Safety and feasibility of minocycline in treatment of acute traumatic brain injury.

BACKGROUND: Minocycline is a pleomorphic neuroprotective agent well studied in animal models of traumatic brain injury (TBI) and brain ischemia. METHODS: To test the hypothesis that administration of minocycline in moderate to severe TBI (Glasgow Coma Score 3-12). Fifteen patients were enrolled in a two-dose escalation study of minocycline to evaluate the safety of twice the recommended antibiotic dosage; tier 1 n = 7 at a loading dose of 800 mg followed by 200 mg twice a day (BID) for 7 days; tier 2 n = 8 at a loading dose of 800 mg followed by 400 mg BID for 7 days. RESULTS: The mean initial GCS was 5.6 for Tier 1 patients and 5.4 for Tier 2. The Disability Rating Scale (DRS) had a trend towards improvement with the higher dose 12.5 SD ± 7.7 (N = 5) for Tier 1 at 4 weeks and 8.5 SD ± 9.9 at week 12 (N = 5), whereas for Tier 2 it was 9.7 ± 6.9 (N = 6) for week 4 and 6.0 SD ± 6.1 (N = 7) for week 12 (p = .251 repeated measures ANOVA). Liver function tests increased but resolved after the first week and there were no infections. CONCLUSIONS: Minocycline was safe for moderate to severe TBI at a dose twice that as recommended for treatment of infection. The higher dose did trend towards an improved outcome.

Head Impact Burden and Change in Neurocognitive Function During a Season of Youth Football.

OBJECTIVE: To determine the association of repetitive subconcussive head impacts with functional outcomes in primary and high school tackle football players. SETTING: Youth football fields and an outpatient sports neurology clinic. PARTICIPANTS: A total of 112 primary school (n = 55, age 9-12 years) and high school (n = 57, age 15-18 years) football players. DESIGN: A prospective cohort study. MAIN MEASURES: Helmet-based sensors were used to record head impacts during practices and games during the 2016 football season. Impact g-forces were summed to yield a measure of cumulative impact. History of self-reported premorbid medical diagnoses was obtained preseason. Players completed assessments of a variety of outcomes both pre- and postseason: neuropsychological test performance, symptoms, vestibular and ocular-motor screening, balance, parent-completed attention-deficit hyperactivity disorder (ADHD) symptoms, and self-reported behavioral adjustment. RESULTS: Average cumulative impact was 3700 (standard deviation = 2700) g-forces for the season and did not differ between age groups (P = .594). Cumulative impact did not predict pre- to postseason change scores on any outcome measures (all P > .05). Instead, younger age group and reported history of premorbid ADHD predicted change scores on several cognitive testing measures and parent-reported ADHD symptoms, while reported history of premorbid anxiety and depression predicted change scores on symptom reporting. CONCLUSIONS: In youth tackle football, subconcussive head impacts sustained over the course of a single season may not be associated with neurocognitive functional outcomes. The absence of a significant association may reflect the relatively short follow-up interval, and signals the need for studies across multiple seasons.

Intraoperative hippocampal electrocorticography frequently captures electrographic seizures and correlates with hippocampal pathology.

OBJECTIVE: Relationship between electrographic seizures on hippocampal electrocorticography (IH-ECoG) and presence/type of hippocampal pathology remains unclear. METHODS: IH-ECoG was recorded for 10-20 min from the ventricular surface of the hippocampus following removal of the temporal neocortex in 40 consecutive patients. Correlation between intraoperative hippocampal seizures and preoperative MRI, hippocampal histopathology, and EEG from invasive monitoring was determined. RESULTS: IH-ECoG captured electrographic seizures in 15/40 patients (in 8/23 with abnormal hippocampal signal on MRI and 7/17 patients without MRI abnormality). Hippocampal neuronal loss was observed in 22/40 (Group 1), while 18/40 had no significant neuronal loss (Group 2). In Group 1, 4/22 had seizures on IH-ECoG, while 11/18 had electrographic seizures in Group 2. In 24/40 patients who underwent prolonged extraoperative intracranial EEG (IC-EEG) recording, hippocampal seizures were captured in 14. Of these, 7 also had seizures during IH-ECoG. In 10/24 IC-EEG patients without seizures, 3 had seizures on IH-ECoG. CONCLUSIONS: IH-ECoG frequently captures spontaneous electrographic seizures. These are more likely to occur in patients with pathologic processes that do not disrupt/infiltrate hippocampus compared to patients with intractable epilepsy associated with disrupted hippocampal architecture. SIGNIFICANCE: Intraoperative hippocampal seizures may result from deafferentation from the temporal neocortex and disinhibition of the perforant pathway.

Altered metabolomic-genomic signature: A potential noninvasive biomarker of epilepsy.

OBJECTIVE: This study aimed to identify noninvasive biomarkers of human epilepsy that can reliably detect and localize epileptic brain regions. Having noninvasive biomarkers would greatly enhance patient diagnosis, patient monitoring, and novel therapy development. At the present time, only surgically invasive, direct brain recordings are capable of detecting these regions with precision, which severely limits the pace and scope of both clinical management and research progress in epilepsy. METHODS: We compared high versus low or nonspiking regions in nine medically intractable epilepsy surgery patients by performing integrated metabolomic-genomic-histological analyses of electrically mapped human cortical regions using high-resolution magic angle spinning proton magnetic resonance spectroscopy, cDNA microarrays, and histological analysis. RESULTS: We found a highly consistent and predictive metabolite logistic regression model with reduced lactate and increased creatine plus phosphocreatine and choline, suggestive of a chronically altered metabolic state in epileptic brain regions. Linking gene expression, cellular, and histological differences to these key metabolites using a hierarchical clustering approach predicted altered metabolic vascular coupling in the affected regions. Consistently, these predictions were validated histologically, showing both neovascularization and newly discovered, millimeter-sized microlesions. SIGNIFICANCE: Using a systems biology approach on electrically mapped human cortex provides new evidence for spatially segregated, metabolic derangements in both neurovascular and synaptic architecture in human epileptic brain regions that could be a noninvasively detectable biomarker of epilepsy. These findings both highlight the immense power of a systems biology approach and identify a potentially important role that magnetic resonance spectroscopy can play in the research and clinical management of epilepsy.

Evaluating signal-correlated noise as a control task with language-related gamma activity on electrocorticography.

OBJECTIVE: Our recent electrocorticography (ECoG) study suggested reverse speech, a widely used control task, to be a poor control for non-language-related auditory activity. We hypothesized that this may be due to retained perception as a human voice. We report a follow-up ECoG study in which we contrast forward and reverse speech with a signal-correlated noise (SCN) control task that cannot be perceived as a human voice. METHODS: Ten patients were presented 90 audible stimuli, including 30 each of corresponding forward speech, reverse speech, and SCN trials, during ECoG recording with evaluation of gamma activity between 50 and 150 Hz. RESULTS: Sites of the lateral temporal gyri activated throughout speech stimuli were generally less activated by SCN, while some temporal sites seemed to process both human and non-human sounds. Reverse speech trials were associated with activities across the temporal lobe similar to those associated with forward speech. CONCLUSIONS: Findings herein externally validate functional neuroimaging studies utilizing SCN as a control for non-language-specific auditory function. Our findings are consistent with the notion that stimuli perceived as originating from a human voice are poor controls for non-language auditory function. SIGNIFICANCE: Our findings have implications in functional neuroimaging research as well as improved clinical mapping of auditory functions.

Gamma activity modulated by picture and auditory naming tasks: intracranial recording in patients with focal epilepsy.

OBJECTIVE: We measured the spatial, temporal and developmental patterns of gamma activity augmented by picture- and auditory-naming tasks and determined the clinical significance of naming-related gamma-augmentation. METHODS: We studied 56 epileptic patients (age: 4-56 years) who underwent extraoperative electrocorticography. The picture-naming task consisted of naming of a visually-presented object; the auditory-naming task consisted of answering an auditorily-presented sentence question. RESULTS: Naming-related gamma-augmentation at 50-120 Hz involved the modality-specific sensory cortices during stimulus presentation and inferior-Rolandic regions during responses. Gamma-augmentation in the bilateral occipital and inferior/medial-temporal regions was more intense in the picture-naming than auditory-naming task, whereas that in the bilateral superior-temporal, left middle-temporal, left inferior-parietal, and left frontal regions was more intense in the auditory-naming task. Patients above 10 years old, compared to those younger, showed more extensive gamma-augmentation in the left dorsolateral-premotor region. Resection of sites showing naming-related gamma-augmentation in the left hemisphere assumed to contain essential language function was associated with increased risk of post-operative language deficits requiring speech therapy (p < 0.05). CONCLUSIONS: Measurement of gamma-augmentation elicited by either naming task was useful to predict postoperative language deficits. SIGNIFICANCE: A smaller degree of frontal engagement in the picture-naming task can be explained by no requirement of syntactic processing or less working memory load. More extensive gamma-augmentation in the left dorsolateral-premotor region in older individuals may suggest more proficient processing by the mature brain.

Crying with sorrow evoked by electrocortical stimulation.

Dacrystic seizures are rare and have been reported in patients with hypothalamic hamartoma as well as fronto-temporal epilepsy, involving the non-dominant hemisphere. We describe the first reported case of cortical stimulation of the left posterior orbito-frontal gyrus, generating consistent and reproducible crying with affective content in a 41-year-old woman with medically intractable left temporal lobe epilepsy, who underwent extraoperative intracranial video-EEG monitoring for resective non-lesional epilepsy surgery.

Clinical significance and developmental changes of auditory-language-related gamma activity.

OBJECTIVE: We determined the clinical impact and developmental changes of auditory-language-related augmentation of gamma activity at 50-120 Hz recorded on electrocorticography (ECoG). METHODS: We analyzed data from 77 epileptic patients ranging 4-56 years in age. We determined the effects of seizure-onset zone, electrode location, and patient-age upon gamma-augmentation elicited by an auditory-naming task. RESULTS: Gamma-augmentation was less frequently elicited within seizure-onset sites compared to other sites. Regardless of age, gamma-augmentation most often involved the 80-100 Hz frequency band. Gamma-augmentation initially involved bilateral superior-temporal regions, followed by left-side dominant involvement in the middle-temporal, medial-temporal, inferior-frontal, dorsolateral-premotor, and medial-frontal regions and concluded with bilateral inferior-Rolandic involvement. Compared to younger patients, those older than 10 years had a larger proportion of left dorsolateral-premotor and right inferior-frontal sites showing gamma-augmentation. The incidence of a post-operative language deficit requiring speech therapy was predicted by the number of resected sites with gamma-augmentation in the superior-temporal, inferior-frontal, dorsolateral-premotor, and inferior-Rolandic regions of the left hemisphere assumed to contain essential language function (r(2) = 0.59; p = 0.001; odds ratio = 6.04 [95% confidence-interval: 2.26-16.15]). CONCLUSIONS: Auditory-language-related gamma-augmentation can provide additional information useful to localize the primary language areas. SIGNIFICANCE: These results derived from a large sample of patients support the utility of auditory-language-related gamma-augmentation in presurgical evaluation.

Variability in carotid endarterectomy practice patterns within a metropolitan area.

BACKGROUND AND PURPOSE: Previous clinical studies have suggested that patients with carotid stenosis with high surgical risk features may fare better with carotid artery stenting or aggressive medical therapy. The extent to which carotid endarterectomy is still being performed in this group of patients is unclear. METHODS: A retrospective audit was performed among 4 hospitals over a 2-year period. The proportion of high surgical risk patients was compared and the in-hospital stroke, myocardial infarction, and death rates were compared among conventional and high surgical risk patients. RESULTS: Three hundred thirty-five carotid endarterectomy operations were performed (63% asymptomatic) with 37.9% being high surgical risk subjects. The stroke, myocardial infarction, and death rate was 4.6% in conventional risk subjects and 10.2% in high surgical risk patients (P<0.05). The only hospital with multidisciplinary carotid conferences had the lowest proportion of carotid endarterectomy operations in asymptomatic patients. CONCLUSIONS: A substantial proportion of carotid endarterectomy operations are performed in patients with high surgical risk features. These patients experienced a 2-fold increase in major in-hospital complications, raising doubts about whether they benefit from carotid surgery. The use of preintervention multidisciplinary conferences may improve patient safety.

Multimodality language mapping in patients with left-hemispheric language dominance on Wada test.

OBJECTIVE: We determined the utility of electrocorticography (ECoG) and stimulation for detecting language-related sites in patients with left-hemispheric language-dominance on Wada test. METHODS: We studied 13 epileptic patients who underwent language mapping using event-related gamma-oscillations on ECoG and stimulation via subdural electrodes. Sites showing significant gamma-augmentation during an auditory-naming task were defined as language-related ECoG sites. Sites at which stimulation resulted in auditory perceptual changes, failure to verbalize a correct answer, or sensorimotor symptoms involving the mouth were defined as language-related stimulation sites. We determined how frequently these methods revealed language-related sites in the superior-temporal, inferior-frontal, dorsolateral-premotor, and inferior-Rolandic regions. RESULTS: Language-related sites in the superior-temporal and inferior-frontal gyri were detected by ECoG more frequently than stimulation (p < 0.05), while those in the dorsolateral-premotor and inferior-Rolandic regions were detected by both methods equally. Stimulation of language-related ECoG sites, compared to the others, more frequently elicited language symptoms (p < 0.00001). One patient developed dysphasia requiring in-patient speech therapy following resection of the dorsolateral-premotor and inferior-Rolandic regions containing language-related ECoG sites not otherwise detected by stimulation. CONCLUSIONS: Language-related gamma-oscillations may serve as an alternative biomarker of underlying language function in patients with left-hemispheric language-dominance. SIGNIFICANCE: Measurement of language-related gamma-oscillations is warranted in presurgical evaluation of epileptic patients.

Evaluating reverse speech as a control task with language-related gamma activity on electrocorticography.

Reverse speech has often been used as a control task in brain-mapping studies of language utilizing various non-invasive modalities. The rationale is that reverse speech is comparable to forward speech in terms of auditory characteristics, while omitting the linguistic components. Thus, it may control for non-language auditory functions. This finds some support in fMRI studies indicating that reverse speech resulted in less blood-oxygen-level-dependent (BOLD) signal intensity in perisylvian regions than forward speech. We attempted to externally validate a reverse speech control task using intracranial electrocorticography (ECoG) in eight patients with intractable focal epilepsy. We studied adolescent and adult patients who underwent extraoperative ECoG prior to resective epilepsy surgery. All patients received an auditory language task during ECoG recording. Patients were presented 115 audible question stimuli, including 30 reverse speech trials. Reverse speech trials more strongly engaged bilateral superior temporal sites than did the corresponding forward speech trials. Forward speech trials elicited larger gamma-augmentation at frontal lobe sites not attributable to sensorimotor function. Other temporal and frontal sites of significant augmentation showed no significant difference between reverse and forward speech. Thus, we failed to validate reported evidence of weaker activation of temporal neocortices during reverse compared to forward speech. Superior temporal lobe engagement may indicate increased attention to reverse speech. Reverse speech does not appear to be a suitable task for the control of non-language auditory functions on ECoG.

High inter-reviewer variability of spike detection on intracranial EEG addressed by an automated multi-channel algorithm.

OBJECTIVE: The goal of this study was to determine the consistency of human reviewer spike detection and then develop a computer algorithm to make the intracranial spike detection process more objective and reliable. METHODS: Three human reviewers marked interictal spikes on samples of intracranial EEGs from 10 patients. The sensitivity, precision and agreement in channel ranking by activity were calculated between reviewers. A computer algorithm was developed to parallel the way human reviewers detect spikes by first identifying all potential spikes on each channel using frequency filtering and then block scaling all channels at the same time in order to exclude potential spikes that fall below an amplitude and slope threshold. Its performance was compared to the human reviewers on the same set of patients. RESULTS: Human reviewers showed surprisingly poor inter-reviewer agreement, but did broadly agree on the ranking of channels for spike activity. The computer algorithm performed as well as the human reviewers and did especially well at ranking channels from highest to lowest spike frequency. CONCLUSIONS: Our algorithm showed good agreement with the different human reviewers, even though they demonstrated different criteria for what constitutes a 'spike' and performed especially well at the clinically important task of ranking channels by spike activity. SIGNIFICANCE: An automated, objective method to detect interictal spikes on intracranial recordings will improve both research and the surgical management of epilepsy patients.

γ-oscillations modulated by picture naming and word reading: intracranial recording in epileptic patients.

OBJECTIVE: We measured cortical gamma-oscillations in response to visual-language tasks consisting of picture naming and word reading in an effort to better understand human visual-language pathways. METHODS: We studied six patients with focal epilepsy who underwent extraoperative electrocorticography (ECoG) recording. Patients were asked to overtly name images presented sequentially in the picture naming task and to overtly read written words in the reading task. RESULTS: Both tasks commonly elicited gamma-augmentation (maximally at 80-100 Hz) on ECoG in the occipital, inferior-occipital-temporal and inferior-Rolandic areas, bilaterally. Picture naming, compared to reading task, elicited greater gamma-augmentation in portions of pre-motor areas as well as occipital and inferior-occipital-temporal areas, bilaterally. In contrast, word reading elicited greater gamma-augmentation in portions of bilateral occipital, left occipital-temporal and left superior-posterior-parietal areas. Gamma-attenuation was elicited by both tasks in portions of posterior cingulate and ventral premotor-prefrontal areas bilaterally. The number of letters in a presented word was positively correlated to the degree of gamma-augmentation in the medial occipital areas. CONCLUSIONS: Gamma-augmentation measured on ECoG identified cortical areas commonly and differentially involved in picture naming and reading tasks. Longer words may activate the primary visual cortex for the more peripheral field. SIGNIFICANCE: The present study increases our understanding of the visual-language pathways.

Transient shivering during Wada test provides insight into human thermoregulation.

PURPOSE: Some patients with pharmacoresistant epilepsy undergoing the Wada test experience transient shivering. The purpose of this study was to investigate various clinical and radiographic characteristics of these individuals to delineate underlying mechanisms of this phenomenon. METHODS: A systematic review of prospectively collected information on patients undergoing the Wada test was performed. All demographic, clinical, and radiographic information was obtained and reviewed by the appropriate expert in the field; statistical analysis was performed to determine the predictors of transient shivering. RESULTS: A total of 120 consecutive carotid artery injections in 59 patients were included in the study. Shivering was observed in 46% of the patients, and it was not significantly affected by gender, age, location of epileptogenic zone, brain lesion on magnetic resonance imaging (MRI), side of the first injection, duration of the hemiparesis, or excess slow wave activity on electroencephalography (EEG). However, shivering was more likely to follow sodium amobarbital injection if there was no filling of the posterior circulation on cerebral angiogram. DISCUSSION: Transient shivering during the Wada test is common. A transient but selective functional lesion of the anterior hypothalamus produced by the effects of sodium amobarbital may result in disinhibition of the posterior hypothalamus and other brainstem thermoregulatory centers, thereby inducing transient shivering.

Fitness to drive in multiple sclerosis: awareness of deficit moderates risk.

Fitness to drive was examined among 78 individuals with multiple sclerosis (MS) who participated with a knowledgeable informant. Illness severity, neuropsychological functioning, and external social influences each made unique contributions to the prediction of driving status. Among drivers, perceptions of social influences against driving accounted for the most variance in miles driven, whereas social influences, informants' perceptions of the patients' fitness to drive, and illness severity accounted for the most variance in adverse driving incidents. Importantly, awareness of deficit moderated fitness to drive: Drivers who were unaware of their deficits perceived less need to engage in compensatory behaviors; moreover, as perceived need to compensate decreased, miles driven and driving incidents increased. The findings have implications for interventions with persons with MS who drive.

Paradoxical imaging findings in cerebral gliomas.

Gliomas represent approximately one-third of all intracranial tumors in adults and commonly present clinically with seizures. We report two seizure patients with paradoxical imaging findings on preoperative grading of their cerebral gliomas. A 53-year-old man with a history of temporal lobe epilepsy originating from a mass in the right medial temporal region (patient 1) and a 44-year-old man with a history of predominantly left sided sensory seizures with a mass in the right posterior parietal region (patient 2) underwent presurgical evaluation including MRI and glucose PET, followed by surgery to remove cerebral tumors associated with seizure onset. Preoperatively, patient 1 had a homogenous non-enhancing lesion on MRI and hypometabolism on PET imaging, suggesting a low-grade tumor. Postoperative histopathology was consistent with a glioblastoma multiforme (grade IV). Patient 2 had a heterogeneous lesion with cyst formation, edema, and contrast enhancement on preoperative MRI imaging, and interictal hypermetabolism on PET scan, thus suggesting a high-grade tumor. Postoperative histopathology was consistent with an oligodendroglioma (grade II) without anaplastic features. We conclude preoperative grading of cerebral gliomas may be inaccurate occasionally even in cases with concordant structural and functional imaging findings. This should be considered when counseling patients.

Range of sensory gating values and test-retest reliability in normal subjects.

This article characterizes gating in normal subjects using P50, N100, and P200 components in a paired-click paradigm and compares the test-retest reliabilities of the three components. Sixty-seven normal subjects had gating data from a standard paired-click paradigm; 30 had test-retest data. The test-retest reliability of the amplitudes, latencies, and sensory gating indices derived from the P50, N100, and P200 responses were compared. Measured gating ratios showed either normal or positively skewed distributions. Test-retest reliability of the P50 gating ratio did not reach significance, but N100 and P200 ratios showed better reliability (.50 and .64). The P50 difference score was more reliable (.61), and the N100 and P200 test-retest reliabilities of difference scores were high (.83 and .81, respectively). N100 and P200 attenuation is reliable; further work is needed to develop more reliable P50 gating measures.

Seizures lead to elevation of intracranial pressure in children undergoing invasive EEG monitoring.

PURPOSE: To study the effects of intracranial subdural grid electrode placement and seizures on intracranial pressure (ICP) in children undergoing invasive EEG monitoring. METHODS: Sixteen children with pharmacoresistant epilepsy who underwent two-stage epilepsy surgery with subdural grid placement were included in the study. The ICP was recorded at baseline and with each seizure prospectively. A variety of seizure parameters including type of seizure, length of seizure, extent of seizure spread, and number of subdural grid electrodes inserted were analyzed retrospectively and correlated with the change in ICP. RESULTS: A total of 48 seizures in 16 children were studied. The mean baseline ICP correlated positively with age of the child. Generalized tonic-clonic seizures were associated with the highest rise in ICP. Similarly, ICP rise was associated with seizures involving more electrodes indicating a larger area of brain participating in the seizure. CONCLUSION: Seizures in general and generalized tonic-clonic seizures, in particular, increase ICP temporarily in patients who are undergoing invasive EEG monitoring with subdural grids.

Word list generation performance in Alzheimer's disease and vascular dementia.

Word list generation (WLG) was examined among clinical samples of individuals with Alzheimer's disease (AD) (n = 73) or ischemic vascular dementia (IVD) (n = 85), equivalent in age, education, current and estimated premorbid intellectual functioning, and proportion of men and women. The AD group performed significantly better than did the IVD group on lexical WLG, and a trend was observed indicating superior performance among the IVD group on categorical WLG. Within-groups, comparisons of group means, and profile analyses of individual performance patterns all indicated that persons with AD demonstrated a lexical > categorical pattern significantly more often than did IVD participants. The absolute difference in average performance between the AD and IVD groups on lexical and categorical WLG was small; the findings, however, generally support the clinical utility of the lexical > categorical WLG pattern in the differential diagnosis of AD and IVD. The patterns of performance support the presence of relative impairment in semantic processing among the individuals with AD and global deficits in retrieval and processing speed in individuals with IVD.