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OBJECTIVE Report pilot findings of neurobehavioral gains and network changes observed in persons with disordered consciousness (DoC) who received repetitive transcranial magnetic stimulation (rTMS) or amantadine (AMA), and then rTMS+AMA. PARTICIPANTS Four persons with DoC 1 to 15 years after traumatic brain injury (TBI). DESIGN Alternate treatment-order, within-subject, baseline-controlled trial. MAIN MEASURES For group and individual neurobehavioral analyses, predetermined thresholds, based on mixed linear-effects models and conditional minimally detectable change, were used to define meaningful neurobehavioral change for the Disorders of Consciousness Scale-25 (DOCS) total and Auditory-Language measures. Resting-state functional connectivity (rsFC) of the default mode and 6 other networks was examined. RESULTS Meaningful gains in DOCS total measures were observed for 75% of treatment segments and auditory-language gains were observed after rTMS, which doubled when rTMS preceded rTMS+AMA. Neurobehavioral changes were reflected in rsFC for language, salience, and sensorimotor networks. Between networks interactions were modulated, globally, after all treatments. CONCLUSIONS For persons with DoC 1 to 15 years after TBI, meaningful neurobehavioral gains were observed after provision of rTMS, AMA, and rTMS+AMA. Sequencing and combining of treatments to modulate broad-scale neural activity, via differing mechanisms, merits investigation in a future study powered to determine efficacy of this approach to enabling neurobehavioral recovery.

Optimizing transcranial magnetic stimulation (TMS) treatments in traumatic brain injury (TBI) and co-occurring conditions may benefit from neuroimaging-based customization. PARTICIPANTS Our total sample (N = 97) included 58 individuals with TBI (49 mild, 8 moderate, and 1 severe in a state of disordered consciousness), of which 24 had co-occurring conditions (depression in 14 and alcohol use disorder in 10). Of those without TBI, 6 individuals had alcohol use disorder and 33 were healthy controls. Of our total sample, 54 were veterans and 43 were civilians. DESIGN Proof-of-concept study incorporating data from 5 analyses/studies that used multimodal approaches to integrate neuroimaging with TMS. MAIN MEASURES Multimodal neuroimaging methods including structural magnetic resonance imaging (MRI), MRI-guided TMS navigation, functional MRI, diffusion MRI, and TMS-induced electric fields. Outcomes included symptom scales, neuropsychological tests, and physiological measures. RESULTS It is feasible to use multimodal neuroimaging data to customize TMS targets and understand brain-based changes in targeted networks among people with TBI. CONCLUSIONS TBI is an anatomically heterogeneous disorder. Preliminary evidence from the 5 studies suggests that using multimodal neuroimaging approaches to customize TMS treatment is feasible. To test whether this will lead to increased clinical efficacy, studies that integrate neuroimaging and TMS targeting data with outcomes are needed.

For people with disordered consciousness (DoC) after traumatic brain injury (TBI), relationships between treatment-induced changes in neural connectivity and neurobehavioral recovery have not been explored. To begin building a body of evidence regarding the unique contributions of treatments to changes in neural network connectivity relative to neurobehavioral recovery, we conducted a pilot study to identify relationships meriting additional examination in future research. To address this objective, we examined previously unpublished neural connectivity data derived from a randomized clinical trial (RCT). We leveraged these data because treatment efficacy, in the RCT, was based on a comparison of a placebo control with a specific intervention, the familiar auditory sensory training (FAST) intervention, consisting of autobiographical auditory-linguistic stimuli. We selected a subgroup of RCT participants with high-quality imaging data (FAST n = 4 and placebo n = 4) to examine treatment-related changes in brain network connectivity and how and if these changes relate to neurobehavioral recovery. To discover promising relationships among the FAST intervention, changes in neural connectivity, and neurobehavioral recovery, we examined 26 brain regions and 19 white matter tracts associated with default mode, salience, attention, and language networks, as well as three neurobehavioral measures. Of the relationships discovered, the systematic filtering process yielded evidence supporting further investigation of the relationship among the FAST intervention, connectivity of the left inferior longitudinal fasciculus, and auditory-language skills. Evidence also suggests that future mechanistic research should focus on examining the possibility that the FAST supports connectivity changes by facilitating redistribution of brain resources. For a patient population with limited treatment options, the reported findings suggest that a simple, yet targeted, passive sensory stimulation treatment may have altered functional and structural connectivity. If replicated in future research, then these findings provide the foundation for characterizing the unique contributions of the FAST intervention and could inform development of new treatment strategies. For persons with severely damaged brain networks, this report represents a first step toward advancing understanding of the unique contributions of treatments to changing brain network connectivity and how these changes relate to neurobehavioral recovery for persons with DoC after TBI. Clinical Trial Registry: NCT00557076, The Efficacy of Familiar Voice Stimulation During Coma Recovery (http://www.clinicaltrials.gov).

Research Objectives To explore the relationship between attention/working memory (WM) performance and grey matter volume in the dorsal attention network (DAN), a neural network in the brain that supports encoding and maintenance of external information. Design Observational. Setting Data obtained from the Parkinson's Progression Marker Initiative (PPMI; www.ppmi-info.org ), an international longitudinal multisite study. Participants Participants with persistent WM impairment (n= 10) and persistent normal WM performance (n=10) were compared. WM was measured using the Letter Number Sequencing (LNS) test. Persistent impairment was defined by a standardized test score of 8 or less for 4 consecutive years since baseline imaging. Normal WM performance was defined by a standardized test score of 10 or more for 4 consecutive years since baseline imaging. Groups were matched on sex, age, years of education, and disease duration. Interventions Not Applicable. Main Outcome Measures Grey matter volume was measured using voxel-based morphometry (VBM) through SPM12 and CAT12. Region of interest analysis within the DAN (Schaeffer et al., 2018 100-parcel atlas), was conducted. Whole brain cluster analysis was conducted for confirmatory evidence. Significant clusters within a DAN mask (Schaeffer et al., 2018 100-parcel atlas) are reported with a FDR (p=0.05). Results For ROI analysis, grey matter atrophy in the bilateral visuomotor cortex (p=0.005), bilateral intraparietal sulcus (p=0.04), and right superior parietal lobule (p=0.021) was found in the impaired WM group compared to the normal WM group. Between groups, differences in several clusters within the DAN masks were observed. Conclusions These promising preliminary findings support the notion that changes in grey matter volume within cognitive neural networks, such as the DAN, can be a biomarker for decline in cognitive function, as well as treatment responsiveness in people living with PD. Author(s) Disclosures None.

Congenital amusia is a neurogenetic disorder predominately defined by impaired perception of musical tonal relationships. This study examined amusics’ responses to a gradient of pitch interval complexity in fractal music. Eighteen Mandarin-speaking amusics and 18 controls rated random tone sequences for perceptual (complexity, melodicity) and affective (interest, ease, mood) attributes, and performed a recognition memory task. Sequences were created using fractal model (1/fs) with s-values ranging from 0.0 (most complex) to 2.6 (least complex). As predicted, both groups rated complexity based on the s-values, demonstrating that amusics perceived the gradient of pitch interval complexity. However, amusics’ ratings deviated from controls in measures of melodicity, affect, and memory performance. For controls, moderately complex sequences (fractal s-values =1.4–1.6) were rated the most melodious, drove the highest emotional responses, and were the easiest to remember, whereas amusics’ ratings did not respond to this range, but rather followed a more linear trend. These findings suggest that amusics not only have problems with perception of pitch interval relationships (not complexity), but also lack heightened sensitivity to the moderate range in fractal music. This deficit is reflected in broader musical processing including the perception of melody, affective response, and memory for musical sequences. [This work was supported by National Science Foundation Grant BCS-0719666 to P.C.M.W. and Shanghai Normal University funding to C.J.]