Reynolds, B.B., J. Patrie, E.J. Henry, H.P. Goodkin, D.K. Broshek, M. Wintermark, and T.J. Druzgal. Comparative Analysis of Head Impact in Male Contact Sports. Journal of Neurotrauma, 2016 [Epub ahead of print].  PMID: 27541183.

As concerns about head impact in American football have grown, similar concerns have started to extend to other sports thought to experience less head impact, such as soccer and lacrosse. However, the amount of head impact experienced in soccer and lacrosse is relatively unknown, particularly compared with the substantial amount of data from football. This pilot study quantifies and compares head impact from four different types of sports teams: college football, high school football, college soccer, and college lacrosse. During the 2013 and 2014 seasons, 61 players wore mastoid patch accelerometers to quantify head impact during official athletic events (i.e., practices and games). In both practices and games, college football players experienced the most or second-most impacts per athletic event, highest average peak resultant linear and rotational acceleration per impact, and highest cumulative linear and rotational acceleration per athletic event. For average peak resultant linear and rotational acceleration per individual impact, college football was followed by high school football, then college lacrosse, and then college soccer, with similar trends in both practices and games. In the four teams under study, college football players experienced a categorically higher burden of head impact. However, for cumulative impact burden, the high school football cohort was not significantly different from the college soccer cohort. The results suggest that head impact in sport substantially varies by both the type of sport (football vs. soccer vs. lacrosse) and level of play (college vs. high school).




Fox, M., D.A. Lawrence, B.M. Trotta, F.H. Shen, and T.J. Druzgal. Imaging characteristics of cervical spine extra-arachnoid fluid collections managed conservatively. Skeletal Radiology, 2016, 45(9): p.1285-9. PMID: 27380319.

OBJECTIVE: Determine the MRI characteristics of large post-traumatic cervical spine extra-arachnoid collections managed conservatively in clinically stable patients and whether evidence of clinical or imaging deterioration materialized. MATERIALS AND METHODS: Following IRB approval, we conducted a retrospective search for all patients (>16 years old) over a 17-months period who had an extra-arachnoid fluid collection reported on a post-traumatic cervical spine MRI. Patients were excluded if they had surgery for an unstable fracture (n = 21), emergent decompression (n = 1) or lacked a follow-up MRI within 15 days (n = 1). Two MSK radiologists recorded the size, morphology and MRI signal characteristics of the collections. RESULTS: Eight patients (5 male, 3 female) met the inclusion criteria (mean age 40 years; range 19-78 years). Seven of the eight patients had fluid collections that demonstrated thin, tapered margins, extended >7 vertebral bodies and involved >180 degrees of the spinal canal. The signal characteristics of these collections varied: hyper-T1/iso-T2 (n = 1), iso-T1/T2 (n = 3), hyper-T1/hypo-T2 (n = 3) and mixed-T1/T2 (n = 1). Six of seven collections were ventral. Follow-up MRI demonstrated resolution/significant decrease in size (n = 4 between 1 and 12 days) or no change/slight decrease in size (n = 3; between 2 and 11 days). None of the seven fluid collections enlarged, no patient had abnormal cord signal, and no patient's neurologic symptoms worsened. One of eight patients had a dorsal "mass-like" collection that was slightly smaller 9 days later. CONCLUSION: In stable patients with large, tapered post-traumatic cervical spine extra-arachnoid collections managed non-surgically, none developed (1) clinical worsening, (2) abnormal cord signal or (3) collection enlargement, regardless of the collection's signal characteristics.




Reynolds, B.B., J. Patrie, E.J. Henry, H.P. Goodkin, D.K. Broshek, M. Wintermark, and T.J. Druzgal. Quantifying head impact in collegiate lacrosse. American Journal of Sports Medicine, 2016, 44(11): p.2947-56.

Background: Concussion and repetitive head impact in sports has increased interest and concern for clinicians, scientists, and athletes. Lacrosse is the fastest growing sport in the United States, but the burden of head impact in lacrosse is unknown. Purpose: The goal of this pilot study was to quantify head impact associated with practicing and playing collegiate lacrosse while subjects were fitted with wearable accelerometers. Study Design: Descriptive epidemiology study. Methods: In a single year, a collegiate cohort of 14 women’s and 15 men’s lacrosse players wore mastoid-patch accelerometers to measure the frequency and severity of head impacts during official practices and games. Average impact severity, mean number of impacts, and cumulative acceleration were evaluated, stratified by sport and event type. Results: Men’s and women’s collegiate lacrosse players did not significantly differ in the number of head impacts received during games (11.5 for men vs 9.2 for women) or practices (3.1 vs 3.1). Men’s lacrosse players had significantly higher average head acceleration per impact during games compared with women (21.1g vs 14.7g) but not during practices (21.3g vs 18.1g). For both men and women, more impacts occurred during games than during practices (men, 11.5 vs 3.1; women, 9.2 vs 3.1), but impact severity did not significantly differ between events for either sport (men, 21.1g vs 21.3g; women, 14.7g vs 18.1g). Conclusion: The study data suggest a higher impact burden during games compared with practices, but this effect is driven by the quantity rather than severity of impacts. In contrast, sex-based effects in impact burden are driven by average impact severity rather than quantity. Data collected from larger multisite trials and/or different age groups could be used to inform ongoing debates, including headgear and practice regulations, that might appreciably affect the burden of head impacts in lacrosse. Clinical Relevance: While most head impacts do not result in a clinical diagnosis of concussion, evidence indicates that subconcussive head impacts may increase susceptibility to concussion and contribute to long-term neurodegeneration.




Reynolds, B.B., J. Patrie, E.J. Henry, H.P. Goodkin, D.K. Broshek, M. Wintermark, and T.J. Druzgal. Practice type effects on head impact in collegiate football. Journal of Neurosurgery, 2015, 124(2): p.501-10.

Object: This study directly compares the number and severity of subconcussive head impacts sustained during helmet-only practices, shell practices, full-pad practices, and competitive games in a National Collegiate Athletic Association (NCAA) Division I-A football team. The goal of the study was to determine whether subconcussive head impact in collegiate athletes varies with practice type, which is currently unregulated by the NCAA. Methods: Over an entire season, a cohort of 20 collegiate football players wore impact-sensing mastoid patches that measured the linear and rotational acceleration of all head impacts during a total of 890 athletic exposures. Data were analyzed to compare the number of head impacts, head impact burden, and average impact severity during helmet-only, shell, and full-pad practices, and games. Results: Helmet-only, shell, and full-pad practices and games all significantly differed from each other (p ≤ 0.05) in the mean number of impacts for each event, with the number of impacts being greatest for games, then full-pad practices, then shell practices, and then helmet-only practices. The cumulative distributions for both linear and rotational acceleration differed between all event types (p < 0.01), with the acceleration distribution being similarly greatest for games, then full-pad practices, then shell practices, and then helmet-only practices. For both linear and rotational acceleration, helmet-only practices had a lower average impact severity when compared with other event types (p < 0.001). However, the average impact severity did not differ between any comparisons of shell and full-pad practices, and games. Conclusions: Helmet-only, shell, and full-pad practices, and games result in distinct head impact profiles per event, with each succeeding event type receiving more impacts than the one before. Both the number of head impacts and cumulative impact burden during practice are categorically less than in games. In practice events, the number and cumulative burden of head impacts per event increases with the amount of equipment worn. The average severity of individual impacts is relatively consistent across event types, with the exception of helmet-only practices. The number of hits experienced during each event type is the main driver of event type differences in impact burden per athletic exposure, rather than the average severity of impacts that occur during the event. These findings suggest that regulation of practice equipment could be a fair and effective way to substantially reduce subconcussive head impact in thousands of collegiate football players.





Wintermark, M., L. Coombs, T.J. Druzgal, A.S. Field, C.G. Filippi, R. Hicks, R. Horton, Y.W. Lui, M. Law, P. Mukherjee, A. Norbash, G. Riedy, P.C. Sanelli, J.R. Stone, G. Sze, M. Tilkin, C.T. Whitlow, E.A. Wilde, G. York, and J.M. Provenzale; on behalf of the American College of Radiology Head Injury Institute. Traumatic brain injury research roadmap. AJNR Am J Neuroradiol, 2015, 36(3): p.E12-23.

The past decade has seen impressive advances in the types of neuroimaging information that can be acquired in patients with traumatic brain injury. However, despite this increase in information, understanding of the contribution of this information to prognostic accuracy and treatment pathways for patients is limited. Available techniques often allow us to infer the presence of microscopic changes indicative of alterations in physiology and function in brain tissue. However, because histologic confirmation is typically lacking, conclusions reached by using these techniques remain solely inferential in almost all cases. Hence, a need exists for validation of these techniques by using data from large population samples that are obtained in a uniform manner, analyzed according to well-accepted procedures, and correlated with closely monitored clinical outcomes. At present, many of these approaches remain confined to population-based research rather than diagnosis at an individual level, particularly with regard to traumatic brain injury that is mild or moderate in degree. A need and a priority exist for patient-centered tools that will allow advanced neuroimaging tools to be brought into clinical settings. One barrier to developing these tools is a lack of an age-, sex-, and comorbidities-stratified, sequence-specific, reference imaging data base that could provide a clear understanding of normal variations across populations. Such a data base would provide researchers and clinicians with the information necessary to develop computational tools for the patient-based interpretation of advanced neuroimaging studies in the clinical setting. The recent "Joint ASNR-ACR HII-ASFNR TBI Workshop: Bringing Advanced Neuroimaging for Traumatic Brain Injury into the Clinic" on May 23, 2014, in Montreal, Quebec, Canada, brought together neuroradiologists, neurologists, psychiatrists, neuropsychologists, neuroimaging scientists, members of the National Institute of Neurologic Disorders and Stroke, industry representatives, and other traumatic brain injury stakeholders to attempt to reach consensus on issues related to and develop consensus recommendations in terms of creating both a well-characterized normative data base of comprehensive imaging and ancillary data to serve as a reference for tools that will allow interpretation of advanced neuroimaging tests at an individual level of a patient with traumatic brain injury. The workshop involved discussions concerning the following: 1) designation of the policies and infrastructure needed for a normative data base, 2) principles for characterizing normal control subjects, and 3) standardizing research neuroimaging protocols for traumatic brain injury. The present article summarizes these recommendations and examines practical steps to achieve them.





Wintermark, M., D.S. Huss, B.B. Shah, N. Tustison, J. Druzgal, N. Kassell, and W.J. Elias. Thalamic Connectivity in Patients with Essential Tremor Treated with MR Imaging—guided Focused Ultrasound: In Vivo Fiber Tracking by Using Diffusion-Tensor MR Imaging. Radiology, 2014. 272(1): p.202-9.

PURPOSE: To use diffusion-tensor (DT) magnetic resonance (MR) imaging in patients with essential tremor who were treated with transcranial MR imaging-guided focused ultrasound lesion inducement to identify the structural connectivity of the ventralis intermedius nucleus of the thalamus and determine how DT imaging changes correlated with tremor changes after lesion inducement. MATERIALS AND METHODS: With institutional review board approval, and with prospective informed consent, 15 patients with medication-refractory essential tremor were enrolled in a HIPAA-compliant pilot study and were treated with transcranial MR imaging-guided focused ultrasound surgery targeting the ventralis intermedius nucleus of the thalamus contralateral to their dominant hand. Fourteen patients were ultimately included. DT MR imaging studies at 3.0 T were performed preoperatively and 24 hours, 1 week, 1 month, and 3 months after the procedure. Fractional anisotropy (FA) maps were calculated from the DT imaging data sets for all time points in all patients. Voxels where FA consistently decreased over time were identified, and FA change in these voxels was correlated with clinical changes in tremor over the same period by using Pearson correlation. RESULTS: Ipsilateral brain structures that showed prespecified negative correlation values of FA over time of -0.5 or less included the pre- and postcentral subcortical white matter in the hand knob area; the region of the corticospinal tract in the centrum semiovale, in the posterior limb of the internal capsule, and in the cerebral peduncle; the thalamus; the region of the red nucleus; the location of the central tegmental tract; and the region of the inferior olive. The contralateral middle cerebellar peduncle and bilateral portions of the superior vermis also showed persistent decrease in FA over time. There was strong correlation between decrease in FA and clinical improvement in hand tremor 3 months after lesion inducement (P < .001). CONCLUSION: DT MR imaging after MR imaging-guided focused ultrasound thalamotomy depicts changes in specific brain structures. The magnitude of the DT imaging changes after thalamic lesion inducement correlates with the degree of clinical improvement in essential tremor.



Myint, Z.W., J.M. Sen, N.L. Watts, J.E. Boyer, T.J. Druzgal, and P.M. Fracasso. Regorafenib-induced reversible posterior leukoencephalopathy syndrome: A case report and literature review of reversible posterior leukoencephalopathy syndrome associated with multikinase inhibitors. Clinical Colorectal Cancer, 2014. 13(2): p. 127-30.

Clinical Practice Points: •Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare complication of angiogenesis inhibitors. •Anti-vascular endothelial growth factor-directed therapies, including the novel vascular endothelial growth factor multikinase inhibitor regorafenib, are used in metastatic colorectal cancer. •A 46-year-old man presented with seizures, agitation, altered mental status, and hypertension 4 days after starting regorafenib. •Magnetic resonance imaging of the brain suggested RPLS. •After discontinuation of regorafenib and the management of hypertension, no further seizure activity occurred and his mental status improved. •Antineoplastic agents, including the new oral angiogenesis inhibitors, sunitinib, sorafenib, and pazopanib, have been linked to RPLS. •The literature review indicates our case is the first published report of RPLS during regorafenib treatment.





Wintermark, M., J. Druzgal, D.S. Huss, M.A. Khaled, S. Monteith, P. Raghavan, T. Heurta, L.C. Schweickert, B. Burkholder, J.J. Loomba, Y. Qiao, T. Voss, J. Snell, M. Eames, R. Frysinger, N. Kassell, and W.J. Elias. Imaging Findings in MR-Guided Focused Ultrasound Treatment for Patients with Essential Tremor. AJNR Am J Neuroradiol, 2014. 35(5), p. 891-96. PMID: 24371027.

BACKGROUND AND PURPOSE: MR imaging–guided focused sonography surgery is a new stereotactic technique that uses high-intensity focused sonography to heat and ablate tissue. The goal of this study was to describe MR imaging findings pre- and post-ventralis intermedius nucleus lesioning by MR imaging–guided focused sonography as a treatment for essential tremor and to determine whether there was an association between these imaging features and the clinical response to MR imaging–guided focused sonography. MATERIALS AND METHODS: Fifteen patients with medication-refractory essential tremor prospectively gave consent; were enrolled in a single-site, FDA-approved pilot clinical trial; and were treated with transcranial MR imaging–guided focused sonography. MR imaging studies were obtained on a 3T scanner before the procedure and 24 hours, 1 week, 1 month, and 3 months following the procedure. RESULTS: On T2-weighted imaging, 3 time-dependent concentric zones were seen at the site of the focal spot. The inner 2 zones showed reduced ADC values at 24 hours in all patients except one. Diffusion had pseudonormalized by 1 month in all patients, when the cavity collapsed. Very mild postcontrast enhancement was seen at 24 hours and again at 1 month after MR imaging–guided focused sonography. The total lesion size and clinical response evolved inversely compared with each other (coefficient of correlation = 0.29, P value = .02). CONCLUSIONS: MR imaging–guided focused sonography can accurately ablate a precisely delineated target, with typical imaging findings seen in the days, weeks, and months following the treatment. Tremor control was optimal early when the lesion size and perilesional edema were maximal and was less later when the perilesional edema had resolved.



Anderson, J.S., T.J. Druzgal, A. Froehlich, M.B. DuBray, N. Lange, A.L. Alexander, T. Abildskov, J.A. Nielsen, A.N. Cariello, J.R. Cooperrider, E.D. Bigler, and J.E. Lainhart, Decreased interhemispheric functional connectivity in autism. Cereb Cortex, 2011. 21(5): p. 1134-46.

The cortical underconnectivity theory asserts that reduced long-range functional connectivity might contribute to a neural mechanism for autism. We examined resting-state blood oxygen level--dependent interhemispheric correlation in 53 males with high-functioning autism and 39 typically developing males from late childhood through early adulthood. By constructing spatial maps of correlation between homologous voxels in each hemisphere, we found significantly reduced interhemispheric correlation specific to regions with functional relevance to autism: sensorimotor cortex, anterior insula, fusiform gyrus, superior temporal gyrus, and superior parietal lobule. Observed interhemispheric connectivity differences were better explained by diagnosis of autism than by potentially confounding neuropsychological metrics of language, IQ, or handedness. Although both corpus callosal volume and gray matter interhemispheric connectivity were significantly reduced in autism, no direct relationship was observed between them, suggesting that structural and functional metrics measure different aspects of interhemispheric connectivity. In the control but not the autism sample, there was decreasing interhemispheric correlation with subject age. Greater differences in interhemispheric correlation were seen for more lateral regions in the brain. These findings suggest that long-range connectivity abnormalities in autism are spatially heterogeneous and that transcallosal connectivity is decreased most in regions with functions associated with behavioral abnormalities in autism. Autism subjects continue to show developmental differences in interhemispheric connectivity into early adulthood.





Anderson, J.S., T.J. Druzgal, M. Lopez-Larson, E.K. Jeong, K. Desai, and D. Yurgelun-Todd, Network anticorrelations, global regression, and phase-shifted soft tissue correction. Hum Brain Mapp. 2011. 32(6): p. 919-34.

Synchronized low-frequency BOLD fluctuations are observed in dissociable large-scale, distributed networks with functional specialization. Two such networks, referred to as the taskpositive network (TPN) and the task-negative network (TNN) because they tend to be active or inactive during cognitively demanding tasks, show reproducible anticorrelation of resting BOLD fluctuations after removal of the global brain signal. Because global signal regression mandates that anticorrelated regions to a given seed region must exist, it is unclear whether such anticorrelations are an artifact of global regression or an intrinsic property of neural activity. In this study, we demonstrate from simulated data that spurious anticorrelations are introduced during global regression for any two networks as a linear function of their size. Using actual resting state data, we also show that both the TPN and TNN become anticorrelated with the orbits when soft tissues are included in the global regression algorithm. Finally, we propose a technique using phase-shifted soft tissue regression (PSTCor) that allows improved correction of global physiological artifacts without global regression that shows improved anatomic specificity to global regression but does not show significant network anticorrelations. These results imply that observed anticorrelations between TNN and TPN may be largely or entirely artifactual in the resting state. These results also imply that differences in network anticorrelations attributed to pathophysiological or behavioral states may be due to differences in network size or recruitment rather than actual anticorrelations.


Anderson, J.S., N. Lange, A. Froehlich, M.B. DuBray, T.J. Druzgal, M.P. Froimowitz, A.L. Alexander, E.D. Bigler, and J.E. Lainhart, Decreased left posterior insular activity during auditory language in autism. AJNR Am J Neuroradiol, 2010. 31(1): p. 131-9.

Background and Purpose—Individuals with autism spectrum disorders often exhibit atypical language patterns including delay of speech onset, literal speech interpretation, and poor recognition of social and emotional cues in speech. We acquired fMRI images during an auditory language task to evaluate for systematic differences in language network activation between control and high-functioning autistic populations. Materials and Methods—41 right-handed male subjects (26 high-functioning autistic, 15 control) were studied using an auditory phrase recognition task, and areas of differential activation between groups were identified. Hand preference, verbal IQ, age, and language function testing were included as covariables in the analysis. Results—Control and autistic subjects showed similar language activation networks, with two notable differences. Control subjects showed significantly increased activation in the left posterior insula compared to autistic subjects (p<0.05, FDR), and autistic subjects showed increased bilaterality of receptive language compared to control subjects. Higher receptive language score on standardized testing was associated with greater activation of the posterior aspect of left Wernicke’s area. Higher verbal IQ was associated with greater activation of bilateral Broca’s area and involvement of prefrontal cortex and lateral premotor cortex. Conclusion—Control subjects showed greater activation of the posterior insula during receptive language, which may correlate with impaired emotive processing of language in autism. Autism subjects showed greater bilateral activation of receptive language areas that was out of proportion to differences in hand preference in autism and control populations.


Landau, S.M., E.H. Schumacher, H. Garavan, T.J. Druzgal, and M. D’Esposito*, A functional MRI study of the influence of practice on component processes of working memory. Neuroimage, 2004. 22(1): p. 211-21.

Previous neuroimaging studies have shown that neural activity changes with task practice. The types of changes reported have been inconsistent, however, and the neural mechanisms involved remain unclear. In this study, we investigated the influence of practice on different component processes of working memory (WM) using a face WM task. Event-related functional magnetic resonance imaging (fMRI) methodology allowed us to examine signal changes from early to late in the scanning session within different task stages (i.e., encoding, delay, retrieval), as well as to determine the influence of different levels of WM load on neural activity. We found practicerelated decreases in fMRI signal and effects of memory load occurring primarily during encoding. This suggests that practice improves encoding efficiency, especially at higher memory loads. The decreases in fMRI signal we observed were not accompanied by improved behavioral performance; in fact, error rate increased for high WM load trials, indicating that practice-related changes in activation may occur during a scanning session without behavioral evidence of learning. Our results suggest that practice influences particular component processes of WM differently, and that the efficiency of these processes may not be captured by performance measures alone.


Postle, B.R., T.J. Druzgal, and M. D'Esposito, Seeking the neural substrates of visual working memory storage. Cortex, 2003. 39(4-5): p. 927-46.

It is widely assumed that the prefrontal cortex (PFC) is a critical site of working memory storage in monkeys and humans. Recent reviews of the human lesion literature and recent neuroimaging results, however, challenge this view. To test these alternatives, we used event-related fMRI to trace the retention of working memory representation of target faces across three delay periods that were interposed between the presentation of each of four stimuli. Across subjects, only posterior fusiform gyrus demonstrated reliable retention of target-specific activity across all delay periods. Our results suggest that no part of frontal cortex, including PFC, stores mnemonic representation of faces reliably across distracted delay periods. Rather, working memory storage of faces is mediated by a domain-specific network in posterior cortex.


Druzgal, T.J. and M. D'Esposito, Dissecting contributions of prefrontal cortex and fusiform face area to face working memory. J Cogn Neurosci, 2003. 15(6): p. 771-84.

Interactions between prefrontal cortex (PFC) and stimulus-specific visual cortical association areas are hypothesized to mediate visual working memory in behaving monkeys. To clarify the roles for homologous regions in humans, event-related fMRI was used to assess neural activity in PFC and fusiform face area (FFA) of subjects performing a delay-recognition task for faces. In both PFC and FFA, activity increased parametrically with memory load during encoding and maintenance of face stimuli, despite quantitative differences in the magnitude of activation. Moreover, timing differences in PFC and FFA activation during memory encoding and retrieval implied a context dependence in the flow of neural information. These results support existing neurophysiological models of visual working memory developed in the nonhuman primate.



Druzgal, T.J. and M. D'Esposito, Activity in fusiform face area modulated as a function of working memory load. Cogn Brain Res, 2001. 10(3): p. 355-64.

Previous fMRI results suggest that extrastriate visual areas have a predominant role in perceptual processing while the prefrontal cortex (PFC) has a predominant role in working memory. In contrast, single-unit recording studies in monkeys have demonstrated a relationship between extrastriate visual areas and visual working memory tasks. In this study we tested whether activity in both the PFC and fusiform face area (FFA) changed with increasing demands of an n-back task for gray-scale faces. Since stimulus presentation was identical across conditions, the n-back task allowed us to parametrically vary working memory demands across conditions while holding perceptual and motor demands constant. This study replicated the result of PFC areas of activation that increased directly with load n of the task. The novel finding in all subjects was FFA activation that also increased directly with load n of the task. Since perceptual demands were equivalent across the three task conditions, these findings suggest that activity in both the PFC and the FFA vary with face working memory demands.


Druzgal, T.J. and M. D'Esposito, A neural network reflecting decisions about human faces. Neuron, 2001. 32(5): p. 947-55.

Anatomic structures have been linked  to the mnemonic component of working memory, but the neural network underlying associated decision processes remains elusive. Here we present an event-related functional magnetic resonance imaging study that measured activity during the decision period of a delayed face recognition task. A double dissociation of activity between anterior cingulate cortex (ACC), and a network including left fusiform face area (FFA) and left dorsolateral prefrontal cortex (DLPFC), reflected whether a probe face matched the remembered face at the time of decision. Greater activity in the left FFA and left DLPFC correlated with probe faces that matched the remembered face; in contrast, activity in ACC was greater with the probe face did not match the remembered face. These results support a model where frontal regions act in concert with stimulus-specific temporal structures to make recognition decisions about visual stimuli.