The practice of "microdosing", or the use of repeated, very low doses of LSD to improve mood or cognition, has received considerable public attention, but empirical studies are lacking. Controlled studies are needed to investigate both the therapeutic potential and the neurobiological underpinnings of this pharmacologic treatment. Methods. The present study was designed to examine the effects of a single low dose of LSD (13 micrograms) vs placebo on resting-state functional connectivity and cerebral blood flow in healthy young adults. Twenty men and women, aged 18-35, participated in two fMRI scanning sessions in which they received placebo or LSD under double-blind conditions. During each session, the participants completed drug effect and mood questionnaires, and physiological measures were recorded. During expected peak drug effect, they underwent resting-state BOLD and ASL scans. Cerebral blood flow as well as amygdala and thalamic connectivity were analyzed. Results. LSD increased amygdala seed-based connectivity with the right angular gyrus, right middle frontal gyrus, and the cerebellum, and decreased amygdala connectivity with the left and right postcentral gyrus and the superior temporal gyrus. This low dose of LSD had weak and variable effects on mood, but its effects on positive mood were positively correlated with the increase in amygdala -middle frontal gyrus connectivity strength. Conclusions. These preliminary findings show that a very low dose of LSD, which produces negligible subjective changes, alters brain connectivity in limbic circuits. Additional studies, especially with repeated dosing, will reveal whether these neural changes are related to the drug's purported antidepressant effect. NCT03790358

Sensory processing dysfunction (SPD) is characterized by a behaviorally observed difference in the response to sensory information from the environment. While the cerebellum is involved in normal sensory processing, it has not yet been examined in SPD. Diffusion tensor imaging scans of children with SPD (n = 42) and typically developing controls (TDC; n = 39) were compared for fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) across the following cerebellar tracts: the middle cerebellar peduncles (MCP), superior cerebellar peduncles (SCP), and cerebral peduncles (CP). Compared to TDC, children with SPD show reduced microstructural integrity of the SCP and MCP, characterized by reduced FA and increased MD and RD, which correlates with abnormal auditory behavior, multisensory integration, and attention, but not tactile behavior or direct measures of auditory discrimination. In contradistinction, decreased CP microstructural integrity in SPD correlates with abnormal tactile and auditory behavior and direct measures of auditory discrimination, but not multisensory integration or attention. Hence, altered cerebellar white matter organization is associated with complex sensory behavior and attention in SPD, which prompts further consideration of diagnostic measures and treatments to better serve affected individuals.

Diffusion tensor imaging (DTI) literature on single-center studies contains conflicting results regarding acute effects of mild traumatic brain injury (mTBI) on white matter (WM) microstructure and the prognostic significance. This larger-scale multi-center DTI study aimed to determine how acute mTBI affects WM microstructure over time and how early WM changes affect long-term outcome. From Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI), a cohort study at 11 United States level 1 trauma centers, a total of 391 patients with acute mTBI ages 17 to 60 years were included and studied at two weeks and six months post-injury. Demographically matched friends or family of the participants were the control group ( n = 148). Axial diffusivity (AD), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were the measures of WM microstructure. The primary outcome was the Glasgow Outcome Scale Extended (GOSE) score of injury-related functional limitations across broad life domains at six months post-injury. The AD, MD, and RD were higher and FA was lower in mTBI versus friend control (FC) at both two weeks and six months post-injury throughout most major WM tracts of the cerebral hemispheres. In the mTBI group, AD and, to a lesser extent, MD decreased in WM from two weeks to six months post-injury. At two weeks post-injury, global WM AD and MD were both independently associated with six-month incomplete recovery (GOSE <8 vs = 8) even after accounting for demographic, clinical, and other imaging factors. DTI provides reliable imaging biomarkers of dynamic WM microstructural changes after mTBI that have utility for patient selection and treatment response in clinical trials. Continued technological advances in the sensitivity, specificity, and precision of diffusion magnetic resonance imaging hold promise for routine clinical application in mTBI.

Diffusion tensor imaging (DTI) studies have demonstrated white matter microstructural differences between the left and right hemispheres of the brain. However, the basis of these hemispheric asymmetries is not yet understood in terms of the biophysical properties of white matter microstructure, especially in children. There are reports of altered hemispheric white matter lateralization in ASD; however, this has not been studied in other related neurodevelopmental disorders such as sensory processing disorder (SPD). Firstly, we postulate that biophysical compartment modeling of diffusion MRI (dMRI), such as Neurite Orientation Dispersion and Density Imaging (NODDI), can elucidate the hemispheric microstructural asymmetries observed from DTI in children with neurodevelopmental concerns. Secondly, we hypothesize that sensory over-responsivity (SOR), a common type of SPD, will show altered hemispheric lateralization relative to children without SOR. Eighty-seven children (29 females, 58 males), ages 8–12 years, presenting at a community-based neurodevelopmental clinic were enrolled, 48 with SOR and 39 without. Participants were evaluated using the Sensory Processing 3 Dimensions (SP3D). Whole brain 3 T multi-shell multiband dMRI (b = 0, 1,000, 2,500 s/mm2) was performed. Tract Based Spatial Statistics were used to extract DTI and NODDI metrics from 20 bilateral tracts of the Johns Hopkins University White-Matter Tractography Atlas and the lateralization Index (LI) was calculated for each left–right tract pair. With DTI metrics, 12 of 20 tracts were left lateralized for fractional anisotropy and 17/20 tracts were right lateralized for axial diffusivity. These hemispheric asymmetries could be explained by NODDI metrics, including neurite density index (18/20 tracts left lateralized), orientation dispersion index (15/20 tracts left lateralized) and free water fraction (16/20 tracts lateralized). Children with SOR served as a test case of the utility of studying LI in neurodevelopmental disorders. Our data demonstrated increased lateralization in several tracts for both DTI and NODDI metrics in children with SOR, which were distinct for males versus females, when compared to children without SOR. Biophysical properties from NODDI can explain the hemispheric lateralization of white matter microstructure in children. As a patient-specific ratio, the lateralization index can eliminate scanner-related and inter-individual sources of variability and thus potentially serve as a clinically useful imaging biomarker for neurodevelopmental disorders.

Sensory processing dysfunction (SPD) is characterized by a behaviorally observed difference in the response to sensory information from the environment. While the cerebellum is involved in normal sensory processing, it has not yet been examined in SPD. Diffusion tensor imaging scans of children with SPD (n=42) and typically developing controls (TDC; n=39) were compared for fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD) across the following cerebellar tracts: the middle cerebellar peduncles (MCP), superior cerebellar peduncles (SCP), and cerebral peduncles (CP). Compared to TDC, children with SPD show reduced microstructural integrity of the SCP and MCP, which correlates with abnormal auditory behavior, multisensory integration, and attention, but not tactile behavior or direct measures of auditory discrimination. In contradistinction, decreased CP microstructural integrity in SPD correlates with abnormal tactile and auditory behavior and direct measures of auditory discrimination, but not multisensory integration or attention. Hence, altered cerebellar white matter organization is associated with complex sensory behavior and attention in SPD, which prompts further consideration of diagnostic measures and treatments to better serve affected individuals.