Demographics, Genotypes and Clinical Ratings
In the schizophrenia group, there were 32 BDNF Val homozygotes (mean age 27+5, 22 male, 26 Caucasian, 27 right-handers, 21 COMT Val carriers, mean age at onset 21+4, mean illness duration 6+4) and 15 BDNF Met carriers (mean age 29+9, 12 male, 11 Caucasian, 13 right-handers, 10 COMT Val carriers, mean age at onset 19+3, mean illness duration 10+8). In the control group there were 49 BDNF Val homozygotes (mean age 30+7, 34 male, 43 Caucasian, 45 right-handers, 32 COMT Val carriers) and 25 BDNF Met carriers (mean age 29+7, 16 male, 19 Caucasian, 23 right-handers, 17 COMT Val carriers). Across these four groups, there were no significant differences in age (F(3,117)=1.223, p=0.304) or in sex, race, handedness, or COMT genotype distributions (all Fisher’s exact test statistics ≤1.612, p≥0.711). Healthy and patient groups did not differ in BDNF genotype distribution (χ2(1,N=121)=0.045, p=0.831). No deviations from Hardy-Weinberg equilibrium existed for either gene (all p’s≥0.133). Within the patient group, there were no significant differences in illness duration by genotype (t(45)=1.674, p=0.112).
Inpatient PANSS ratings were available for all but five individuals whose data were lost due to transcription error. Average ratings for total PANSS (maximum 210), and Negative (maximum 49), Positive (maximum 49), and General Psychopathology (maximum 112) subscales were 72+22, 20+7, 17+7, and 34+11, respectively, and did not significantly vary between genotypes (all t’s(40)≤1.237; p≥0.223).
Resting rCBF data were available for all participants. Working memory rCBF data for nine patients were excluded due to data acquisition problems (three) or 2-back performance at or below chance (six). The remaining patient group contained 25 Val homozygotes (mean age 26+5) and 13 Met carriers (mean age 27+8). Mean age differences across groups did not reach statistical significance (F(3,108)=1.904, p=0.133). Post-hoc pair-wise age comparisons (Tukey’s HSD test) of all groups were performed and indicated that control Val homozygotes (mean age 30+7) non-significantly tended to be older than patient Val homozygotes (p=0.128; all other p’s>0.483). Demographic comparisons across these subgroups remained nonsignificant for sex, race, handedness, and COMT genotype distributions (Fisher’s exact test statistics (N=112)≤2.298, p≥0.517). Again, healthy and patient groups did not differ in BDNF genotype distributions (χ2(1,N=112)=0.002, p=0.964).
Inpatient PANSS ratings were available for all but two individuals in the working memory patient group. Average ratings on the total PANSS, and Negative, Positive, and General Psychopathology subscales were 66+16, 19+6, 16+5, and 32+9, respectively. These did not significantly vary between genotypes (t’s(34)≤0.501, p≥0.620).
Working Memory Task Performance
As expected, patients showed worse accuracy on the 2-back task than healthy volunteers (patients mean=70%+0.2, controls mean=83%+0.16; t(108)=3.912, p<0.001), but all performed above chance (25%) level. A trend for worse accuracy among Met carriers was not significant (Met carriers mean=76%+0.19, Val homozygotes mean=81%+0.17; t(108)=1.744, p=0.084), and there was no significant diagnosis-by-genotype interaction (t(108)=0.355, p=0.186).
Resting Hippocampal rCBF: ROI Comparisons
Planned, two-tailed contrast tests revealed a main effect of diagnostic group on mean hippocampal resting rCBF (t(117)=3.042; p=0.003) indicating lower basal hippocampal rCBF in patients. No main effect of genotype existed (t(117)=0.511, p=0.611), but a highly robust diagnosis-by-genotype interaction (t(117)=3.258, p=0.001) did: whereas control Met carriers had greater resting hippocampal rCBF than Val homozygotes (t(117)=2.224, p=0.028), patients showed the opposite pattern (t(117)=2.396, p=0.018), with abnormally low rCBF in patient Met carriers. Notably, this same interaction pattern was observed within the 0-back (t(108)=2.841, p=0.005) and 2-back (t(108)=2.414, p=0.017) conditions alone (). PANSS ratings (total and subscales) did not correlate with resting hippocampal rCBF in patients (all r’s≤|0.075|, p’s≥0.635).
Scaled Mean Hippocampal Regional Cerebral Blood Flow (rCBF) by Diagnosis and BDNF Val66Met Genotype During Rest, Sensorimotor (0-back), and Working Memory (2-back) Conditions.
Resting Hippocampal rCBF: Voxel-wise Comparisons
Confirmatory voxel-wise hippocampal rCBF comparisons identified bilateral diagnosis effects (controls>patients), with the strongest difference in the left anterior hippocampus; ). As with the ROI analyses above, no main effects of genotype on hippocampal rCBF were found. The robust diagnosis-by-genotype interaction observed in the ROI analyses also localized bilaterally, with the strongest effect in the left mid-posterior hippocampus (; Supplementary Table 1
Resting Hippocampal Functional Coupling: Voxel-wise Comparisons
When whole-brain, voxel-wise patterns of resting hippocampal functional coupling were explored, there was no significant main effect of diagnosis. A genotype main effect arose in several midline regions, including the medial frontal gyrus and several cingulate cortex clusters as well as in the amygdala and left inferior temporal and postcentral gyri, where strong positive relationships with hippocampal rCBF occurred in Met carriers but not Val homozygotes. The opposite effect (Val homozygotes showing more positive relationships with hippocampal rCBF than Met carriers) existed in the middle occipital and superior temporal gyri. Importantly, a highly significant diagnosis-by-genotype interaction localized to a large lateral prefrontal cortex (PFC) region (): whereas healthy Val homozygotes showed a significant positive relationship between resting hippocampal and prefrontal rCBF, healthy Met carriers had a trend for an inverse relationship between these regions; in contrast, patients evidenced the opposite pattern, with Met carriers, but not Val homozygotes, demonstrating a strong positive hippocampal-PFC relationship (). Less significant diagnosis-by-genotype interactions occurred in select posterior regions: lingual and fusiform gyri and posterior cingulate ().
Results for Voxel-Wise Analyses of Hippocampal Resting rCBF (Upper) and Activation (2-Back Greater Than 0-Back; Lower) Functional Coupling by Diagnosis and BDNF Val66Met Genotype Groups.
Hippocampal-Prefrontal Functional Coupling by Diagnosis and BDNF Val66Met Genotype During Rest.
Working Memory-Related Hippocampal Activation: ROI Comparisons
As expected from previous reports32,39
, hippocampal rCBF was generally lower during working memory relative to during the sensorimotor 0-back condition (i.e., ‘deactivation’; see ). However, planned two-tailed contrast tests revealed a significant diagnosis main effect on mean hippocampal working memory activation (t(108)=2.330; p=0.022) indicating that patients showed diminished hippocampal deactivation. Also, whereas healthy volunteers showed no significant genotype-related hippocampal activation differences (t(108)=1.158, p=0.249), patient Met
carriers had significantly less hippocampal deactivation than Val
homozygote patients (t(108)=3.564, p=0.001), resulting in an overall main effect of genotype (t(108)=3.570; p=0.001) and diagnosis-by-genotype interaction (t(108)=2.218, p=0.029; ) Working memory performance did not correlate with hippocampal activation (r=−0.05, p=0.603), and diagnosis, genotype and diagnosis-by-genotype interactions remained significant even when accounting for performance or age in the model (all p’s≤0.024). In patients, correlations between PANSS ratings (total and subscales) and hippocampal activation did not reach significance (all r’s<0.274, p≥0.106).
Scaled Mean Hippocampal Working Memory Activation (2-back – 0-back) by Diagnosis and BDNF Val66Met Genotype.
Working Memory-Related Hippocampal Activation: Voxel-wise Comparisons
Confirmatory voxel-wise comparisons of hippocampal working memory activation identified greatest effects of diagnosis (less deactivation in patients), genotype (less deactivation in Met
carriers), and diagnosis-by-genotype interaction (greater genotype effect in patients) in the left anterior hippocampus (; Supplementary Table 1
). These results remained significant even when accounting for performance or age in the model.
Working Memory-Related Hippocampal Activation Functional Coupling: Voxel-wise Comparisons
When voxel-wise patterns of hippocampal covariation across the brain were explored, diagnosis predicted differences in functional coupling within critical working memory and ‘default’ network nodes, including the lateral PFC and cingulate cortices respectively (). In patients but not controls, greater hippocampal deactivation predicted stronger activation in the lateral PFC and stronger deactivation in the anterior and posterior cingulate cortices. Additionally, there was a regionally specific main effect of genotype in the left inferior frontal gyrus, where greater hippocampal deactivation was more predictive of less activation among Met carriers relative to Val homozygotes. A significant diagnosis-by-genotype interaction existed in the left inferior parietal lobule, where greater activation was predicted by less hippocampal deactivation only in patient Met carriers and control Val homozygotes. No interactions existed in the PFC.