Prefrontal Cortex, Thalamus, and Cerebellar Volumes in ...

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BRAIN VOLUMES IN YOUTHS 1595 Table 3. Brain structures of subjects with an adolescent-onset AUD and matched comparison subjects Structures (cm 3 ) AUD AUD males AUD females Control Controlmales Controlfemales AUD vs.controls Covariate, t 1,39, p value Intracranial volume 1477.8 � 105.4 1503.0 � 117.2 1444.2 � 185.3 1547.7 � 135.0 1618.9 � 104.8 1452.8 � 115.1 t � -1.68 p � 0.1 — Cerebral volume 1283.5 � 103.2 1307.0 � 116.7 1252.2 � 81.1 1322.0 � 153.3 1404.5 � 89.0 1211.9 � 154.1 t � -0.85 p � 0.40 — Cerebral CSF 37.7 � 12.8 36.7 � 15.3 39.0� 9.9 41.2 � 11.8 39.3 � 11.9 45.7 � 11.4 t � -0.82 p � 0.42 — PFC volume 157.1 � 18.1 158.1 � 18.0 155.7 � 19.8 175.9 � 26.6 184.2 � 23.2 164.9 � 27.7 t � -2.38 p � 0.02 Group: t � -2.47, p � 0.0 Cerebral Vol: t � 6.23, p � 0.0001 PFC gray matter 107.1 � 12.1 106.6 � 12.9 107.8 � 12.2 114.9 � 17.6 117.1 � 15.9 111.8 � 20.0 t 40 � -1.48 p � 0.15 Group: t � -1.19, p � 0.24 Cerebral Vol: t � 4.14, p � 0.0002 PFC white matter 50.0 � 8.2 51.5 � 8.0 47.9 � 8.9 61.0 � 13.2 67.1 � 10.8 53.0 � 12.1 t 40 � -2.86 p � 0.007 Group: t � -3.09, p � 0.004 Cerebral Vol: t � 5.99, p � 0.0001 PFC CSF 8.3 � 4.1 8.1 � 3.6 8.6 � 4.9 5.0 � 2.0 4.6 � 2.2 5.6 � 1.4 t 1 � 2.83 p � 0.01 Group: t � 3.48, p � 0.001 Cerebral Vol: t � 0.25, p � 0.80 Thalamus (total) 8.4 � 2.0 8.5 � 1.9 8.2 � 2.2 7.4 � 2.0 7.4 � 1.8 7.4 � 2.3 t 40 � 1.34 p � 0.19 Group: t � 1.38, p � 0.18 Cerebral Vol: t � 0.61, p � 0.54 Right thalamus 4.2 � 1.0 4.2 � 1.1 4.1 � 1.1 3.7 � 1.0 3.7 � 0.9 3.8 � 1.2 t 40 � 1.28 p � 0.21 Group: t � 1.30, p � 0.20 Cerebral Vol: t � 0.46, p � 0.64 Left thalamus 4.2 � 1.0 4.2 � 0.9 4.1 � 1.2 3.7 � 1.1 3.8 � 0.9 3.7 � 1.2 t 40 � 1.32 p � 0.20 Group: t � 1.37, p � 0.18 Cerebral Vol: t � 0.73, p � 0.47 Pons/brainstem 26.1 � 2.5 26.5 � 2.3 25.5 � 2.9 26.2 � 2.9 27.1 � 3.2 25.0 � 2.0 t 40 � -0.12 p � 0.90 Group: t � 0.10, p � 0.92 Cerebral Vol: t � 1.67, p � 0.1 Cerebellum(total) 141.3 � 9.1 141.0 � 10.1 141.7 � 8.5 143.8 � 13.3 150.7 � 13.1 134.7 � 6.3 t 40 � -0.63 p � 0.53 Group: t � -0.26, p � 0.79 Cerebral Vol: t � 3.24, p � 0.002 Right cerebellum 70.9 � 4.9 70.8 � 5.9 71.0 � 3.8 72.3 � 6.9 75.7 � 6.7 67.7 � 4.2 t 40 � -0.67 p � 0.51 Group: t � -0.33, p � 0.74 Cerebral Vol: t � 2.99, p � 0.005 Left cerebellum 69.7 � 5.2 69.6 � 6.0 69.9 � 4.3 71.4 � 6.7 74.6 � 6.4 67.1 � 4.3 t 40 � -0.80 p � 0.43 Group: t � -0.47, p � 0.64 Cerebral Vol: t � 2.91, p � 0.006 Cerebellar vermis 7.86 � 0.59 7.84 � 0.67 7.9 � 0.51 7.34 � 1.25 7.64 � 1.04 6.95 � 1.45 t 40 � 1.46 p � 0.15 Group: t � 1.65, p � 0.1 Cerebral (total) Vol: t � 1.43, p � 0.16 CV, cerebral volume. significant differences when PFC volumes adjusted for cerebral volumes in AUD subjects with PTSD (mean, 163.2 � 18.6 cm 3 ) and without PTSD (mean, 163.2 � 8.4 cm 3 )(t 1,12 � -0.73, p � 0.48) or with conduct disorder (mean, 159.3 � 12.5 cm 3 ) and without conduct disorder (mean, 163.2 � 19.8 cm 3 )(t 1,12 � 0.45, p � 0.66) were compared within AUD groups. Right, left and total thalamic, pons/brainstem, right and left cerebellar hemispheres and total cerebellum and cerebellar vermis volumes did not differ between groups. See Table 3. There was a significant sex-by-group effect, indicating that males with an adolescent-onset AUD compared with control males had smaller cerebellar volumes (male AUD mean: 141.8 � 8.5 cm 3; male control mean: 150.7 � 13.1 cm 3 )(F � 4.16, df � 1,37, p � 0.05), whereas the two female groups were not different on this variable (female AUD mean: 141.0 � 10.1 cm 3; female control mean: 134.7 � 6.3 cm 3 ). It should be noted six of the eight AUD males also had comorbid attention deficit hyperactivity disorder, combined type, whereas only one adolescent female had this diagnosis. No other significant sex-by-group interactions were seen. PFC variables adjusted for cerebral volume to correct for individual differences in brain size with regard to gender were correlated with six alcohol consumption variables (age of onset of AUD, duration of an AUD, average number of drink per drinking episode, most number of drinks per maximum drinking episode, quantity/frequency grouping, and lifetime number of drinks), using Spearman correlation coefficients. The average number of drinks per drinking episode significantly correlated with the PFC gray matter volume (r s � -0.6, df � 12, p � 0.03). The number of drinks per maximum drinking episode significantly correlated with the PFC volume (r s � -0.57, df � 12, p � 0.03) and PFC gray mater volume (r s � -0.78, df � 12, p � 0.0009). See Fig. 4. Quantity/frequency grouping negatively correlated with the PFC gray matter volume (r s � -0.71, df � 12, p � 0.005). No significant relationships were seen between PFC, PFC gray, or prefrontal white matter measures with age of onset of an AUD or duration of an AUD. No significant relationships were seen between PFC gray or white matter measures with age of onset or duration of cannabis use disorder. Fig. 3 DISCUSSION Adolescents and young adults with adolescent-onset AUD and comorbid mental disorders were found to have significantly smaller PFC and PFC white matter volumes and greater amounts of PFC CSF compared with healthy comparison subjects. The findings of greater PFC CSF persisted when controlling for comorbidity. PFC volume variables significantly and negatively correlated with the most number of drinks per maximum drinking episode. Right, left, and total thalamic, pons/brainstem, right and left cerebellar hemispheres, and total cerebellum and cer-
1596 DE BELLIS ET AL. Fig. 3. PFC volumes (cm 3 ) adjusted for cerebral volume of adolescents and young adults with an adolescent-onset AUD and comparison subjects. Female subjects are shown in circles. Male subjects are shown in squares. Subjects in blue indicate history of major depression; open circles or squares indicate history of ADHD. Fig. 4. Correlation between PFC gray matter volume (cm 3 ) adjusted for cerebral volume of adolescents and young adults with an adolescent-onset AUD with the most number of drinks per maximum drinking episode (r s � -0.78, df � 12, p � 0.0009). Female subjects are shown in circles. Male subjects are shown in squares. Subjects in blue indicate history of major depression; open circles or squares indicate history of ADHD. ebellar vermis volumes did not differ between groups. There was a significant sex-by-group effect for males with an adolescent-onset AUD to have smaller cerebellar volumes than control males. To our knowledge, this is the first study to examine the association of an adolescent-onset AUD on the prefrontal, thalamic, and cerebellar morphology of adolescents and young adults. There are several possible explanations for the smaller PFC volumes and PFC white matter volumes found in adolescents and young adults with adolescent-onset AUD. Since the PFC is maturing during adolescence, PFC maturation may be impeded by the neurotoxic effects of alcohol, despite the significantly different drinking patterns seen in adolescents, who tend to binge drink relative to adults, who are more likely to drink daily. Alcohol affects N-methyl-D- aspartate (NMDA) receptors, a subclass of glutamate receptors in the PFC that are maturing during adolescence (Breese et al., 1995; Lovinger, 1993). Alcohol withdrawal leads to increased excitatory transmission through its effects on NMDA receptors. This process can result in discrete excitotoxic neuronal damage or a more severe and complicated alcohol withdrawal syndrome including withdrawal seizures (Becker, 1999). Binging, or chronic intermittent alcohol exposure, may be more neurotoxic to adolescent neurons secondary to many brief episodes of withdrawal (Lundqvist et al., 1995; Lundqvist et al., 1994). However, only two of our AUD subjects had symptoms of withdrawal. Adolescence is a period of active myelination in PFC regions (Paus et al., 2001). Alcoholism is also associated with white matter loss (Harding et al., 1997). Although the findings of smaller PFC volumes did not correlate with age of onset or duration of an AUD, significant negative correlations were seen between PFC and PFC gray matter volume measures with alcohol consumption variables. Thus, we may speculate that the smaller PFC volumes may be a result of the adverse effects of an AUD on the adolescent PFC either through a direct or indirect (via withdrawal) toxic effects on adolescent PFC development. Another explanation for the smaller PFC and PFC white matter volumes may be that PFC maturation is impeded by the neurotoxic effects of other illicit substances on the adolescent brain. Eleven of the 14 subjects in this study also had cannabis abuse or dependence. The active component of the marijuana plant, cannabis sativa, is 9-tetrahydrocannabinol, which affects growth factor gene expression in the adult rat forebrain (Mailleux et al., 1994). Preclinical data suggest that cannabinoids modulate the release of neurotransmitters (i.e., L-glutamate, GABA, noradrenaline, dopamine, serotonin, and acetylcholine) from axon terminals (Iversen, 2003). Although GABA functions primarily as an inhibitory neurotransmitter, it can also act as a trophic factor during nervous system development to influence events such as proliferation, migration, differentiation, synapse maturation, and cell death (Owens and Kriegstein, 2002). Thus, cannabis use disorder through its effects on GABA and other neurotransmitters may negatively influence adolescent brain development. Although multivariate regression analysis examining the results controlling for the presence of a cannabis use disorder as well as comorbidity also suggested smaller PFC and smaller PFC gray and white matter volumes in the AUD subjects compared with control subjects, because no adolescentonset AUD subject had an alcohol use disorder only, it is not impossible to conclude that an adolescent-onset AUD is toxic to PFC maturation. A third explanation for the smaller PFC and PFC white matter volumes of adolescents and young adults with an adolescent-onset AUD is an inherent vulnerability for delayed PFC maturation that enhances the risk for poorer executive cognitive functioning and adolescent substance
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