Correlation of telomere length in brain tissue with peripheral tissues in living human subjects.

Telomeres are important to chromosomal stability, and changes in their length correlate with disease, potentially relevant to brain disorders. Assessing telomere length in human brain is invasive, but whether peripheral tissue telomere length correlates with that in brain is not known. Saliva, buccal, blood, and brain samples were collected at time points before, during, and after subjects undergoing neurosurgery (n = 35) for intractable epilepsy. DNA was isolated from samples and average telomere length assessed by qPCR. Correlations of telomere length between tissue samples were calculated across subjects. When data were stratified by sex, saliva telomere length correlated with brain telomere length in males only. Buccal telomere length correlated with brain telomere length when males and females were combined. These findings indicate that in living subjects, telomere length in peripheral tissues variably correlates with that in brain and may be dependent on sex. Peripheral tissue telomere length may provide insight into brain telomere length, relevant to assessment of brain disorder pathophysiology.

Processing of auditory novelty in human cortex during a semantic categorization task.

Auditory semantic novelty - a new meaningful sound in the context of a predictable acoustical environment - can probe neural circuits involved in language processing. Aberrant novelty detection is a feature of many neuropsychiatric disorders. This large-scale human intracranial electrophysiology study examined the spatial distribution of gamma and alpha power and auditory evoked potentials (AEP) associated with responses to unexpected words during performance of semantic categorization tasks. Participants were neurosurgical patients undergoing monitoring for medically intractable epilepsy. Each task included repeatedly presented monosyllabic words from different talkers ("common") and ten words presented only once ("novel"). Targets were words belonging to a specific semantic category. Novelty effects were defined as differences between neural responses to novel and common words. Novelty increased task difficulty and was associated with augmented gamma, suppressed alpha power, and AEP differences broadly distributed across the cortex. Gamma novelty effect had the highest prevalence in planum temporale, posterior superior temporal gyrus (STG) and pars triangularis of the inferior frontal gyrus; alpha in anterolateral Heschl's gyrus (HG), anterior STG and middle anterior cingulate cortex; AEP in posteromedial HG, lower bank of the superior temporal sulcus, and planum polare. Gamma novelty effect had a higher prevalence in dorsal than ventral auditory-related areas. Novelty effects were more pronounced in the left hemisphere. Better novel target detection was associated with reduced gamma novelty effect within auditory cortex and enhanced gamma effect within prefrontal and sensorimotor cortex. Alpha and AEP novelty effects were generally more prevalent in better performing participants. Multiple areas, including auditory cortex on the superior temporal plane, featured AEP novelty effect within the time frame of P3a and N400 scalp-recorded novelty-related potentials. This work provides a detailed account of auditory novelty in a paradigm that directly examined brain regions associated with semantic processing. Future studies may aid in the development of objective measures to assess the integrity of semantic novelty processing in clinical populations.

Spinal fMRI demonstrates segmental organisation of functionally connected networks in the cervical spinal cord: A test-retest reliability study.

Resting functional magnetic resonance imaging (fMRI) studies have identified intrinsic spinal cord activity, which forms organised motor (ventral) and sensory (dorsal) resting-state networks. However, to facilitate the use of spinal fMRI in, for example, clinical studies, it is crucial to first assess the reliability of the method, particularly given the unique anatomical, physiological, and methodological challenges associated with acquiring the data. Here, we characterise functional connectivity relationships in the cervical cord and assess their between-session test-retest reliability in 23 young healthy volunteers. Resting-state networks were estimated in two ways (1) by estimating seed-to-voxel connectivity maps and (2) by calculating seed-to-seed correlations. Seed regions corresponded to the four grey matter horns (ventral/dorsal and left/right) of C5-C8 segmental levels. Test-retest reliability was assessed using the intraclass correlation coefficient. Spatial overlap of clusters derived from seed-to-voxel analysis between sessions was examined using Dice coefficients. Following seed-to-voxel analysis, we observed distinct unilateral dorsal and ventral organisation of cervical spinal resting-state networks that was largely confined in the rostro-caudal extent to each spinal segmental level, with more sparse connections observed between segments. Additionally, strongest correlations were observed between within-segment ipsilateral dorsal-ventral connections, followed by within-segment dorso-dorsal and ventro-ventral connections. Test-retest reliability of these networks was mixed. Reliability was poor when assessed on a voxelwise level, with more promising indications of reliability when examining the average signal within clusters. Reliability of correlation strength between seeds was highly variable, with the highest reliability achieved in ipsilateral dorsal-ventral and dorso-dorsal/ventro-ventral connectivity. However, the spatial overlap of networks between sessions was excellent. We demonstrate that while test-retest reliability of cervical spinal resting-state networks is mixed, their spatial extent is similar across sessions, suggesting that these networks are characterised by a consistent spatial representation over time.

Effects of transcranial magnetic stimulation on the human brain recorded with intracranial electrocorticography.

Transcranial magnetic stimulation (TMS) is increasingly used as a noninvasive technique for neuromodulation in research and clinical applications, yet its mechanisms are not well understood. Here, we present the neurophysiological effects of TMS using intracranial electrocorticography (iEEG) in neurosurgical patients. We first evaluated safety in a gel-based phantom. We then performed TMS-iEEG in 22 neurosurgical participants with no adverse events. We next evaluated intracranial responses to single pulses of TMS to the dorsolateral prefrontal cortex (dlPFC) (N = 10, 1414 electrodes). We demonstrate that TMS is capable of inducing evoked potentials both locally within the dlPFC and in downstream regions functionally connected to the dlPFC, including the anterior cingulate and insular cortex. These downstream effects were not observed when stimulating other distant brain regions. Intracranial dlPFC electrical stimulation had similar timing and downstream effects as TMS. These findings support the safety and promise of TMS-iEEG in humans to examine local and network-level effects of TMS with higher spatiotemporal resolution than currently available methods.

Magnetic Resonance Imaging of Iron Metabolism with T2* Mapping Predicts an Enhanced Clinical Response to Pharmacologic Ascorbate in Patients with GBM.

PURPOSE: Pharmacologic ascorbate (P-AscH-) is hypothesized to be an iron (Fe)-dependent tumor-specific adjuvant to chemoradiation in treating glioblastoma (GBM). This study determined the efficacy of combining P-AscH- with radiation and temozolomide in a phase II clinical trial while simultaneously investigating a mechanism-based, noninvasive biomarker in T2* mapping to predict GBM response to P-AscH- in humans. PATIENTS AND METHODS: The single-arm phase II clinical trial (NCT02344355) enrolled 55 subjects, with analysis performed 12 months following the completion of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and compared across patient subgroups with log-rank tests. Forty-nine of 55 subjects were evaluated using T2*-based MRI to assess its utility as an Fe-dependent biomarker. RESULTS: Median OS was estimated to be 19.6 months [90% confidence interval (CI), 15.7-26.5 months], a statistically significant increase compared with historic control patients (14.6 months). Subjects with initial T2* relaxation < 50 ms were associated with a significant increase in PFS compared with T2*-high subjects (11.2 months vs. 5.7 months, P < 0.05) and a trend toward increased OS (26.5 months vs. 17.5 months). These results were validated in preclinical in vitro and in vivo model systems. CONCLUSIONS: P-AscH- combined with temozolomide and radiotherapy has the potential to significantly enhance GBM survival. T2*-based MRI assessment of tumor iron content is a prognostic biomarker for GBM clinical outcomes. See related commentary by Nabavizadeh and Bagley, p. 255.

Reliability of quantitative sensory testing in the assessment of somatosensory function after high-frequency stimulation-induced sensitisation of central nociceptive pathways.

ABSTRACT: The high frequency stimulation (HFS) model can be used alongside quantitative sensory testing (QST) to assess the sensitisation of central nociceptive pathways. However, the validity and between-session reliability of using QST z -score profiles to measure changes in mechanical and thermal afferent pathways in the HFS model are poorly understood. In this study, 32 healthy participants underwent QST before and after HFS (5× 100 Hz trains; 10× electrical detection threshold) in the same heterotopic skin area across 2 repeated sessions. The only mechanical QST z -score profiles that demonstrated a consistent gain of function across repeated test sessions were mechanical pain threshold (MPT) and mechanical pain sensitivity (MPS), which were associated with moderate and good reliability, respectively. There was no relationship between HFS intensity and MPT and MPS z -score profiles. There was no change in low intensity, but a consistent facilitation of high-intensity pin prick stimuli in the mechanical stimulus response function across repeated test sessions. There was no change in cold pain threshold (CPT) and heat pain threshold (HPT) z -score profiles across session 1 and 2, which were associated with moderate and good reliability, respectively. There were inconsistent changes in the sensitivity to innocuous thermal QST parameters, with cool detection threshold (CDT), warm detection threshold (WDT), and thermal sensory limen (TSL) all producing poor reliability. These data suggest that HFS-induced changes in MPS z -score profiles is a reliable way to assess experimentally induced central sensitisation and associated secondary mechanical hyperalgesia in healthy participants.

Immediate neural impact and incomplete compensation after semantic hub disconnection.

The human brain extracts meaning using an extensive neural system for semantic knowledge. Whether broadly distributed systems depend on or can compensate after losing a highly interconnected hub is controversial. We report intracranial recordings from two patients during a speech prediction task, obtained minutes before and after neurosurgical treatment requiring disconnection of the left anterior temporal lobe (ATL), a candidate semantic knowledge hub. Informed by modern diaschisis and predictive coding frameworks, we tested hypotheses ranging from solely neural network disruption to complete compensation by the indirectly affected language-related and speech-processing sites. Immediately after ATL disconnection, we observed neurophysiological alterations in the recorded frontal and auditory sites, providing direct evidence for the importance of the ATL as a semantic hub. We also obtained evidence for rapid, albeit incomplete, attempts at neural network compensation, with neural impact largely in the forms stipulated by the predictive coding framework, in specificity, and the modern diaschisis framework, more generally. The overall results validate these frameworks and reveal an immediate impact and capability of the human brain to adjust after losing a brain hub.

Activity-induced gene expression in the human brain.

Activity-induced gene expression underlies synaptic plasticity and brain function. Here, using molecular sequencing techniques, we define activity-dependent transcriptomic and epigenomic changes at the tissue and single-cell level in the human brain following direct electrical stimulation of the anterior temporal lobe in patients undergoing neurosurgery. Genes related to transcriptional regulation and microglia-specific cytokine activity displayed the greatest induction pattern, revealing a precise molecular signature of neuronal activation in the human brain.

Anterolateral temporal lobe localization of dysnomia after temporal lobe epilepsy surgery.

Objectives: To evaluate what factors influence naming ability after temporal lobectomy in patients with drug-resistant epilepsy. Methods: 85 participants with drug-resistant epilepsy who underwent temporal lobe (TL) resective surgery were retrospectively identified (49 left TL and 36 right TL). Naming ability was assessed before and >3 months post-surgery using the Boston Naming Test (BNT).Multivariate lesion-symptom mapping was performed to evaluate whether lesion location related to naming deficits. Multiple regression analyses were conducted to examine if other patient characteristics were significantly associated with pre-to post-surgery changes in naming ability. Results: Lesion laterality and location were important predictors of post-surgical naming performance. Naming performance significantly improved after right temporal lobectomy ( p = 0.015) while a decrement in performance was observed following left temporal lobectomy ( p = 0.002). Lesion-symptom mapping showed the decline in naming performance was associated with surgical resection of the anterior left middle temporal gyrus (Brodmann area 21, r =0.41, p = <.001). For left hemisphere surgery, later onset of epilepsy was associated with a greater reduction in post-surgical naming performance ( p = 0.01). Significance: There is a wide range of variability in outcomes for naming ability after temporal lobectomy, from significant improvements to decrements observed. If future studies support the association of left anterior middle temporal gyrus resection and impaired naming this may help in surgical planning and discussions of prognosis.

Failure to breathe persists without air hunger or alarm following amygdala seizures.

Postictal apnea is thought to be a major cause of sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying postictal apnea are unknown. To understand causes of postictal apnea, we used a multimodal approach to study brain mechanisms of breathing control in 20 patients (ranging from pediatric to adult) undergoing intracranial electroencephalography for intractable epilepsy. Our results indicate that amygdala seizures can cause postictal apnea. Moreover, we identified a distinct region within the amygdala where electrical stimulation was sufficient to reproduce prolonged breathing loss persisting well beyond the end of stimulation. The persistent apnea was resistant to rising CO2 levels, and air hunger failed to occur, suggesting impaired CO2 chemosensitivity. Using es-fMRI, a potentially novel approach combining electrical stimulation with functional MRI, we found that amygdala stimulation altered blood oxygen level-dependent (BOLD) activity in the pons/medulla and ventral insula. Together, these findings suggest that seizure activity in a focal subregion of the amygdala is sufficient to suppress breathing and air hunger for prolonged periods of time in the postictal period, likely via brainstem and insula sites involved in chemosensation and interoception. They further provide insights into SUDEP, may help identify those at greatest risk, and may lead to treatments to prevent SUDEP.

Delirium and Delirium Prevention in the Emergency Department.

This article covers the epidemiology of delirium and the overlapping condition of altered mental status and encephalopathy that is relevant to those who practice in the emergency department.

TMS provokes target-dependent intracranial rhythms across human cortical and subcortical sites.

Transcranial magnetic stimulation (TMS) is increasingly deployed in the treatment of neuropsychiatric illness, under the presumption that stimulation of specific cortical targets can alter ongoing neural activity and cause circuit-level changes in brain function. While the electrophysiological effects of TMS have been extensively studied with scalp electroencephalography (EEG), this approach is most useful for evaluating low-frequency neural activity at the cortical surface. As such, little is known about how TMS perturbs rhythmic activity among deeper structures - such as the hippocampus and amygdala - and whether stimulation can alter higher-frequency oscillations. Recent work has established that TMS can be safely used in patients with intracranial electrodes (iEEG), allowing for direct neural recordings at sufficient spatiotemporal resolution to examine localized oscillatory responses across the frequency spectrum. To that end, we recruited 17 neurosurgical patients with indwelling electrodes and recorded neural activity while patients underwent repeated trials of single-pulse TMS at several cortical sites. Stimulation to the dorsolateral prefrontal cortex (DLPFC) drove widespread low-frequency increases (3-8Hz) in frontolimbic cortices, as well as high-frequency decreases (30-110Hz) in frontotemporal areas, including the hippocampus. Stimulation to parietal cortex specifically provoked low-frequency responses in the medial temporal lobe. While most low-frequency activity was consistent with brief evoked responses, anterior frontal regions exhibited induced theta oscillations following DLPFC stimulation. Taken together, we established that non-invasive stimulation can (1) provoke a mixture of low-frequency evoked power and induced theta oscillations and (2) suppress high-frequency activity in deeper brain structures not directly accessed by stimulation itself.

Delirium, confusion, or altered mental status as a risk for abnormal head CT in older adults in the emergency department: A systematic review and meta-analysis.

BACKGROUND: Altered mental status (including delirium) is a common presentations among older adults to the emergency department (ED). We aimed to report the association between altered mental status in older ED patients and acute abnormal findings on head computed tomogram (CT). METHODS: A systematic review was conducted using Ovid Medline, Embase, Clinicaltrials.gov, Web of Science, and Cochrane Central from conception to April 8th, 2021. We included citations if they described patients aged 65 years or older who received head imaging at the time of ED assessment, and reported whether patients had delirium, confusion, or altered mental status. Screening, data extraction, and bias assessment were performed in duplicate. We estimated the odds ratios (OR) for abnormal neuroimaging in patients with altered mental status. RESULTS: The search strategy identified 3031 unique citations, of which two studies reporting on 909 patients with delirium, confusion or altered mental status were included. No identified study formally assessed for delirium. The OR for abnormal head CT findings in patients with delirium, confusion or altered mental status was 0.35 (95% CI 0.031 to 3.97) compared to patients without delirium, confusion or altered mental status. CONCLUSION: We did not find a statistically significant association between delirium, confusion or altered mental status and abnormal head CT findings in older ED patients.

Harnessing the power of endogenous pain control mechanisms for novel therapeutics: how might innovations in neuroimaging help?

PURPOSE OF REVIEW: This review explores the potential of using novel imaging approaches to deepen our understanding of descending modulatory mechanisms in pain, focussing on functional magnetic resonance imaging (fMRI) of the spinal cord and novel approaches to combining molecular and fMRI data. This review sheds light on the neural processes involved in pain modulation, paving the way for the development of targeted treatments. RECENT FINDINGS: The reviewed literature demonstrates significant advancements in pain research. Recent studies show the potential of using fMRI to investigate the spinal cord's role in pain modulation. Furthermore, novel analytical approaches integrating molecular and fMRI data show promise in elucidating the complex neurobiological processes underlying pain regulation. The main themes explored here include the identification of neurochemical markers associated with pain modulation and the characterisation of neural circuits involved in descending pain control. SUMMARY: A comprehensive understanding of descending modulatory mechanisms in pain can inform the development of novel treatments, targeting dysfunction of these key pathways. By leveraging spinal fMRI and integrating molecular data into brain fMRI, researchers can identify potential therapeutic targets throughout the neuraxis. These advances may contribute to the development of personalised medicine approaches, allowing for tailored interventions based on individual pain profiles.

Distribution of multiunit pitch responses recorded intracranially from human auditory cortex.

The perception of pitch is a fundamental percept, which is mediated by the auditory system, requiring the abstraction of stimulus properties related to the spectro-temporal structure of sound. Despite its importance, there is still debate as to the precise areas responsible for its encoding, which may be due to species differences or differences in the recording measures and choices of stimuli used in previous studies. Moreover, it was unknown whether the human brain contains pitch neurons and how distributed such neurons might be. Here, we present the first study to measure multiunit neural activity in response to pitch stimuli in the auditory cortex of intracranially implanted humans. The stimulus sets were regular-interval noise with a pitch strength that is related to the temporal regularity and a pitch value determined by the repetition rate and harmonic complexes. Specifically, we demonstrate reliable responses to these different pitch-inducing paradigms that are distributed throughout Heschl's gyrus, rather than being localized to a particular region, and this finding was evident regardless of the stimulus presented. These data provide a bridge across animal and human studies and aid our understanding of the processing of a critical percept associated with acoustic stimuli.

Temporally organized representations of reward and risk in the human brain.

The value and uncertainty associated with choice alternatives constitute critical features along which decisions are made. While the neural substrates supporting reward and risk processing have been investigated, the temporal organization by which these computations are encoded remains elusive. Here we leverage the high spatiotemporal precision of intracranial electroencephalography (iEEG) to uncover how representations of decision-related computations unfold in time. We present evidence of locally distributed representations of reward and risk variables that are temporally organized across multiple regions of interest. Reward outcome representations across wide-spread regions follow a temporally cascading order along the anteroposterior axis of the brain. In contrast, expected value can be decoded from multiple regions at the same time, and error signals in both reward and risk domains reflect a mixture of sequential and parallel encoding. We highlight the role of the anterior insula in generalizing between reward prediction error (RePE) and risk prediction error (RiPE), within which the encoding of RePE in the distributed iEEG signal predicts RiPE. Together our results emphasize the utility of uncovering temporal dynamics in the human brain for understanding how computational processes critical for value-based decisions under uncertainty unfold.

From neurotransmitters to networks: Transcending organisational hierarchies with molecular-informed functional imaging.

The human brain exhibits complex interactions across micro, meso-, and macro-scale organisational principles. Recent synergistic multi-modal approaches have begun to link micro-scale information to systems level dynamics, transcending organisational hierarchies and offering novel perspectives into the brain's function and dysfunction. Specifically, the distribution of micro-scale properties (such as receptor density or gene expression) can be mapped onto macro-scale measures from functional MRI to provide novel neurobiological insights. Methodological approaches to enrich functional imaging analyses with molecular information are rapidly evolving, with several streams of research having developed relatively independently, each offering unique potential to explore the trans-hierarchical functioning of the brain. Here, we address the three principal streams of research - spatial correlation, molecular-enriched network, and in-silico whole brain modelling analyses - to provide a critical overview of the different sources of molecular information, how this information can be utilised within analyses of fMRI data, the merits and pitfalls of each methodology, and, through the use of key examples, highlight their promise to shed new light on key domains of neuroscientific inquiry.

The Adjustable Cranial Plate: A Novel Implant Designed to Eliminate the Need for Cranioplasty Surgery Following a Hemicraniectomy Operation.

BACKGROUND: Decompressive hemicraniectomy (DHC) is performed to relieve life-threatening intracranial pressure elevations. After swelling abates, a cranioplasty is performed for mechanical integrity and cosmesis. Cranioplasty is costly with high complication rates. Prior attempts to obviate second-stage cranioplasty have been unsuccessful. The Adjustable Cranial Plate (ACP) is designed for implantation during DHC to afford maximal volumetric expansion with later repositioning without requiring a second major operation. METHODS: The ACP has a mobile section held by a tripod fixation mechanism. Centrally located gears adjust the implant between the up and down positions. Cadaveric ACP implantation was performed. Virtual DHC and ACP placement were done using imaging data from 94 patients who had previously undergone DHC to corroborate our cadaveric results. Imaging analysis methods were used to calculate volumes of cranial expansion. RESULTS: The ACP implantation and adjustment procedures are feasible in cadaveric testing without wound closure difficulties. Results of the cadaveric study showed total volumetric expansion achieved was 222 cm3. Results of the virtual DHC procedure showed the volume of cranial expansion achieved by removing a standardized bone flap was 132 cm3 (range, 89-171 cm3). Applied to virtual craniectomy patients, the total volume of expansion achieved with the ACP implantation operation was 222 cm3 (range, 181-263 cm3). CONCLUSIONS: ACP implantation during DHC is technically feasible. It achieves a volume of cranial expansion that will accommodate that observed following survivable hemicraniectomy operations. Moving the implant from the up to the down position can easily be performed as a simple outpatient or inpatient bedside procedure, thus potentially eliminating second-stage cranioplasty procedures.