Optimal approaches to analyzing functional MRI data in glioma patients.

BACKGROUND: Resting-state fMRI is increasingly used to study the effects of gliomas on the functional organization of the brain. A variety of preprocessing techniques and functional connectivity analyses are represented in the literature. However, there so far has been no systematic comparison of how alternative methods impact observed results. NEW METHOD: We first surveyed current literature and identified alternative analytical approaches commonly used in the field. Following, we systematically compared alternative approaches to atlas registration, parcellation scheme, and choice of graph-theoretical measure as regards differentiating glioma patients (N = 59) from age-matched reference subjects (N = 163). RESULTS: Our results suggest that non-linear, as opposed to affine registration, improves structural match to an atlas, as well as measures of functional connectivity. Functionally- as opposed to anatomically-derived parcellation schemes maximized the contrast between glioma patients and reference subjects. We also demonstrate that graph-theoretic measures strongly depend on parcellation granularity, parcellation scheme, and graph density. COMPARISON WITH EXISTING METHODS AND CONCLUSIONS: Our current work primarily focuses on technical optimization of rs-fMRI analysis in glioma patients and, therefore, is fundamentally different from the bulk of papers discussing glioma-induced functional network changes. We report that the evaluation of glioma-induced alterations in the functional connectome strongly depends on analytical approaches including atlas registration, choice of parcellation scheme, and graph-theoretical measures.

Brain mechanisms underlying the emotion processing bias in treatment-resistant depression.

Depression is associated with a cognitive bias towards negative information and away from positive information. This biased emotion processing may underlie core depression symptoms, including persistent feelings of sadness or low mood and a reduced capacity to experience pleasure. The neural mechanisms responsible for this biased emotion processing remain unknown. Here, we had a unique opportunity to record stereotactic electroencephalography (sEEG) signals in the amygdala and prefrontal cortex (PFC) from 5 treatment-resistant depression (TRD) patients and 12 epilepsy patients (as control) while they participated in an affective bias task in which happy and sad faces were rated. First, compared with the control group, patients with TRD showed increased amygdala responses to sad faces in the early stage (around 300 ms) and decreased amygdala responses to happy faces in the late stage (around 600 ms) following the onset of faces. Further, during the late stage of happy face processing, alpha-band activity in PFC as well as alpha-phase locking between the amygdala and PFC were significantly greater in TRD patients compared to the controls. Second, after deep brain stimulation (DBS) delivered to bilateral subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VC/VS), atypical amygdala and PFC processing of happy faces in TRD patients remitted toward the normative pattern. The increased amygdala activation during the early stage of sad face processing suggests an overactive bottom-up processing system in TRD. Meanwhile, the reduced amygdala response during the late stage of happy face processing could be attributed to inhibition by PFC through alpha-band oscillation, which can be released by DBS in SCC and VC/VS.

Precision functional MRI mapping reveals distinct connectivity patterns for depression associated with traumatic brain injury.

Depression associated with traumatic brain injury (TBI) is believed to be clinically distinct from primary major depressive disorder (MDD) and may be less responsive to conventional treatments. Brain connectivity differences between the dorsal attention network (DAN), default mode network (DMN), and subgenual cingulate have been implicated in TBI and MDD. To characterize these distinctions, we applied precision functional mapping of brain network connectivity to resting-state functional magnetic resonance imaging data from five published patient cohorts, four discovery cohorts (n = 93), and one replication cohort (n = 180). We identified a distinct brain connectivity profile in TBI-associated depression that was independent of TBI, MDD, posttraumatic stress disorder (PTSD), depression severity, and cohort. TBI-associated depression was independently associated with decreased DAN-subgenual cingulate connectivity, increased DAN-DMN connectivity, and the combined effect of both. This effect was stronger when using precision functional mapping relative to group-level network maps. Our results support the possibility of a physiologically distinct "TBI affective syndrome," which may benefit from individualized neuromodulation approaches to target its distinct neural circuitry.

Structural gray matter alterations in glioblastoma and high-grade glioma-A potential biomarker of survival.

Background: Patients with glioblastoma (GBM) and high-grade glioma (HGG, World Health Organization [WHO] grade IV glioma) have a poor prognosis. Consequently, there is an unmet clinical need for accessible and noninvasively acquired predictive biomarkers of overall survival in patients. This study evaluated morphological changes in the brain separated from the tumor invasion site (ie, contralateral hemisphere). Specifically, we examined the prognostic value of widespread alterations of cortical thickness (CT) in GBM/HGG patients. Methods: We used FreeSurfer, applied with high-resolution T1-weighted MRI, to examine CT, evaluated prior to standard treatment with surgery and chemoradiation in patients (GBM/HGG, N = 162, mean age 61.3 years) and 127 healthy controls (HC; 61.9 years mean age). We then compared CT in patients to HC and studied patients' associated changes in CT as a potential biomarker of overall survival. Results: Compared to HC cases, patients had thinner gray matter in the contralesional hemisphere at the time of tumor diagnosis. patients had significant cortical thinning in parietal, temporal, and occipital lobes. Fourteen cortical parcels showed reduced CT, whereas in 5, it was thicker in patients' cases. Notably, CT in the contralesional hemisphere, various lobes, and parcels was predictive of overall survival. A machine learning classification algorithm showed that CT could differentiate short- and long-term survival patients with an accuracy of 83.3%. Conclusions: These findings identify previously unnoticed structural changes in the cortex located in the hemisphere contralateral to the primary tumor mass. Observed changes in CT may have prognostic value, which could influence care and treatment planning for individual patients.

Individualized precision targeting of dorsal attention and default mode networks with rTMS in traumatic brain injury-associated depression.

At the group level, antidepressant efficacy of rTMS targets is inversely related to their normative connectivity with subgenual anterior cingulate cortex (sgACC). Individualized connectivity may yield better targets, particularly in patients with neuropsychiatric disorders who may have aberrant connectivity. However, sgACC connectivity shows poor test-retest reliability at the individual level. Individualized resting-state network mapping (RSNM) can reliably map inter-individual variability in brain network organization. Thus, we sought to identify individualized RSNM-based rTMS targets that reliably target the sgACC connectivity profile. We used RSNM to identify network-based rTMS targets in 10 healthy controls and 13 individuals with traumatic brain injury-associated depression (TBI-D). These "RSNM targets" were compared with consensus structural targets and targets based on individualized anti-correlation with a group-mean-derived sgACC region ("sgACC-derived targets"). The TBI-D cohort was also randomized to receive active (n = 9) or sham (n = 4) rTMS to RSNM targets with 20 daily sessions of sequential high-frequency left-sided stimulation and low-frequency right-sided stimulation. We found that the group-mean sgACC connectivity profile was reliably estimated by individualized correlation with default mode network (DMN) and anti-correlation with dorsal attention network (DAN). Individualized RSNM targets were thus identified based on DAN anti-correlation and DMN correlation. These RSNM targets showed greater test-retest reliability than sgACC-derived targets. Counterintuitively, anti-correlation with the group-mean sgACC connectivity profile was also stronger and more reliable for RSNM-derived targets than for sgACC-derived targets. Improvement in depression after RSNM-targeted rTMS was predicted by target anti-correlation with the portions of sgACC. Active treatment also led to increased connectivity within and between the stimulation sites, the sgACC, and the DMN. Overall, these results suggest that RSNM may enable reliable individualized rTMS targeting, although further research is needed to determine whether this personalized approach can improve clinical outcomes.

Preoperative functional connectivity by magnetic resonance imaging for refractory neocortical epilepsy.

Objective: Patients with refractory epilepsy experience extensive and invasive clinical testing for seizure onset zones treatable by surgical resection. However, surgical resection can fail to provide therapeutic benefit, and patients with neocortical epilepsy have the poorest therapeutic outcomes. This case series studied patients with neocortical epilepsy who were referred for surgical treatment. Prior to surgery, patients volunteered for resting-state functional magnetic resonance imaging (rs-fMRI) in addition to imaging for the clinical standard of care. This work examined the variability of functional connectivity in patients, estimated from rs-fMRI, for associations with surgical outcomes. Methods: This work examined pre-operative structural imaging, pre-operative rs-fMRI, and post-operative structural imaging from seven epilepsy patients. Review of the clinical record provided Engel classifications for surgical outcomes. A novel method assessed pre-operative rs-fMRI from patients using comparative rs-fMRI from a large cohort of healthy control subjects and estimated Gibbs distributions for functional connectivity in patients compared to healthy controls. Results: Three patients had Engel classification Ia, one patient had Engel classification IIa, and three patients had Engel classification IV. Metrics for variability of functional connectivity, including absolute differences of the functional connectivity of each patient from healthy control averages and probabilistic scores for absolute differences, were higher for patients classified as Engel IV, for whom epilepsy surgery provided no meaningful improvement. Significance: This work continues on-going efforts to use rs-fMRI to characterize abnormal functional connectivity in the brain. Preliminary evidence indicates that the topography of variant functional connectivity in epilepsy patients may be clinically relevant for identifying patients unlikely to have favorable outcomes after epilepsy surgery. Widespread topographic variations of functional connectivity also support the hypothesis that epilepsy is a disease of brain resting-state networks.

Gold nanoparticle-enhanced X-ray microtomography of the rodent reveals region-specific cerebrospinal fluid circulation in the brain.

Cerebrospinal fluid (CSF) is essential for the development and function of the central nervous system (CNS). However, the brain and its interstitium have largely been thought of as a single entity through which CSF circulates, and it is not known whether specific cell populations within the CNS preferentially interact with the CSF. Here, we develop a technique for CSF tracking, gold nanoparticle-enhanced X-ray microtomography, to achieve micrometer-scale resolution visualization of CSF circulation patterns during development. Using this method and subsequent histological analysis in rodents, we identify previously uncharacterized CSF pathways from the subarachnoid space (particularly the basal cisterns) that mediate CSF-parenchymal interactions involving 24 functional-anatomic cell groupings in the brain and spinal cord. CSF distribution to these areas is largely restricted to early development and is altered in posthemorrhagic hydrocephalus. Our study also presents particle size-dependent CSF circulation patterns through the CNS including interaction between neurons and small CSF tracers, but not large CSF tracers. These findings have implications for understanding the biological basis of normal brain development and the pathogenesis of a broad range of disease states, including hydrocephalus.

Pharyngoesophageal Damage from Hardware Extrusion at an Average of 7.5 Years After Anterior Cervical Diskectomy and Fusion: A Case Series, Discussion of Risk Factors, and Guide for Management.

OBJECTIVE: We present a single-institution case series of patients who experienced pharyngoesophageal damage, specifically from extruded hardware occurring at an average of 7.5 years after anterior cervical diskectomy and fusion (ACDF). METHODS: A retrospective chart review was conducted of patients who had undergone ACDF with subsequent delayed pharyngoesophageal perforation or erosion from extruded hardware ≥1 year after surgery. A discussion of the literature surrounding this complication, including risk factors and management, is also presented. RESULTS: Nine patients were identified (average age 58 years, 66.7% male) among a total of 4122 ACDF patients (incidence: 0.22%). Average time to injury was 7.5 years. Indications for initial ACDF were degenerative cervical disease (n = 7), ankylosing spondylitis (n = 1), and cervical fracture (n = 1). Eight patients had prior multilevel ACDF spanning 2 (n = 4), 3 (n = 1), or 4 levels (n = 2). Fusion levels for prior ACDF included C5-C7 (n = 3), C3-C7 (n = 2), C4-C7 (n = 1), C4-C6 (n = 1), C2-C5 (n = 1), and C6-C7 (n = 1). Pharyngoesophageal injuries included esophageal perforation (n = 3), pharyngeal perforation (n = 2), esophageal erosion (n = 3), and pharyngoesophageal erosion (n = 1). In most (n = 6) cases, the cause of pharyngoesophageal damage was due to ≥1 extruded screws. Dysphagia (n = 8) was the most common presenting symptom. For perforations (n = 5), 2 repairs used a rotational flap to reinforce a primary closure; the other 3 cases were repaired via primary closure. CONCLUSIONS: Pharyngoesophageal damage caused by extruded hardware may occur several years after ACDF. These delayed complications are difficult to predict. Proper screw placement may be the most important factor for minimizing the chances of this potentially devastating complication, particularly with multilevel constructs.

Resting-State Functional Magnetic Resonance Imaging Networks as a Quantitative Metric for Impact of Neurosurgical Interventions.

Objective: Resting-state functional MRI (rs-fMRI) has been used to evaluate brain network connectivity as a result of intracranial surgery but has not been used to compare different neurosurgical procedures. Laser interstitial thermal therapy (LITT) is an alternative to conventional craniotomy for the treatment of brain lesions such as tumors and epileptogenic foci. While LITT is thought of as minimally invasive, its effect on the functional organization of the brain is still under active investigation and its impact on network changes compared to conventional craniotomy has not yet been explored. We describe a novel computational method for quantifying and comparing the impact of two neurosurgical procedures on brain functional connectivity. Methods: We used a previously described seed-based correlation analysis to generate resting-state network (RSN) correlation matrices, and compared changes in correlation patterns within and across RSNs between LITT and conventional craniotomy for treatment of 24 patients with singular intracranial tumors at our institution between 2014 and 2017. Specifically, we analyzed the differences in patient-specific changes in the within-hemisphere correlation patterns of the contralesional hemisphere. Results: In a post-operative follow-up period up to 2 years within-hemisphere connectivity of the contralesional hemisphere after surgery was more highly correlated to the pre-operative state in LITT patients when compared to craniotomy patients (P = 0.0287). Moreover, 4 out of 11 individual RSNs demonstrated significantly higher degrees of correlation between pre-operative and post-operative network connectivity in patients who underwent LITT (all P < 0.05). Conclusion: Rs-fMRI may be used as a quantitative metric to determine the impact of different neurosurgical procedures on brain functional connectivity. Global and individual network connectivity in the contralesional hemisphere may be more highly preserved after LITT when compared to craniotomy for the treatment of brain tumors.

Homotopic functional connectivity disruptions in glioma patients are associated with tumor malignancy and overall survival.

BACKGROUND: Gliomas exhibit widespread bilateral functional connectivity (FC) alterations that may be associated with tumor grade. Limited studies have examined the connection-level mechanisms responsible for these effects. Given the typically strong FC observed between mirroring/homotopic brain regions in healthy subjects, we hypothesized that homotopic connectivity (HC) is altered in low-grade and high-grade glioma patients and the extent of disruption is associated with tumor grade and predictive of overall survival (OS) in a cohort of de novo high-grade glioma (World Health Organization [WHO] grade 4) patients. METHODS: We used a mirrored FC-derived cortical parcellation to extract blood-oxygen-level-dependent (BOLD) signals and to quantify FC differences between homotopic pairs in normal-appearing brain in a retrospective cohort of glioma patients and healthy controls. RESULTS: Fifty-nine glioma patients (WHO grade 2, n = 9; grade 4 = 50; mean age, 57.5 years) and 30 healthy subjects (mean age, 65.9 years) were analyzed. High-grade glioma patients showed lower HC compared with low-grade glioma patients and healthy controls across several cortical locations and resting-state networks. Connectivity disruptions were also strongly correlated with hemodynamic lags between homotopic regions. Finally, in high-grade glioma patients with known survival times (n = 42), HC in somatomotor and dorsal attention networks were significantly correlated with OS. CONCLUSIONS: These findings demonstrate an association between tumor grade and HC alterations that may underlie global FC changes and provide prognostic information.

Functional connectivity within glioblastoma impacts overall survival.

BACKGROUND: Glioblastoma (GBM; World Health Organization grade IV) assumes a variable appearance on MRI owing to heterogeneous proliferation and infiltration of its cells. As a result, the neurovascular units responsible for functional connectivity (FC) may exist within gross tumor boundaries, albeit with altered magnitude. Therefore, we hypothesize that the strength of FC within GBMs is predictive of overall survival. METHODS: We used predefined FC regions of interest (ROIs) in de novo GBM patients to characterize the presence of within-tumor FC observable via resting-state functional MRI and its relationship to survival outcomes. RESULTS: Fifty-seven GBM patients (mean age, 57.8 ±â€…13.9 y) were analyzed. Functionally connected voxels, not identifiable on conventional structural images, can be routinely found within the tumor mass and was not significantly correlated to tumor size. In patients with known survival times (n = 31), higher intranetwork FC strength within GBM tumors was associated with better overall survival even after accounting for clinical and demographic covariates. CONCLUSIONS: These findings suggest the possibility that functionally intact regions may persist within GBMs and that the extent to which FC is maintained may carry prognostic value and inform treatment planning.

A Review of Passive Brain Mapping Techniques in Neurological Surgery.

Brain mapping is a quintessential part of neurosurgical practice. Accordingly, much of our understanding of the brain's functional organization, and in particular the motor homunculus, is largely attributable to the clinical investigations of past neurosurgeons. Traditionally mapping was invasive and involved the application of electrical current to the exposed brain to observe focal disruption of function or to elicit overt actions. More recently, a wide variety of techniques have been developed that do not require electrical stimulation and often do not require any explicit participation by the subject. Collectively we refer to these as passive mapping modalities. Here we review the spectrum of passive mapping used by neurosurgeons for mapping and surgical planning that ranges from invasive intracranial recordings to noninvasive imaging as well as regimented task-based protocols to completely task-free paradigms that can be performed intraoperatively while under anesthesia.

Mapping of the Language Network With Deep Learning.

Background: Pre-surgical functional localization of eloquent cortex with task-based functional MRI (T-fMRI) is part of the current standard of care prior to resection of brain tumors. Resting state fMRI (RS-fMRI) is an alternative method currently under investigation. Here, we compare group level language localization using T-fMRI vs. RS-fMRI analyzed with 3D deep convolutional neural networks (3DCNN). Methods: We analyzed data obtained in 35 patients with brain tumors that had both language T-fMRI and RS-MRI scans during pre-surgical evaluation. The T-fMRI data were analyzed using conventional techniques. The language associated resting state network was mapped using a 3DCNN previously trained with data acquired in >2,700 normal subjects. Group level results obtained by both methods were evaluated using receiver operator characteristic analysis of probability maps of language associated regions, taking as ground truth meta-analytic maps of language T-fMRI responses generated on the Neurosynth platform. Results: Both fMRI methods localized major components of the language system (areas of Broca and Wernicke). Word-stem completion T-fMRI strongly activated Broca's area but also several task-general areas not specific to language. RS-fMRI provided a more specific representation of the language system. Conclusion: 3DCNN was able to accurately localize the language network. Additionally, 3DCNN performance was remarkably tolerant of a limited quantity of RS-fMRI data.

Mapping language function with task-based vs. resting-state functional MRI.

BACKGROUND: Use of functional MRI (fMRI) in pre-surgical planning is a non-invasive method for pre-operative functional mapping for patients with brain tumors, especially tumors located near eloquent cortex. Currently, this practice predominantly involves task-based fMRI (T-fMRI). Resting state fMRI (RS-fMRI) offers an alternative with several methodological advantages. Here, we compare group-level analyses of RS-fMRI vs. T-fMRI as methods for language localization. PURPOSE: To contrast RS-fMRI vs. T-fMRI as techniques for localization of language function. METHODS: We analyzed data obtained in 35 patients who had both T-fMRI and RS-fMRI scans during the course of pre-surgical evaluation. The RS-fMRI data were analyzed using a previously trained resting-state network classifier. The T-fMRI data were analyzed using conventional techniques. Group-level results obtained by both methods were evaluated in terms of two outcome measures: (1) inter-subject variability of response magnitude and (2) sensitivity/specificity analysis of response topography, taking as ground truth previously reported maps of the language system based on intraoperative cortical mapping as well as meta-analytic maps of language task fMRI responses. RESULTS: Both fMRI methods localized major components of the language system (areas of Broca and Wernicke) although not with equal inter-subject consistency. Word-stem completion T-fMRI strongly activated Broca's area but also several task-general areas not specific to language. RS-fMRI provided a more specific representation of the language system. CONCLUSION: We demonstrate several advantages of classifier-based mapping of language representation in the brain. Language T-fMRI activated task-general (i.e., not language-specific) functional systems in addition to areas of Broca and Wernicke. In contrast, classifier-based analysis of RS-fMRI data generated maps confined to language-specific regions of the brain.

Custom Shunt System for Increased Baseline Intracranial Pressure in a Patient with Idiopathic Intracranial Hypertension.

BACKGROUND: Standard treatment of idiopathic intracranial hypertension (IIH) involves reduction of intracranial pressure (ICP) to normal range, often via a ventriculoperitoneal shunt (VPS). We describe a case of a middle-aged man who presented with symptoms consistent with IIH. After ICP was normalized with a VPS, the patient had neurologic deterioration into a coma. He completely recovered after a month when his ICP was allowed to increase and remain above the normal range. CASE DESCRIPTION: A 50-year-old man presented with daily headaches, visual loss (right > left), and increased lumbar opening pressure consistent with IIH. A VPS was inserted using a Strata II valve with a pressure setting of 1.5, lowering ICP into the normal range. The patient initially had a normal postoperative course, but then became comatose and developed imaging signs consistent with intracranial hypotension. A Codman Certas valve was placed at a setting of 7 and a distal slit-cut peritoneal catheter was used (as opposed to standard open output). This custom system drained at pressure >26 mm Hg based on intraoperative manometry. The patient tolerated this well and is currently planned for a gradual reduction in ICP with valve setting adjustments as an outpatient. CONCLUSIONS: In patients with chronic IIH, reduction to normal ICP may unexpectedly lead to encephalopathic changes. Personalized shunts may facilitate reduction of ICP to still elevated but tolerable levels in these patients.

Resting-state network mapping in neurosurgical practice: a review.

Resting-state functional MRI (rs-fMRI) is a well-established method for studying intrinsic connectivity and mapping the topography of functional networks in the human brain. In the clinical setting, rs-fMRI has been used to define functional topography, typically language and motor systems, in the context of preoperative planning for neurosurgery. Intraoperative mapping of critical speech and motor areas with electrocortical stimulation (ECS) remains standard practice, but preoperative noninvasive mapping has the potential to reduce operative time and provide functional localization when awake mapping is not feasible. Task-based fMRI has historically been used for this purpose, but it can be limited by the young age of the patient, cognitive impairment, poor cooperation, and need for sedation. Resting-state fMRI allows reliable analysis of all functional networks with a single study and is inherently independent of factors affecting task performance. In this review, the authors provide a summary of the theory and methods for resting-state network mapping. They provide case examples illustrating clinical implementation and discuss limitations of rs-fMRI and review available data regarding performance in comparison to ECS. Finally, they discuss novel opportunities for future clinical applications and prospects for rs-fMRI beyond mapping of regions to avoid during surgery but, instead, as a tool to guide novel network-based therapies.

A comparison of resting state functional magnetic resonance imaging to invasive electrocortical stimulation for sensorimotor mapping in pediatric patients.

Localizing neurologic function within the brain remains a significant challenge in clinical neurosurgery. Invasive mapping with direct electrocortical stimulation currently is the clinical gold standard but is impractical in young or cognitively delayed patients who are unable to reliably perform tasks. Resting state functional magnetic resonance imaging non-invasively identifies resting state networks without the need for task performance, hence, is well suited to pediatric patients. We compared sensorimotor network localization by resting state fMRI to cortical stimulation sensory and motor mapping in 16 pediatric patients aged 3.1 to 18.6 years. All had medically refractory epilepsy that required invasive electrographic monitoring and stimulation mapping. The resting state fMRI data were analyzed using a previously trained machine learning classifier that has previously been evaluated in adults. We report comparable functional localization by resting state fMRI compared to stimulation mapping. These results provide strong evidence for the utility of resting state functional imaging in the localization of sensorimotor cortex across a wide range of pediatric patients.

Individualized Connectome-Targeted Transcranial Magnetic Stimulation for Neuropsychiatric Sequelae of Repetitive Traumatic Brain Injury in a Retired NFL Player.

OBJECTIVE: The recent advent of individualized resting-state network mapping (RSNM) has revealed substantial interindividual variability in anatomical localization of brain networks identified by using resting-state functional MRI (rsfMRI). RSNM enables personalized targeting of focal neuromodulation techniques such as repetitive transcranial magnetic stimulation (rTMS). rTMS is believed to exert antidepressant efficacy by modulating connectivity between the stimulation site, the default mode network (DMN), and the subgenual anterior cingulate cortex (sgACC). Personalized rTMS may be particularly useful after repetitive traumatic brain injury (TBI), which is associated with neurodegenerative tauopathy in medial temporal limbic structures. These degenerative changes are believed to be related to treatment-resistant neurobehavioral disturbances observed in many retired athletes. METHODS: The authors describe a case in which RSNM was successfully used to target rTMS to treat these neuropsychiatric disturbances in a retired NFL defensive lineman whose symptoms were not responsive to conventional treatments. RSNM was used to identify left-right dorsolateral prefrontal rTMS targets with maximal difference between dorsal attention network and DMN correlations. These targets were spatially distinct from those identified by prior methods. Twenty sessions of left-sided excitatory and right-sided inhibitory rTMS were administered at these targets. RESULTS: Treatment led to improvement in Montgomery-Åsberg Depression Rating Scale (72%), cognitive testing, and headache scales scores. Compared with healthy individuals and subjects with TBI-associated depression, baseline rsfMRI revealed substantially elevated DMN connectivity with the medial temporal lobe (MTL). Serial rsfMRI scans revealed gradual improvement in MTL-DMN connectivity and stimulation site connectivity with sgACC. CONCLUSIONS: These results highlight the possibility of individualized neuromodulation and biomarker-based monitoring for neuropsychiatric sequelae of repetitive TBI.