninvasive allostatic methodology for relaxation and auto-calibration of neural oscillations. Brain Behav. 2013; 3(2): 193-205.
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