Faculty Bibliography

OBJECTIVE:White matter hyperintensities (WMH) are linked to deficits in cognitive functioning, including cognitive control and memory; however, the structural, and functional mechanisms are largely unknown. We investigated the relationship between estimated regional disruptions to white matter fiber tracts from WMH, resting state functional connectivity (RSFC), and cognitive functions in older adults. DESIGN/METHODS:Cross-sectional study. SETTING/METHODS:Community. PARTICIPANTS/METHODS:Fifty-eight cognitively-healthy older adults. MEASUREMENTS/METHODS:Tasks of cognitive control and memory, structural MRI, and resting state fMRI. We estimated the disruption to white matter fiber tracts from WMH and its impact on gray matter regions in the cortical and subcortical frontoparietal network, default mode network, and ventral attention network by overlaying each subject's WMH mask on a normative tractogram dataset. We calculated RSFC between nodes in those same networks. We evaluated the interaction of regional WMH burden and RSFC in predicting cognitive control and memory. RESULTS:The interaction of estimated regional WMH burden and RSFC in cortico-striatal regions of the default mode network and frontoparietal network was associated with delayed recall. Models predicting working memory, cognitive inhibition, and set-shifting were not significant. CONCLUSION/CONCLUSIONS:Findings highlight the role of network-level structural and functional alterations in resting state networks that are related to WMH and impact memory in older adults.

Neuroimaging features of small vessel disease (SVD) are highly prevalent in older adulthood and associated with significant variability in clinical symptoms, yet the factors predicting these symptom disparities are poorly understood. We employed a novel metric of SVD, peak width of skeletonized mean diffusivity (PSMD), to elucidate the relationship of late-life depression (LLD) to the cognitive presentation of vascular pathology. A total of 109 older adults without a diagnosis of a neurocognitive disorder were enrolled in the study; 44 with major depressive disorder and 65 age-matched controls. Subjects completed neuropsychological testing and magnetic resonance imaging including FLAIR and diffusion tensor imaging sequences, from which white matter hyperintensity volume and diffusion metrics (fractional anisotropy, mean diffusivity, PSMD) were quantified. In hierarchical models, the relationship between vascular burden and cognitive performance varied as a function of diagnostic status, such that the negative association between PSMD and processing speed was significantly stronger in participants with LLD compared to controls. Greater PSMD also predicted poorer performance on delayed memory and executive function tasks specifically among those with LLD, while there were no associations between PSMD and task performance among controls. PSMD outperformed conventional SVD and diffusion markers in predicting cognitive performance and dysexecutive behaviors in participants with LLD. These data suggest that LLD may confer a vulnerability to the cognitive manifestations of white matter abnormalities in older adulthood. PSMD, a novel biomarker of diffuse microstructural changes in SVD, may be a more sensitive marker of subtle cognitive deficits stemming from vascular pathology in LLD.

Over the past century, advancements in psychiatric treatments have freed countless individuals from the burden of life-long, incapacitating mental illness. These treatments have largely been discovered by chance. Theory has driven advancement in the natural sciences and other branches of medicine, but psychiatry remains a field in its "infancy". The targets for healing in psychiatry lie within the realm of the mind's subjective experience and thought, which we cannot yet describe in terms of their biological underpinnings in the brain. Our technology is sufficiently advanced to study brain neurons and their interactions on an electrophysiological and molecular level, but we cannot say how these form a single feeling or thought. While psychiatry waits for its "Copernican Revolution", we continue the work in developing theories and associated experiments based on our existing diagnostic systems, for example, the Diagnostic and Statistical Manual of Mental Disorders (DSM), International Classification of Diseases (ICD), or the more newly introduced Research Domain Criteria (RDoC) framework. Understanding the subjective reality of the mind in biological terms would doubtless lead to huge advances in psychiatry, as well as to ethical dilemmas, from which we are spared for the time being.

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

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.

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: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.

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.

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.