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Gilman, J. M., W. A. Schmitt, K. Potter, B. Kendzior, G. N. Pachas, S. Hickey, M. Makary, M. A. Huestis, and E. A. Evins, "Correction to: Identification of ∆9-tetrahydrocannabinol (THC) impairment using functional brain imaging.", Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, vol. 47, issue 6, pp. 1282, 2022.
Gilman, J. M., W. A. Schmitt, K. Potter, B. Kendzior, G. N. Pachas, S. Hickey, M. Makary, M. A. Huestis, and E. A. Evins, "Identification of ∆9-tetrahydrocannabinol (THC) impairment using functional brain imaging.", Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, vol. 47, issue 4, pp. 944-952, 2022. Abstract

The primary cannabinoid in cannabis, Δ9-tetrahydrocannabinol (THC), causes intoxication and impaired function, with implications for traffic, workplace, and other situational safety risks. There are currently no evidence-based methods to detect cannabis-impaired driving, and current field sobriety tests with gold-standard, drug recognition evaluations are resource-intensive and may be prone to bias. This study evaluated the capability of a simple, portable imaging method to accurately detect individuals with THC impairment. In this double-blind, randomized, cross-over study, 169 cannabis users, aged 18-55 years, underwent functional near-infrared spectroscopy (fNIRS) before and after receiving oral THC and placebo, at study visits one week apart. Impairment was defined by convergent classification by consensus clinical ratings and an algorithm based on post-dose tachycardia and self-rated "high." Our primary outcome, prefrontal cortex (PFC) oxygenated hemoglobin concentration (HbO), was increased after THC only in participants operationalized as impaired, independent of THC dose. ML models using fNIRS time course features and connectivity matrices identified impairment with 76.4% accuracy, 69.8% positive predictive value (PPV), and 10% false-positive rate using convergent classification as ground truth, which exceeded Drug Recognition Evaluator-conducted expanded field sobriety examination (67.8% accuracy, 35.4% PPV, and 35.4% false-positive rate). These findings demonstrate that PFC response activation patterns and connectivity produce a neural signature of impairment, and that PFC signal, measured with fNIRS, can be used as a sole input to ML models to objectively determine impairment from THC intoxication at the individual level. Future work is warranted to determine the specificity of this classifier to acute THC Identifier: NCT03655717.

Housman, H., L. Brusaferri, M. Datko, S. Tohyama, K. Round, R. G. G. Gomez, R. L. Gollub, R. R. Edwards, M. Makary, B. R. Rosen, et al., "In Vivo Molecular Imaging of Neuroinflammation in Patients with Migraine", The Journal of Pain, vol. 23, issue 5, pp. 44, 2022.
Brusaferri, L., Z. Alshelh, D. Martins, M. Kim, A. Weerasekera, H. Housman, E. J. Morrissey, P. C. Knight, K. A. Castro-Blanco, D. S. Albrecht, et al., "The pandemic brain: Neuroinflammation in non-infected individuals during the COVID-19 pandemic.", Brain, behavior, and immunity, vol. 102, pp. 89-97, 2022. Abstract

While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other "sickness behavior"-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven 'Pre-Pandemic' and fifteen 'Pandemic' datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.

Murray, K., Y. Lin, M. M. Makary, P. G. Whang, and P. Geha, "Brain Structure and Function of Chronic Low Back Pain Patients on Long-Term Opioid Analgesic Treatment: A Preliminary Study.", Molecular pain, vol. 17, pp. 1744806921990938, 2021. Abstract

Chronic low back pain (CLBP) is often treated with opioid analgesics (OA), a class of medications associated with a significant risk of misuse. However, little is known about how treatment with OA affect the brain in chronic pain patients. Gaining this knowledge is a necessary first step towards understanding OA associated analgesia and elucidating long-term risk of OA misuse. Here we study CLBP patients chronically medicated with opioids without any evidence of misuse and compare them to CLBP patients not on opioids and to healthy controls using structural and functional brain imaging. CLBP patients medicated with OA showed loss of volume in the nucleus accumbens and thalamus, and an overall significant decrease in signal to noise ratio in their sub-cortical areas. Power spectral density analysis (PSD) of frequency content in the accumbens' resting state activity revealed that both medicated and unmedicated patients showed loss of PSD within the slow-5 frequency band (0.01-0.027 Hz) while only CLBP patients on OA showed additional density loss within the slow-4 frequency band (0.027-0.073 Hz). We conclude that chronic treatment with OA is associated with altered brain structure and function within sensory limbic areas.

Makary, M. M., A. Weerasekara, H. Rodham, B. G. Hightower, C. - E. J. Tseng, J. Chan, S. Chew, S. Paganoni, E. - M. Ratai, N. R. Zürcher, et al., "Comparison of Two Clinical Upper Motor Neuron Burden Rating Scales in ALS Using Quantitative Brain Imaging.", ACS chemical neuroscience, vol. 12, issue 5, pp. 906-916, 2021. Abstract

Several clinical upper motor neuron burden scales (UMNSs) variably measure brain dysfunction in amyotrophic lateral sclerosis (ALS). Here, we compare relationship of two widely used clinical UMNSs in ALS (Penn and MGH UMNSs) with (a) neuroimaging markers of brain dysfunction and (b) neurological impairment status using the gold-standard functional measure, the revised ALS Functional Rating Scale (ALSFRS-R). MGH UMNS measures hyperreflexia alone, and Penn UMNS measures hyperreflexia, spasticity, and pseudobulbar affect. Twenty-eight ALS participants underwent both Penn and MGH UMNSs, at a matching time-point as a simultaneous [C]PBR28 positron emission tomography (PBR28-PET)/Magnetic Resonance scan and ALSFRS-R. The two UMNSs were compared for localization and strength of association with neuroimaging markers of: (a) neuroinflammation, PBR28-PET and MR Spectroscopy metabolites (myo-inositol and choline) and (b) corticospinal axonal loss, fractional anisotropy (FA), and MR Spectroscopy metabolite (-acetylaspartate). Among clinical UMN manifestations, segmental hyperreflexia, spasticity, and pseudobulbar affect occurred in 100, 43, and 18% ALS participants, respectively. Pseudobulbar affect did not map to any specific brain regional dysfunction, while hyperreflexia and spasticity subdomains significantly correlated and colocalized neurobiological changes to corticospinal pathways on whole brain voxel-wise analyses. Both UMNS total scores showed significant and similar strength of association with (a) neuroimaging changes (PBR28-PET, FA, MR Spectroscopy metabolites) in primary motor cortices and (b) severity of functional decline (ALSFRS-R). Hyperreflexia is the most frequent clinical UMN manifestation and correlates best with UMN molecular imaging changes in ALS. Among Penn UMNS's subdomains, hyperreflexia carries the weight of association with neuroimaging markers of biological changes in ALS. A clinical UMN scale comprising hyperreflexia items alone is clinically relevant and sufficient to predict the highest yield of molecular neuroimaging abnormalities in ALS.

Bielczyk, N. Z., A. Ando, A. P. Badhwar, C. Caldinelli, M. Gao, A. Haugg, L. M. Hernandez, K. L. Ito, D. Kessler, D. Lurie, et al., "Effective Self-Management for Early Career Researchers in the Natural and Life Sciences.", Neuron, vol. 106, issue 2, pp. 212-217, 2020. Abstract

Early career researchers (ECRs) are faced with a range of competing pressures in academia, making self-management key to building a successful career. The Organization for Human Brain Mapping undertook a group effort to gather helpful advice for ECRs in self-management.

Makary, M. M., P. Polosecki, G. A. Cecchi, I. E. DeAraujo, D. S. Barron, T. R. Constable, P. G. Whang, D. A. Thomas, H. Mowafi, D. M. Small, et al., "Loss of nucleus accumbens low-frequency fluctuations is a signature of chronic pain.", Proceedings of the National Academy of Sciences of the United States of America, vol. 117, issue 18, pp. 10015-10023, 2020. Abstract

Chronic pain is a highly prevalent disease with poorly understood pathophysiology. In particular, the brain mechanisms mediating the transition from acute to chronic pain remain largely unknown. Here, we identify a subcortical signature of back pain. Specifically, subacute back pain patients who are at risk for developing chronic pain exhibit a smaller nucleus accumbens volume, which persists in the chronic phase, compared to healthy controls. The smaller accumbens volume was also observed in a separate cohort of chronic low-back pain patients and was associated with dynamic changes in functional connectivity. At baseline, subacute back pain patients showed altered local nucleus accumbens connectivity between putative shell and core, irrespective of the risk of transition to chronic pain. At follow-up, connectivity changes were observed between nucleus accumbens and rostral anterior cingulate cortex in the patients with persistent pain. Analysis of the power spectral density of nucleus accumbens resting-state activity in the subacute and chronic back pain patients revealed loss of power in the slow-5 frequency band (0.01 to 0.027 Hz) which developed only in the chronic phase of pain. This loss of power was reproducible across two cohorts of chronic low-back pain patients obtained from different sites and accurately classified chronic low-back pain patients in two additional independent datasets. Our results provide evidence that lower nucleus accumbens volume confers risk for developing chronic pain and altered nucleus accumbens activity is a signature of the state of chronic pain.

Bielczyk, N., M. Veldsman, A. Ando, C. Caldinelli, M. M. Makary, A. Nikolaidis, M. A. Scelsi, M. Stefan, and A. P. Badhwar, "Establishing online mentorship for early career researchers: Lessons from the Organization for Human Brain Mapping International Mentoring Programme.", The European journal of neuroscience, vol. 49, issue 9, pp. 1069-1076, 2019. Abstract

Mentorship facilitates personal growth through pairing trainees with mentors who can share their expertise. In times of global integration, geographical proximity between mentors and mentees is relevant to a lesser degree. This has led to popularization of online mentoring programs. In this editorial, we introduce the history and architecture of the International Online Mentoring Programme organized by the Student and Postdoc Special Interest Group of the Organization for Human Brain Mapping.

Makary, M. M., J. Lee, E. Lee, S. Eun, J. Kim, G. - H. Jahng, K. Kim, Y. - S. Youn, J. - H. Lee, and K. Park, "Phantom Acupuncture Induces Placebo Credibility and Vicarious Sensations: A Parallel fMRI Study of Low Back Pain Patients.", Scientific reports, vol. 8, issue 1, pp. 930, 2018 01 17. Abstract

Although acupuncture is an effective therapeutic intervention for pain reduction, the exact difference between real and sham acupuncture has not been clearly understood because a somatosensory tactile component is commonly included in the existing sham acupuncture protocols. In an event-related fMRI experiment, we implemented a novel form of sham acupuncture, phantom acupuncture, that reproduces the acupuncture needling procedure without somatosensory tactile stimulation while maintaining the credibility of the acupuncture treatment context. Fifty-six non-specific low back pain patients received either real (REAL) or phantom (PHNT) acupuncture stimulation in a parallel group study. The REAL group exhibited greater activation in the posterior insula and anterior cingulate cortex, reflecting the needling-specific components of acupuncture. We demonstrated that PHNT could be delivered credibly. Interestingly, the PHNT-credible group exhibited bilateral activation in SI/SII and also reported vicarious acupuncture sensations without needling stimulation. The PHNT group showed greater activation in the bilateral dorsolateral/ventrolateral prefrontal cortex (dlPFC/vlPFC). Moreover, the PHNT group exhibited significant pain reduction, with a significant correlation between the subjective fMRI signal in the right dlPFC/vlPFC and a score assessing belief in acupuncture effectiveness. These results support an expectation-related placebo analgesic effect on subjective pain intensity ratings, possibly mediated by right prefrontal cortex activity.

Makary, M. M., H. M. Bu-Omer, R. S. Soliman, K. Park, and Y. M. Kadah, "Spectral Subtraction Denoising Preprocessing Block to Improve Slow Cortical Potential Based Brain–Computer Interface", Journal of Medical and Biological Engineering: Springer Berlin Heidelberg, pp. 1–12, 2018. Abstract


Makary, M. M., E. Seulgi, and K. Park, "Self-regulation of Primary Motor Cortex Activity with Motor Imagery Induces Functional Connectivity Modulation: A Real-Time fMRI Neurofeedback Study", Proceeding of the 39th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC'17), Jeju, Korea, 2017.
Makary, M. M., E. Seulgi, R. S. Soliman, A. Z. Mohamed, and K. Park, "Self-regulation of Primary Motor Cortex by Motor Imagery modulates Default Mode Network Connectivity", Proceedings of the Organization for Human Brain Mapping Conference (OHBM'17), Vancouver, Canada, 2017.
Soliman, R. S., S. Lee, S. Eun, A. Z. Mohamed, J. Lee, E. Lee, M. M. Makary, S. M. K. Lee, H. - J. Lee, W. S. Choi, et al., "Brain correlates to facial motor imagery and its somatotopy in the primary motor cortex", NeuroReport, vol. 28, no. 5: LWW, pp. 285–291, 2017. Abstract
Makary, M. M., S. Eun, R. S. Soliman, A. Z. Mohamed, J. Lee, and K. Park, "Functional topography of the primary motor cortex during motor execution and motor imagery as revealed by functional MRI", NeuroReport, vol. 28, no. 12: LWW, pp. 731–738, 2017. Abstract
Makary, M. M., S. Eun, and K. Park, "Greater corticostriatal activation associated with facial motor imagery compared with motor execution: a functional MRI study", NeuroReport, vol. 28, no. 10: LWW, pp. 610–617, 2017. Abstract
Kim, J., S. - J. Ko, M. Jun, A. Mohamed, S. Eun, M. Kim, D. H. Kim, M. M. Makary, J. Lee, J. - W. Park, et al., "Altered functional connectivity with pressure- induced abdominal discomfort in functional dyspepsia", Proceedings of the Organization for Human Brain Mapping Conference (OHBM'16), Geneva, Switzerland, 2016.
Leem, J., J. Park, G. Han, S. Eun, M. M. Makary, K. Park, J. Lee, and S. Lee, "Evaluating validity of various acupuncture device types: a random sequence clinical trial", BMC Complementary and Alternative Medicine, vol. 2016, pp. 16:43, 2016.
Makary, M. M., J. Lee, J. H. Lee, E. Lee, S. Eun, J. Y. Shin, G. Jahng, V. Napadow, and K. Park, "Neural Correlates of Acupuncture Effect on Chronic and Acute Low Back Pain: fMRI Study", Proceedings of the Organization for Human Brain Mapping Conference (OHBM'16), Geneva, Switzerland, 2016.
Makary, M. M., J. Lee, J. H. Lee, E. Lee, S. Eun, J. Y. Shin, G. Jahng, V. Napadow, and K. Park, "Neural Correlates of Needling Credibility in Acupuncture on Low Back Pain", Proceedings of the Organization for Human Brain Mapping Conference (OHBM'15), Honolulu, Hawaii, 2015.
Makary, M. M., J. Lee, J. - H. Lee, E. Lee, J. - Y. Shin, V. Napadow, G. Jahng, and K. Park, "Acupuncture differential effect on chronic and acute low back pain using fMRI", Integrative Medicine Research, vol. 4, no. 1: Elsevier, pp. 21, 2015. Abstract
Jungtae Leem, Jimin Park, G. H. S. E. M. M. M. S. M. L. K. P. J. L. S. L., "Difference in Blinding Rate of Phantom Acupuncture Experiment Participants Before and After Notification of Possible Placebo Acupuncture Use", World Congress on Medical Acupuncture, 2015. Abstract
Makary, M. M., J. Lee, J. - H. Lee, E. Lee, J. - Y. Shin, V. Napadow, G. Jahng, and K. Park, "Dissociation of somatosensory needling and needling credibility of the acupuncture effect on low back pain: fMRI study", Integrative Medicine Research, vol. 4, no. 1: Elsevier, pp. 88, 2015. Abstract
Leem, J., J. Park, G. Han, S. Eun, M. Makary, S. W. Shin, K. Kim, K. Park, S. Lee, and J. Lee, "Randomized, crossover clinical trial for evaluating validity of various acupuncture device types", Integrative Medicine Research, vol. 4, no. 1: Elsevier, pp. 108, 2015. Abstract
Makary, M. M., and Y. M. Kadah, Processing Methodologies for Brain Computer Interface, , Germany, LAB Lambert Academic Publishing, 2014. Abstract