Reduction in retinal microvascular perfusion during migraine attacks.

OBJECTIVE: To determine if there are changes in structure and function of the retinal vasculature during and between migraine attacks using optical coherence tomography angiography (OCTA). BACKGROUND: Migraine attacks commonly include visual symptoms, but the potential role of the retina in these symptoms is not well understood. OCTA is a rapid, non-invasive imaging technique that is used to visualize the retinal microvasculature with high spatial resolution in a clinical setting. In this study we used OCTA to quantify different features of the retinal vasculature in patients with migraine during and between attacks, as well as in healthy controls (HCs). METHODS: We performed a prospective cohort study of 37 patients with migraine with aura (MA) (median [interquartile range, IQR] age of 37 [14] years, 86% female) and 30 with migraine without aura (MO) (median [IQR] age of 37 [17] years, 77% female) and 20 HCs (median [IQR] age of 35 [7] years, 50% female). Macular OCTA scans were obtained for all participants for the interictal analysis. In 12 MA and eight MO, scans were captured both during and outside of migraine attacks and five HCs had initial and repeat scans. In addition to analyzing the morphology of the foveal avascular zone, we calculated the vessel flux index (VFI), which is an indicator of retinal perfusion and conventional metrics (such as vessel area density) in the foveal and parafoveal regions. RESULTS: There was a significant difference in the parafoveal VFI in the ictal state between the groups (p = 0.009). During migraine attacks there was a significant reduction in the parafoveal region VFI in MA (-7%, 95% confidence interval [CI] -10% to -4%; p = 0.006) and MO (-7%, 95% CI -10% to -3%; p = 0.016) from their interictal baseline as compared to the change between repeat scans in HCs (2%, 95% CI -3% to 7%). Interictally, there was a mean (standard deviation [SD]) 13% (10%) (p = 0.003) lower blood perfusion in the MA group as compared to the MO group in the foveal region (mean [SD] 0.093 [0.023] vs. 0.107 [0.021], p = 0.003). Interictal analysis also revealed higher circularity in the superficial foveal avascular zone in the MA group compared with the MO group (mean [SD] 0.686 [0.088] vs. 0.629 [0.120], p = 0.004). In addition, interictal analysis of the patients with MA or MO and unilateral headache showed increased retinal vascular parameters consistent with greater perfusion in the eye ipsilateral to the side of the pain as compared with the contralateral eye. CONCLUSIONS: These results indicate that perfusion is reduced in MA and MO in the parafoveal retina during the ictal period. Interictally, the foveal retina in MA has reduced perfusion when compared to the foveal retina in MO. Patients with unilateral headache showed interictal asymmetry of retinal perfusion between eyes. These results indicate that changes in retinal perfusion could be a part of migraine pathophysiology, and that distinct retinal vascular signatures identified with OCTA could represent biomarkers for migraine.

Associations between rapid auditory processing of speech sounds and specific verbal communication skills in autism.

Introduction: The ability to rapidly process speech sounds is integral not only for processing other's speech, but also for auditory processing of one's own speech, which allows for maintenance of speech accuracy. Deficits in rapid auditory processing have been demonstrated in autistic individuals, particularly those with language impairment. We examined rapid auditory processing for speech sounds in relation to performance on a battery of verbal communication measures to determine which aspects of verbal communication were associated with cortical auditory processing in a sample of individuals with autism. Methods: Participants were 57 children and adolescents (40 male and 17 female) ages 5-18 who were diagnosed with an Autism Spectrum Disorder (ASD). Rapid auditory processing of speech sounds was measured via a magnetoencephalographic (MEG) index of the quality of the auditory evoked response to the second of two differing speech sounds ("Ga" / "Da") presented in rapid succession. Verbal communication abilities were assessed on standardized clinical measures of overall expressive and receptive language, vocabulary, articulation, and phonological processing. Associations between cortical measures of left- and right-hemisphere rapid auditory processing and verbal communication measures were examined. Results: Rapid auditory processing of speech sounds was significantly associated with speech articulation bilaterally (r = 0.463, p = 0.001 for left hemisphere and r = 0.328, p = 0.020 for right hemisphere). In addition, rapid auditory processing in the left hemisphere was significantly associated with overall expressive language abilities (r = 0.354, p = 0.013); expressive (r = 0.384, p = 0.005) vocabulary; and phonological memory (r = 0.325, p = 0.024). Phonological memory was found to mediate the relationship between rapid cortical processing and receptive language. Discussion: These results demonstrate that impaired rapid auditory processing for speech sounds is associated with dysfunction in verbal communication in ASD. The data also indicate that intact rapid auditory processing may be necessary for even basic communication skills that support speech production, such as phonological memory and articulatory control.

Rapid auditory processing of puretones is associated with basic components of language in individuals with autism spectrum disorders.

The goal of this study was to identify the specific domains of language that may be affected by deficits in rapid auditory processing in individuals with ASD. Auditory evoked fields were collected from 63 children diagnosed with ASD in order to evaluate processing of puretone sounds presented in rapid succession. Measures of language and its components were assessed via standardized clinical tools to quantify expressive and receptive language, vocabulary, articulation, and phonological processing abilities. Rapid processing was significantly and bilaterally associated with phonological awareness, vocabulary, and articulation. Phonological processing was found to mediate the relationship between rapid processing and language. M100 response latency was not significantly associated with any language measures. Results suggest that rapid processing deficits may impact the basic components of language such as phonological processing, and the downstream effect of this impact may in turn impact overall language development.

Quantitative EEG Biomarkers for Mild Traumatic Brain Injury.

PURPOSE: The development of objective biomarkers for mild traumatic brain injury (mTBI) in the chronic period is an important clinical and research goal. Head trauma is known to affect the mechanisms that support the electrophysiological processing of information within and between brain regions, so methods like quantitative EEG may provide viable indices of brain dysfunction associated with even mTBI. METHODS: Resting-state, eyes-closed EEG data were obtained from 71 individuals with military-related mTBI and 82 normal comparison subjects without traumatic brain injury. All mTBI subjects were in the chronic period of injury (>5 months since the time of injury). Quantitative metrics included absolute and relative power in delta, theta, alpha, beta, high beta, and gamma bands, plus a measure of interhemispheric coherence in each band. Data were analyzed using univariate and multivariate methods, the latter coupled to machine learning strategies. RESULTS: Analyses revealed significant (P < 0.05) group level differences in global relative theta power (increased for mTBI patients), global relative alpha power (decreased for mTBI patients), and global beta-band interhemispheric coherence (decreased for mTBI patients). Single variables were limited in their ability to predict group membership (e.g., mTBI vs. control) for individual subjects, each with a predictive accuracy that was below 60%. In contrast, the combination of a multivariate approach with machine learning methods yielded a composite metric that provided an overall predictive accuracy of 75% for correct classification of individual subjects as coming from control versus mTBI groups. CONCLUSIONS: This study indicates that quantitative EEG methods may be useful in the identification, classification, and tracking of individual subjects with mTBI.

Exploration of the Impact of Brief Noninvasive Vagal Nerve Stimulation on EEG and Event-Related Potentials.

OBJECTIVES: The primary objective of this study was to explore the impact of noninvasive Vagal Nerve Stimulation (nVNS) on brain electrophysiology, as assessed through spontaneous resting-state EEG and stimulus-driven event-related potentials (ERPs). METHODS: A hand-held transcutaneous stimulator was placed on the neck over the main branch of the left vagus (active condition) or more laterally over neck muscles (sham condition), with two 120-sec long bursts of stimulation applied over a five-minute period. For each of eight neurotypical subjects, prior to stimulation, and then again beginning at 15, 120, and 240 min post-stimulation, ten minutes of background EEG data were collected, along with a series of ERPs-N100 auditory sensory-gating; the N1/P2 loudness dependent auditory evoked responses (LDAER); mismatch negativity; P300a; and P300b. Each subject participated in active and sham stimulation sessions. RESULTS: Brief nVNS had a significant (p < 0.05), and in some cases prolonged (>2 hours), impact on the spontaneous EEG (decreased theta and alpha, and increased beta and gamma), and on sensory gating, LDAER, and P300b evoked responses. Based on prior literature, these specific observations may reflect nVNS-induced modulation of particular neurotransmitter systems including those for GABA (gamma power and frequency); acetylcholine (sensory gating); serotonin (LDAER); and noradrenaline (P300b). CONCLUSIONS: Brief nVNS leads to changes in a sub-set of resting-state and event-related electrophysiologic indices of brain activity. These changes are believed to be mediated by vagal afferent projections to the nucleus of the solitary tract, which in turn regulates several neurotransmitter systems through known direct and indirect neuroanatomic pathways.

Addition of ketamine to standard-of-care countermeasures for acute organophosphate poisoning improves neurobiological outcomes.

Rats poisoned with sarin enter into ahyper-cholinergic crisis characterized by excessive salivation, respiratory distress, tremors, seizures, and death. Through the use of rescue medications and an anticonvulsant, death can be avoided in many animals, with the long-term consequences of poisoning partly ameliorated, especially when countermeasures are made available immediately after exposure. However, when anticonvulsant measures are delayed by as little as 30 min, clinical, neurological, cognitive, and psychiatric abnormalities may persist long after the initial exposure. This study sought to determine if the addition of the NMDA receptor antagonist Ketamine to human standard-of-care countermeasures consisting of two rescue medications (2-PAM and atropine) and an anti-convulsant (Midazolam), would afford protection against persistent neurobiological compromise. Rats were exposed to sarin (105 µg/kg via subcutaneous injection), and treated 1 min later with 2-PAM and Atropine Methyl Nitrate (IM) to minimize mortality. One of four anti-convulsant protocols was then initiated at 50 min postsarin:Midazolam alone (MDZ, a single injection (IM) at 0.66 mg/kg); Ketamine alone (KET, a series of five injections (IM) of Ketamine at 7.5 mg/kg, 90 min apart); Midazolam + low dose Ketamine (MDZ + lowKET, a single injection of Midazolam (IM) at 0.66 mg/kg, plus five sequential doses of ketamine (IM) at 2.5 mg/kg, starting at the time of Midazolam dosing and then 90 min apart); Midazolam + high dose Ketamine (MDZ + highKET, a single injection of Midazolam (IM) at 0.66 mg/kg, plus five sequential injections of 7.5 mg/kg Ketamine (IM), starting at the time of Midazolam dosing and then 90 min apart). Animals were preassigned to groups culled at post-exposure Days 1, 7 or 30, for histopathology. For all surviving animals, EEG activity was monitored through skull electrodes for 24-h beginning immediately after sarin exposure. Surviving animals also underwent 24-h EEG monitoring on Days 6, 13, and/or 29, post-sarin. Memory assessment using the Morris Water Maze was performed on Days 1, 4, 7, 14 and 30. Following sarin exposure, 85% of surviving animals demonstrated status epilepticus within 20 min. Each of the anti-convulsant protocols was sufficient to stop convulsions within 1 h of anti-convulsant administration, but all of the animals still showed signs of electrographic status for an additional 2-12 h, without substantial differentiation between treatment groups. However, for post-sarin hours 13-24, the MDZ + highKET group showed significantly less severe EEG abnormalities than the MDZ and KET groups (Mood's Median Test, p < 0.005). At one month post-exposure, 90% of animals that had received Midazolam alone still showed evidence of some epileptiform activity. In contrast, 90% of animals that had received Midazolam + high dose Ketamine combination therapy had EEG profiles that were within normal limits. This difference in EEG outcomes was highly significant (Mood's Median Test, p < 0.001). Likewise, on the water maze, the majority of animals that had received Midazolam combined with either high or low dose Ketamine therapy returned to near baseline levels of mnemonic performance within 2 weeks, whereas the majority of the animals that had received midazolam alone or ketamine alone demonstrated persistent and significant memory impairments even at one month postexposure (Mood's Median Test, p < 0.005). With respect to neuronal necrosis, animals in the MDZ + highKET group showed significantly less overall damage than animals in other treatment groups (Mood's Median Test, p < 0.001). Of special note were findings in the hippocampus, where only 12% of animals in the MDZ + highKET group showed evidence of necrosis on H&E staining, whereas 100% of animals in the KET group, 70% of animals in the MDZ group, and 40% of animals in the MDZ + lowKET group showed evidence of hippocampal necrosis. Overall, the data demonstrate that Ketamine augmentation of an atropine, 2PAM, and Midazolam standard-ofcare for sarin exposure provides clinically-relevant additional protection against the negative neurobiological consequences of sarin, even when initiation of the anti-convulsant countermeasures is delayed by 50 min.

Acceleration of image analyst training with transcranial direct current stimulation.

Humans today are routinely and increasingly presented with vast quantities of data that challenge their capacity for efficient processing. To restore the balance between man and machine, it is worthwhile to explore new methods for enhancing or accelerating this capacity. This study was designed to investigate the efficacy of transcranial DC stimulation (tDCS) to reduce training time and increase proficiency in spatial recognition using a simulated synthetic aperture radar (SAR) task. Twenty-seven Air Force active duty members volunteered to participate in the study. Each participant was assigned to 1 of 3 stimulation groups and received two, 90-min training sessions on a target search and identification task using SAR imagery followed by a test. The tDCS anode was applied to site F10 according to the 10-20 electroencephalographic electrode convention while the cathode was placed on the contralateral bicep. Group 1 received anodal tDCS at 2 mA for 30 min in the first training session and sham tDCS in the second session. Group 2 received the stimulation conditions in the opposite order. Group 3 did not receive stimulation at all. Results showed that participants receiving training plus tDCS attained visual search accuracies ~25% higher than those provided with sham stimulation or no stimulation. However, a corresponding performance improvement was not found in the first training session for the change detection portion of the task. This indicates that experience with the imagery is important in the tDCS-elicited performance improvements in change detection.

Experimental validation of the influence of white matter anisotropy on the intracranial EEG forward solution.

Forward solutions with different levels of complexity are employed for localization of current generators, which are responsible for the electric and magnetic fields measured from the human brain. The influence of brain anisotropy on the forward solution is poorly understood. The goal of this study is to validate an anisotropic model for the intracranial electric forward solution by comparing with the directly measured 'gold standard'. Dipolar sources are created at known locations in the brain and intracranial electroencephalogram (EEG) is recorded simultaneously. Isotropic models with increasing level of complexity are generated along with anisotropic models based on Diffusion tensor imaging (DTI). A Finite Element Method based forward solution is calculated and validated using the measured data. Major findings are (1) An anisotropic model with a linear scaling between the eigenvalues of the electrical conductivity tensor and water self-diffusion tensor in brain tissue is validated. The greatest improvement was obtained when the stimulation site is close to a region of high anisotropy. The model with a global anisotropic ratio of 10:1 between the eigenvalues (parallel: tangential to the fiber direction) has the worst performance of all the anisotropic models. (2) Inclusion of cerebrospinal fluid as well as brain anisotropy in the forward model is necessary for an accurate description of the electric field inside the skull. The results indicate that an anisotropic model based on the DTI can be constructed non-invasively and shows an improved performance when compared to the isotropic models for the calculation of the intracranial EEG forward solution.