Changes in white matter microstructure following serial ketamine infusions in treatment resistant depression.

Ketamine produces fast-acting antidepressant effects in treatment resistant depression (TRD). Though prior studies report ketamine-related changes in brain activity in TRD, understanding of ketamine's effect on white matter (WM) microstructure remains limited. We thus sought to examine WM neuroplasticity and associated clinical improvements following serial ketamine infusion (SKI) in TRD. TRD patients (N = 57, 49.12% female, mean age: 39.9) received four intravenous ketamine infusions (0.5 mg/kg) 2-3 days apart. Diffusion-weighted scans and clinical assessments (Hamilton Depression Rating Scale [HDRS-17]; Snaith Hamilton Pleasure Scale [SHAPS]) were collected at baseline and 24-h after SKI. WM measures including the neurite density index (NDI) and orientation dispersion index (ODI) from the neurite orientation dispersion and density imaging (NODDI) model, and fractional anisotropy (FA) from the diffusion tensor model were compared voxelwise pre- to post-SKI after using Tract-Based Spatial Statistics workflows to align WM tracts across subjects/time. Correlations between change in WM metrics and clinical measures were subsequently assessed. Following SKI, patients showed significant improvements in HDRS-17 (p-value = 1.8 E-17) and SHAPS (p-value = 1.97 E-10). NDI significantly decreased in occipitotemporal WM pathways (p < .05, FWER/TFCE corrected). ΔSHAPS significantly correlated with ΔNDI in the left internal capsule and left superior longitudinal fasciculus (r = -0.614, p-value = 6.24E-09). No significant changes in ODI or FA were observed. SKI leads to significant changes in the microstructural features of neurites within occipitotemporal tracts, and changes in neurite density within tracts connecting the basal ganglia, thalamus, and cortex relate to improvements in anhedonia. NODDI may be more sensitive for detecting ketamine-induced WM changes than DTI.

Modulation of brain networks during MR-compatible transcranial direct current stimulation.

Transcranial direct current stimulation (tDCS) can influence performance on behavioral tasks and improve symptoms of brain conditions. Yet, it remains unclear precisely how tDCS affects brain function and connectivity. Here, we measured changes in functional connectivity (FC) metrics in blood-oxygenation-level-dependent (BOLD) fMRI data acquired during MR-compatible tDCS in a whole-brain analysis with corrections for false discovery rate. Volunteers (n = 64) received active tDCS, sham tDCS, and rest (no stimulation), using one of three previously established electrode tDCS montages targeting left dorsolateral prefrontal cortex (DLPFC, n = 37), lateral temporoparietal area (LTA, n = 16), or superior temporal cortex (STC, n = 11). In brain networks where simulated E field was highest in each montage, connectivity with remote nodes decreased during active tDCS. During active DLPFC-tDCS, connectivity decreased between a fronto-parietal network and subgenual ACC, while during LTA-tDCS connectivity decreased between an auditory-somatomotor network and frontal operculum. Active DLPFC-tDCS was also associated with increased connectivity within an orbitofrontal network overlapping subgenual ACC. Irrespective of montage, FC metrics increased in sensorimotor and attention regions during both active and sham tDCS, which may reflect the cognitive-perceptual demands of tDCS. Taken together, these results indicate that tDCS may have both intended and unintended effects on ongoing brain activity, stressing the importance of including sham, stimulation-absent, and active comparators in basic science and clinical trials of tDCS.

Developmental trajectories of cerebral blood flow and oxidative metabolism at baseline and during working memory tasks.

The neurobiological interpretation of developmental BOLD fMRI findings remains difficult due to the confounding issues of potentially varied baseline of brain function and varied strength of neurovascular coupling across age groups. The central theme of the present research is to study the development of brain function and neuronal activity through in vivo assessments of cerebral blood flow (CBF), oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) both at baseline and during the performance of a working memory task in a cohort of typically developing children aged 7 to 18years. Using a suite of 4 emerging MRI technologies including MR blood oximetry, phase-contrast MRI, pseudo-continuous arterial spin labeling (pCASL) perfusion MRI and concurrent CBF/BOLD fMRI, we found: 1) At baseline, both global CBF and CMRO2 showed an age related decline while global OEF was stable across the age group; 2) During the working memory task, neither BOLD nor CBF responses showed significant variations with age in the activated fronto-parietal brain regions. Nevertheless, detailed voxel-wise analyses revealed sub-regions within the activated fronto-parietal regions that show significant decline of fractional CMRO2 responses with age. These findings suggest that the brain may become more "energy efficient" with age during development.

Assessing intracranial vascular compliance using dynamic arterial spin labeling.

Vascular compliance (VC) is an important marker for a number of cardiovascular diseases and dementia, which is typically assessed in the central and peripheral arteries indirectly by quantifying pulse wave velocity (PWV), and/or pulse pressure waveform. To date, very few methods are available for the quantification of intracranial VC. In the present study, a novel MRI technique for in-vivo assessment of intracranial VC was introduced, where dynamic arterial spin labeling (ASL) scans were synchronized with the systolic and diastolic phases of the cardiac cycle. VC is defined as the ratio of change in arterial cerebral blood volume (ΔCBV) and change in arterial pressure (ΔBP). Intracranial VC was assessed in different vascular components using the proposed dynamic ASL method. Our results show that VC mainly occurs in large arteries, and gradually decreases in small arteries and arterioles. The comparison of intracranial VC between young and elderly subjects shows that aging is accompanied by a reduction of intracranial VC, in good agreement with the literature. Furthermore, a positive association between intracranial VC and cerebral perfusion measured using pseudo-continuous ASL with 3D GRASE MRI was observed independent of aging effects, suggesting loss of VC is associated with a decline in perfusion. Finally, a significant positive correlation between intracranial and central (aortic arch) VC was observed using an ungated phase-contrast 1D projection PWV technique. The proposed dynamic ASL method offers a promising approach for assessing intracranial VC in a range of cardiovascular diseases and dementia.

Transcranial direct current stimulation (tDCS) in depression induces structural plasticity.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique involving administration of well-tolerated electrical current to the brain through scalp electrodes. TDCS may improve symptoms in neuropsychiatric disorders, but mixed results from recent clinical trials underscore the need to demonstrate that tDCS can modulate clinically relevant brain systems over time in patients. Here, we analyzed longitudinal structural MRI data from a randomized, double-blind, parallel-design clinical trial in depression (NCT03556124, N = 59) to investigate whether serial tDCS individually targeted to the left dorso-lateral prefrontal cortex (DLPFC) can induce neurostructural changes. Significant (FWEc p < 0.05) treatment-related gray matter changes were observed with active high-definition (HD) tDCS relative to sham tDCS within the left DLPFC stimulation target. No changes were observed with active conventional tDCS. A follow-up analysis within individual treatment groups revealed significant gray matter increases with active HD-tDCS in brain regions functionally connected with the stimulation target, including the bilateral DLPFC, bilateral posterior cingulate cortex, subgenual anterior cingulate cortex, and the right hippocampus, thalamus and left caudate brain regions. Integrity of blinding was verified, no significant differences in stimulation-related discomfort were observed between treatment groups, and tDCS treatments were not augmented by any other adjunct treatments. Overall, these results demonstrate that serial HD-tDCS leads to neurostructural changes at a predetermined brain target in depression and suggest that such plasticity effects may propagate over brain networks.

A novel technique for accurate electrode placement over cortical targets for transcranial electrical stimulation (tES) clinical trials.

Objective. We present an easy-to-implement technique for accurate electrode placement over repeated transcranial electrical stimulation (tES) sessions across participants and time. tES is an emerging, non-invasive neuromodulation technique that delivers electrical stimulation using scalp electrodes.Approach.The tES electrode placement technique was developed during an exploratory clinical trial aimed at targeting a specific MNI-atlas cortical coordinate inN= 59 depressed participants (32 F, mean age: 31.1 ± 8.3 SD). Each participant completed 12 sessions of active or sham stimulation, administered using high-definition (HD) or conventional sized electrode montages placed according to the proposed technique. Neuronavigation data measuring the distances between the identified and the intended stimulation site, simulations, and cerebral blood flow (CBF) data at baseline and post-treatment were acquired to evaluate the targeting characteristics of the proposed technique.Main results.Neuronavigation measurements indicate accurate electrode placement to within 1 cm of the stimulation target on average across repeated sessions. Simulations predict that these placement characteristics result in minimal electric field differences at the stimulation target (>0.90 correlation, and <10% change in the modal electric field and targeted volume). Additionally, significant changes in %CBF (relative to baseline) under the stimulation target in the active stimulation group relative to sham confirmed that the proposed placement technique introduces minimal bias in the spatial location of the cortical coordinate ultimately targeted. Finally, we show proof of concept that the proposed technique provides similar accuracy of electrode placement at other cortical targets.Significance.For voxel-level cortical targets, existing techniques based on cranial landmarks are suboptimal. Our results show that the proposed electrode placement approach provides high consistency for the accurate targeting of such specific cortical regions. Overall, the proposed technique now enables the accurate targeting of locations not accessible with the existing 10-20 system such as scalp-projections of clinically-relevant cortical coordinates identified by brain mapping studies. Clinical trial ID: NCT03556124.

In-vivo imaging of targeting and modulation of depression-relevant circuitry by transcranial direct current stimulation: a randomized clinical trial.

Recent clinical trials of transcranial direct current stimulation (tDCS) in depression have shown contrasting results. Consequently, we used in-vivo neuroimaging to confirm targeting and modulation of depression-relevant neural circuitry by tDCS. Depressed participants (N = 66, Baseline Hamilton Depression Rating Scale (HDRS) 17-item scores ≥14 and <24) were randomized into Active/Sham and High-definition (HD)/Conventional (Conv) tDCS groups using a double-blind, parallel design, and received tDCS individually targeted at the left dorsolateral prefrontal cortex (DLPFC). In accordance with Ampere's Law, tDCS currents were hypothesized to induce magnetic fields at the stimulation-target, measured in real-time using dual-echo echo-planar-imaging (DE-EPI) MRI. Additionally, the tDCS treatment trial (consisting of 12 daily 20-min sessions) was hypothesized to induce cerebral blood flow (CBF) changes post-treatment at the DLPFC target and in the reciprocally connected anterior cingulate cortex (ACC), measured using pseudo-continuous arterial spin labeling (pCASL) MRI. Significant tDCS current-induced magnetic fields were observed at the left DLPFC target for both active stimulation montages (Brodmann's area (BA) 46: pHD = 0.048, Cohen's dHD = 0.73; pConv = 0.018, dConv = 0.86; BA 9: pHD = 0.011, dHD = 0.92; pConv = 0.022, dConv = 0.83). Significant longitudinal CBF increases were observed (a) at the left DLPFC stimulation-target for both active montages (pHD = 3.5E-3, dHD = 0.98; pConv = 2.8E-3, dConv = 1.08), and (b) at ACC for the HD-montage only (pHD = 2.4E-3, dHD = 1.06; pConv = 0.075, dConv = 0.64). These results confirm that tDCS-treatment (a) engages the stimulation-target, and (b) modulates depression-relevant neural circuitry in depressed participants, with stronger network-modulations induced by the HD-montage. Although not primary outcomes, active HD-tDCS showed significant improvements of anhedonia relative to sham, though HDRS scores did not differ significantly between montages post-treatment.

Concurrent Imaging of Markers of Current Flow and Neurophysiological Changes During tDCS.

Despite being a popular neuromodulation technique, clinical translation of transcranial direct current stimulation (tDCS) is hampered by variable responses observed within treatment cohorts. Addressing this challenge has been difficult due to the lack of an effective means of mapping the neuromodulatory electromagnetic fields together with the brain's response. In this study, we present a novel imaging technique that provides the capability of concurrently mapping markers of tDCS currents, as well as the brain's response to tDCS. A dual-echo echo-planar imaging (DE-EPI) sequence is used, wherein the phase of the acquired MRI-signal encodes the tDCS current induced magnetic field, while the magnitude encodes the blood oxygenation level dependent (BOLD) contrast. The proposed technique was first validated in a custom designed phantom. Subsequent test-retest experiments in human participants showed that tDCS-induced magnetic fields can be detected reliably in vivo. The concurrently acquired BOLD data revealed large-scale networks characteristic of a brain in resting-state as well as a 'cathodal' and an 'anodal' resting-state component under each electrode. Moreover, 'cathodal's BOLD-signal was observed to significantly decrease with the applied current at the group level in all datasets. With its ability to image markers of electromagnetic cause as well as neurophysiological changes, the proposed technique may provide an effective means to visualize neural engagement in tDCS at the group level. Our technique also contributes to addressing confounding factors in applying BOLD fMRI concurrently with tDCS.

A review of transcranial direct current stimulation (tDCS) for the individualized treatment of depressive symptoms.

Transcranial direct current stimulation (tDCS) is a low intensity neuromodulation technique shown to elicit therapeutic effects in a number of neuropsychological conditions. Independent randomized sham-controlled trials and meta- and mega-analyses demonstrate that tDCS targeted to the left dorsolateral prefrontal cortex can produce a clinically meaningful response in patients with major depressive disorder (MDD), but effects are small to moderate in size. However, the heterogeneous presentation, and the neurobiology underlying particular features of depression suggest clinical outcomes might benefit from empirically informed patient selection. In this review, we summarize the status of tDCS research in MDD with focus on the clinical, biological, and intrinsic and extrinsic factors shown to enhance or predict antidepressant response. We also discuss research strategies for optimizing tDCS to improve patient-specific clinical outcomes. TDCS appears suited for both bipolar and unipolar depression, but is less effective in treatment resistant depression. TDCS may also better target core aspects of depressed mood over vegetative symptoms, while pretreatment patient characteristics might inform subsequent response. Peripheral blood markers of gene and immune system function have not yet proven useful as predictors or correlates of tDCS response. Though further research is needed, several lines of evidence suggest that tDCS administered in combination with pharmacological and cognitive behavioral interventions can improve outcomes. Tailoring stimulation to the functional and structural anatomy and/or connectivity of individual patients can maximize physiological response in targeted networks, which in turn could translate to therapeutic benefits.

Differences in high-definition transcranial direct current stimulation over the motor hotspot versus the premotor cortex on motor network excitability.

The effectiveness of transcranial direct current stimulation (tDCS) placed over the motor hotspot (thought to represent the primary motor cortex (M1)) to modulate motor network excitability is highly variable. The premotor cortex-particularly the dorsal premotor cortex (PMd)-may be a promising alternative target to reliably modulate motor excitability, as it influences motor control across multiple pathways, one independent of M1 and one with direct connections to M1. This double-blind, placebo-controlled preliminary study aimed to differentially excite motor and premotor regions using high-definition tDCS (HD-tDCS) with concurrent functional magnetic resonance imaging (fMRI). HD-tDCS applied over either the motor hotspot or the premotor cortex demonstrated high inter-individual variability in changes on cortical motor excitability. However, HD-tDCS over the premotor cortex led to a higher number of responders and greater changes in local fMRI-based complexity than HD-tDCS over the motor hotspot. Furthermore, an analysis of individual motor hotspot anatomical locations revealed that, in more than half of the participants, the motor hotspot is not located over anatomical M1 boundaries, despite using a canonical definition of the motor hotspot. This heterogeneity in stimulation site may contribute to the variability of tDCS results. Altogether, these preliminary findings provide new considerations to enhance tDCS reliability.

In-vivo Imaging of Magnetic Fields Induced by Transcranial Direct Current Stimulation (tDCS) in Human Brain using MRI.

Transcranial direct current stimulation (tDCS) is an emerging non-invasive neuromodulation technique that applies mA currents at the scalp to modulate cortical excitability. Here, we present a novel magnetic resonance imaging (MRI) technique, which detects magnetic fields induced by tDCS currents. This technique is based on Ampere's law and exploits the linear relationship between direct current and induced magnetic fields. Following validation on a phantom with a known path of electric current and induced magnetic field, the proposed MRI technique was applied to a human limb (to demonstrate in-vivo feasibility using simple biological tissue) and human heads (to demonstrate feasibility in standard tDCS applications). The results show that the proposed technique detects tDCS induced magnetic fields as small as a nanotesla at millimeter spatial resolution. Through measurements of magnetic fields linearly proportional to the applied tDCS current, our approach opens a new avenue for direct in-vivo visualization of tDCS target engagement.

The pediatric template of brain perfusion.

Magnetic resonance imaging (MRI) captures the dynamics of brain development with multiple modalities that quantify both structure and function. These measurements may yield valuable insights into the neural patterns that mark healthy maturation or that identify early risk for psychiatric disorder. The Pediatric Template of Brain Perfusion (PTBP) is a free and public neuroimaging resource that will help accelerate the understanding of childhood brain development as seen through the lens of multiple modality neuroimaging and in relation to cognitive and environmental factors. The PTBP uses cross-sectional and longitudinal MRI to quantify cortex, white matter, resting state functional connectivity and brain perfusion, as measured by Arterial Spin Labeling (ASL), in 120 children 7-18 years of age. We describe the PTBP and show, as a demonstration of validity, that global summary measurements capture the trajectories that demarcate critical turning points in brain maturation. This novel resource will allow a more detailed understanding of the network-level, structural and functional landmarks that are obtained during normal adolescent brain development.

Regional correlation between resting state FDG PET and pCASL perfusion MRI.

To determine how arterial spin labeling (ASL) measured perfusion relates to baseline metabolism, we compared resting state cerebral perfusion using pseudo-continuous ASL and cerebral glucose metabolism using (18)F-FDG PET in 20 normal volunteers. Greater regional metabolism relative to perfusion was observed in the putamen, orbitofrontal and temporal lobes, whereas perfusion was relatively higher in the hippocampus and insula. In a region of interest analysis limited to gray matter, the overall mean correlation between perfusion and metabolism across voxels was r=0.43 with considerable regional variability. Cross-voxel correlations between relative perfusion and metabolism in mean ASL and PET images of all 20 subjects were the highest in the striatum (caudate: r=0.78; putamen: r=0.81), and the lowest in medial temporal structures (amygdala: r=0.087; hippocampus: r=-0.26). Correlations between mean relative perfusion and metabolism across 20 subjects were the highest in the striatum (caudate: r=0.76; putamen: r=0.58), temporal lobe (r=0.59), and frontal lobe (r=0.52), but very poor in all other structures (r<0.3), particularly in caudal structures such as the hippocampus (r=-0.0026), amygdala (r=0.18), and insula (r=0.14). Although there was good overall correlation between perfusion and glucose metabolism, regional variability should be considered when using either ASL or (18)F-FDG PET as surrogate markers for neural activity.