Faculty Bibliography

BACKGROUND:Functional connectivity (FC) maps from brain fMRI data are often derived with seed-based methods that estimate temporal correlations between the time course in a predefined region (seed) and other brain regions (SCA, seed-based correlation analysis). Standard dual regression, which uses a set of spatial regressor maps, can detect FC with entire brain "networks," such as the default mode network, but may not be feasible when detecting FC associated with a single small brain region alone (for example, the amygdala). NEW METHOD/UNASSIGNED:We explored seed-based dual regression (SDR) from theoretical and practical points of view. SDR is a modified implementation of dual regression where the set of spatial regressors is replaced by a single binary spatial map of the seed region. RESULTS:SDR allowed detection of FC with small brain regions. Comparison with existing method: For both synthetic and natural fMRI data, detection of FC with SDR was identical to that obtained with SCA after removal of global signal from fMRI data with global signal regression (GSR). In the absence of GSR, detection of FC was significantly improved when using SDR compared with SCA. CONCLUSION/CONCLUSIONS:The improved FC detection achieved with SDR was related to a partial filtering of the global signal that occurred during spatial regression, an integral part of dual regression. This filtering can sometimes lead to spurious negative correlations that result in a widespread negative bias in FC derived with any application of dual regression. We provide guidelines for how to identify and correct this potential problem.

OBJECTIVE:Apathy is common in late-life depression and is associated with poor response to antidepressant drugs. In depressed older adults, apathy may be characterized by neuroanatomical abnormalities of the salience network. The current study examined whether cortical thickness of select salience network structures predicted change in apathy following a 12-week treatment with escitalopram. METHODS:A sample of 46 older adults with major depressive disorder received 12 weeks of escitalopram treatment at a daily target dose of 20 mg. All participants underwent a structural brain MRI scan at baseline, and cortical thickness was estimated in key cortical nodes of the salience network: the caudal anterior cingulate cortex and the insula. We measured baseline and post-treatment symptoms using the Apathy Evaluation Scale and the Hamilton Depression Rating Scale. RESULTS:A thicker insula at baseline predicted reduction in apathy symptoms following 12 weeks of treatment with escitalopram, even when controlling for age, baseline depression severity and change in depressive symptoms. CONCLUSION/CONCLUSIONS:Reduced insular thickness predicted residual apathetic symptoms following escitalopram treatment. These results converge with our previous findings of abnormal functional connectivity of the insular cortex in older depressed individuals with apathy. Older depressed adults with apathy may benefit from alternative treatment approaches or augmentative interventions that target abnormalities of the salience network.

BACKGROUND:Depression affects many children and adolescents, leading to poor academic performance, impaired psychosocial functioning, and an increased frequency of suicidal behavior. Depression has also been notably associated with trauma and distress tolerance. Our study sought to understand the relationships of these variables across age and sex categories in youth and adolescents. METHODS:The current study examined data from a total of 324 participants between the ages of 7 and 17 years-old who were a part of a larger study. Data related to age, sex, depression, trauma, and distress tolerance were examined. RESULTS:A multiple regression revealed a significant interaction between age and sex on depression severity. Further, trauma and age by sex categories significantly predicted depression score, as well as distress tolerance predicting depression score. Lastly, a regression analysis, including trauma, distress tolerance, and age by sex categories were significant predictors of depression. LIMITATIONS/CONCLUSIONS:The results are limited by the cross-sectional design. CONCLUSION/CONCLUSIONS:Clinicians should consider age by sex effects when treating childhood depression. Future research should further the understanding of depression across age and sex groups, as well as among children with extensive trauma experiences. Future research should also seek to further understand the implications of distress tolerance therapy on childhood depression.

Schizophrenia (Sz) is associated with deficits in fluent reading ability that compromise functional outcomes. Here, we utilize a combined eye-tracking, neurophysiological, and computational modeling approach to analyze underlying visual and oculomotor processes. Subjects included 26 Sz patients (SzP) and 26 healthy controls. Eye-tracking and electroencephalography data were acquired continuously during the reading of passages from the Gray Oral Reading Tests reading battery, permitting between-group evaluation of both oculomotor activity and fixation-related potentials (FRP). Schizophrenia patients showed a marked increase in time required per word (d = 1.3, P < .0001), reflecting both a moderate increase in fixation duration (d = .7, P = .026) and a large increase in the total saccade number (d = 1.6, P < .0001). Simulation models that incorporated alterations in both lower-level visual and oculomotor function as well as higher-level lexical processing performed better than models that assumed either deficit-type alone. In neurophysiological analyses, amplitude of the fixation-related P1 potential (P1f) was significantly reduced in SzP (d = .66, P = .013), reflecting reduced phase reset of ongoing theta-alpha band activity (d = .74, P = .019). In turn, P1f deficits significantly predicted increased saccade number both across groups (P = .017) and within SzP alone (P = .042). Computational and neurophysiological methods provide increasingly important approaches for investigating sensory contributions to impaired cognition during naturalistic processing in Sz. Here, we demonstrate deficits in reading rate that reflect both sensory/oculomotor- and semantic-level impairments and that manifest, respectively, as alterations in saccade number and fixation duration. Impaired P1f generation reflects impaired fixation-related reset of ongoing brain rhythms and suggests inefficient information processing within the early visual system as a basis for oculomotor dyscontrol during fluent reading in Sz.

Background: Transcranial photobiomodulation (t-PBM) with nearinfrared (NIR) light penetrates into the cerebral cortex and is absorbed by the mitochondrial enzyme cytochrome c oxidase (CCO), stimulating the mitochondrial respiratory chain. t-PBM also significantly increases cerebral blood flow (CBF) and oxygenation. Small studies have reported that t-PBM may be an effective treatment in major depressive disorder (MDD). However, relationships between t-PBM dose (irradiance and/or total energy) and clinical or biological effects are unclear. In this experimental medicine study, we evaluated the dose-dependent effects of t-PBM in MDD subjects.
Method(s): We enrolled subjects meeting DSM-5 criteria for MDD, not treatment-resistant (0-2 failed antidepressants in the current episode), either unmedicated or on stable doses of antidepressants, with no other significant medical or psychiatric comorbidities. All subjects underwent 4 t-PBM sessions in the MRI scanner, 1 week apart, administered in random order, with 1) sham (no energy emitted); 2) High dose: Pulse wave (PW), average irradiance 300mW/cm2, peak irradiance 900 mW/cm2, 42Hz, 33% duty cycle, 4.3 KJ total energy; 3) Medium dose: Continuous Wave (CW), 300 mW/cm2 irradiance, 2.4 KJ total energy; 4) Low dose: CW, 50mW/cm2 irradiance; 1.4 kJ total energy. Other t-PBM parameters were kept unchanged (808 nm; 12.0 cm2 x 2 treatment area; delivered to the anterior prefrontal cortex, bilaterally). Resting state multi-echo (3), multi-band (2) fMRI was recorded on a 3T Siemens Trio using a 12ch head coil (TR = 2500ms, TE1 = 12.8ms, TE2 = 32.33 ms, TE3 = 51.86 ms, 60 slices, slice thickness 2.5mm) before, during and after t-PBM, using measures of the change in blood-oxygenation-level dependent (BOLD) signal on fMRI as marker of target engagement (t-PBM effect on cerebral blood flow). The BOLD signal was preprocessed using standardized automated tools [AFNI]. In order to test whether t-PBM modulated the BOLD signal during and after tPBM, we performed a region-of-interest (ROI) analysis taking into account the illuminated region of the brain. We extracted the signal from the transverse frontopolar giry, bilateral (ROIs 6 and 81 from the Desikan atlas) and separated the resulting time series into the pre-, peri-, and post-stimulation segments. We then performed spectral analysis in order to measure the BOLD power during each segment, employing the Thomson multitaper technique to increase the signal-to-noise ratio of the ensuing power estimates. This produced three spectra for each echo and dose (before, during, and after stimulation). We then tested for significant differences in BOLD power spectrum both during and after stimulation in each t-PBM dose, compared to sham (Wilcoxon rank sum test, corrected for multiple comparisons by controlling the false discovery rate at 0.05).
Result(s): We analyzed data from the first 7 MDD subjects (age = 32.1 +/- 13.1; 57% female) undergoing all 4 experimental sessions. We found a dose-dependent effect of t-PBM on the BOLD. Namely, low-intensity t-PBM produced a marked decrease in BOLD that was observed in all three echos (p < 0.05, n = 7). The reduction in BOLD was most pronounced near 0.03 Hz at echos 2 and 3. In contrast, CW 300 mW/cm2 t-PBM increased BOLD power, with a significant increase resolved near 0.1 Hz at all 3 echos (p < 0.05, n = 7). This suggests that higher irradiance CW t-PBM increased the power of the "fast" component of the BOLD signal during stimulation. However, no significant differences from sham were observed during PW 300 mW/cm2 stimulation. We were also not able to detect any significant BOLD changes after tPBM (at any echo or t-PBM dose).
Conclusion(s): We found a U-shaped, dose-dependent effect of t-PBM on the BOLD, with the medium dose leading to an increase in the hemodynamic effect. These findings suggest that specific parameters of t-PBM (total energy, irradiance, CW versus PW) modulate the effect of near-infrared light on cerebral blood flow. This is important, as t-PBM doses optimized for their hemodynamic effect might also offer superior clinical efficacy

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation approach in which low level currents are administered over the scalp to influence underlying brain function. Prevailing theories of tDCS focus on modulation of excitation-inhibition balance at the local stimulation location. However, network level effects are reported as well, and appear to depend upon differential underlying mechanisms. Here, we evaluated potential network-level effects of tDCS during the Serial Reaction Time Task (SRTT) using convergent EEG- and fMRI-based connectivity approaches. Motor learning manifested as a significant (p<.0001) shift from slow to fast responses and corresponded to a significant increase in beta-coherence (p<.0001) and fMRI connectivity (p<.01) particularly within the visual-motor pathway. Differential patterns of tDCS effect were observed within different parametric task versions, consistent with network models. Overall, these findings demonstrate objective physiological effects of tDCS at the network level that result in effective behavioral modulation when tDCS parameters are matched to network-level requirements of the underlying task.

BACKGROUND:Problem solving therapy (PST) and "Engage," a reward-exposure" based therapy, are important treatment options for late-life depression, given modest efficacy of antidepressants in this disorder. Abnormal function of the reward and default mode networks has been observed during depressive episodes. This study examined whether resting state functional connectivity (rsFC) of reward and DMN circuitries is associated with treatment outcomes. METHODS:Thirty-two older adults with major depression (mean age = 72.7) were randomized to 9-weeks of either PST or "Engage." We assessed rsFC at baseline and week 6. We placed seeds in three a priori regions of interest: subgenual anterior cingulate cortex (sgACC), dorsal anterior cingulate cortex (dACC), and nucleus accumbens (NAcc). Outcome measures included the Hamilton Depression Rating Scale (HAMD) and the Behavioral Activation for Depression Scale (BADS). RESULTS:In both PST and "Engage," higher rsFC between the sgACC and middle temporal gyrus at baseline was associated with greater improvement in depression severity (HAMD). Preliminary findings suggested that in "Engage" treated participants, lower rsFC between the dACC and dorsomedial prefrontal cortex at baseline was associated with HAMD improvement. Finally, in Engage only, increased rsFC from baseline to week 6 between NAcc and Superior Parietal Cortex was associated with increased BADS scores. CONCLUSION/CONCLUSIONS:The results suggest that patients who present with higher rsFC between the sgACC and a structure within the DMN may benefit from behavioral psychotherapies for late life depression. "Engage" may lead to increased rsFC within the reward system reflecting a reconditioning of the reward systems by reward exposure.

Importance/UNASSIGNED:Prescriptions for antipsychotic medications continue to increase across many brain disorders, including off-label use in children and elderly individuals. Concerning animal and uncontrolled human data suggest antipsychotics are associated with change in brain structure, but to our knowledge, there are no controlled human studies that have yet addressed this question. Objective/UNASSIGNED:To assess the effects of antipsychotics on brain structure in humans. Design, Setting, and Participants/UNASSIGNED:Prespecified secondary analysis of a double-blind, randomized, placebo-controlled trial over a 36-week period at 5 academic centers. All participants, aged 18 to 85 years, were recruited from the multicenter Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II). All participants had major depressive disorder with psychotic features (psychotic depression) and were prescribed olanzapine and sertraline for a period of 12 to 20 weeks, which included 8 weeks of remission of psychosis and remission/near remission of depression. Participants were then were randomized to continue receiving this regimen or to be switched to placebo and sertraline for a subsequent 36-week period. Data were analyzed between October 2018 and February 2019. Interventions/UNASSIGNED:Those who consented to the imaging study completed a magnetic resonance imaging (MRI) scan at the time of randomization and a second MRI scan at the end of the 36-week period or at time of relapse. Main Outcomes and Measures/UNASSIGNED:The primary outcome measure was cortical thickness in gray matter and the secondary outcome measure was microstructural integrity of white matter. Results/UNASSIGNED:Eighty-eight participants (age range, 18-85 years) completed a baseline scan; 75 completed a follow-up scan, of which 72 (32 men and 40 women) were useable for final analyses. There was a significant treatment-group by time interaction in cortical thickness (left, t = 3.3; P = .001; right, t = 3.6; P < .001) but not surface area. No significant interaction was found for fractional anisotropy, but one for mean diffusivity of the white matter skeleton was present (t = -2.6, P = .01). When the analysis was restricted to those who sustained remission, exposure to olanzapine compared with placebo was associated with significant decreases in cortical thickness in the left hemisphere (β [SE], 0.04 [0.009]; t34.4 = 4.7; P <.001), and the right hemisphere (β [SE], 0.03 [0.009]; t35.1 = 3.6; P <.001). Post hoc analyses showed that those who relapsed receiving placebo experienced decreases in cortical thickness compared with those who sustained remission. Conclusions and Relevance/UNASSIGNED:In this secondary analysis of a randomized clinical trial, antipsychotic medication was shown to change brain structure. This information is important for prescribing in psychiatric conditions where alternatives are present. However, adverse effects of relapse on brain structure support antipsychotic treatment during active illness. Trial Registration/UNASSIGNED:ClinicalTrials.gov Identifier: NCT01427608.

Major depressive disorder with psychotic features (psychotic depression) is a severe disorder. Compared with other psychotic disorders such as schizophrenia, relatively few studies on the neurobiology of psychotic depression have been pursued. Neuroimaging studies investigating psychotic depression have provided evidence for distributed structural brain abnormalities implicating the insular cortex and limbic system. We examined structural brain networks in participants (N = 245) using magnetic resonance imaging. This sample included healthy controls (n = 159) and the largest cross-sectional sample of patients with remitted psychotic depression (n = 86) collected to date. All patients participated in the Study of Pharmacotherapy of Psychotic Depression II randomized controlled trial. We used a novel, whole-brain, data-driven parcellation technique-non-negative matrix factorization-and applied it to cortical thickness data to derive structural covariance networks. We compared patients with remitted psychotic depression to healthy controls and found that patients had significantly thinner cortex in five structural covariance networks (insular-limbic, occipito-temporal, temporal, parahippocampal-limbic, and inferior fronto-temporal), confirming our hypothesis that affected brain networks would incorporate cortico-limbic regions. We also found that cross-sectional depression and severity scores at the time of scanning were associated with the insular-limbic network. Furthermore, the insular-limbic network predicted future severity scores that were collected at the time of recurrence of psychotic depression or sustained remission. Overall, decreased cortical thickness was found in five structural brain networks in patients with remitted psychotic depression and brain-behavior relationships were observed, particularly between the insular-limbic network and illness severity.