Neural response properties predict perceived contents and locations elicited by intracranial electrical stimulation of human auditory cortex.

Intracranial electrical stimulation (iES) of auditory cortex can elicit sound experiences with a variety of perceived contents (hallucination or illusion) and locations (contralateral or bilateral side), independent of actual acoustic inputs. However, the neural mechanisms underlying this elicitation heterogeneity remain undiscovered. Here, we collected subjective reports following iES at 3062 intracranial sites in 28 patients (both sexes) and identified 113 auditory cortical sites with iES-elicited sound experiences. We then decomposed the sound-induced intracranial electroencephalogram (iEEG) signals recorded from all 113 sites into time-frequency features. We found that the iES-elicited perceived contents can be predicted by the early high-γ features extracted from sound-induced iEEG. In contrast, the perceived locations elicited by stimulating hallucination sites and illusion sites are determined by the late high-γ and long-lasting α features, respectively. Our study unveils the crucial neural signatures of iES-elicited sound experiences in human and presents a new strategy to hearing restoration for individuals suffering from deafness.

Rapid Processing of Invisible Fearful Faces in the Human Amygdala.

Rapid detection of a threat or its symbol (e.g., fearful face), whether visible or invisible, is critical for human survival. This function is suggested to be enabled by a subcortical pathway to the amygdala independent of the cortex. However, conclusive electrophysiological evidence in humans is scarce. Here, we explored whether the amygdala can rapidly encode invisible fearful faces. We recorded intracranial electroencephalogram (iEEG) responses in the human (both sexes) amygdala to faces with fearful, happy, and neutral emotions rendered invisible by backward masking. We found that a short-latency intracranial event-related potential (iERP) in the amygdala, beginning 88 ms poststimulus onset, was preferentially evoked by invisible fearful faces relative to invisible happy or neutral faces. The rapid iERP exhibited selectivity to the low spatial frequency (LSF) component of the fearful faces. Time-frequency iEEG analyses further identified a rapid amygdala response preferentially for LSF fearful faces at the low gamma frequency band, beginning 45 ms poststimulus onset. In contrast, these rapid responses to invisible fearful faces were absent in cortical regions, including early visual areas, the fusiform gyrus, and the parahippocampal gyrus. These findings provide direct evidence for the existence of a subcortical pathway specific for rapid fear detection in the amygdala and demonstrate that the subcortical pathway can function without conscious awareness and under minimal influence from cortical areas.SIGNIFICANCE STATEMENT Automatic detection of biologically relevant stimuli, such as threats or dangers, has remarkable survival value. Here, we provide direct intracranial electrophysiological evidence that the human amygdala preferentially responds to fearful faces at a rapid speed, despite the faces being invisible. This rapid, fear-selective response is restricted to faces containing low spatial frequency information transmitted by magnocellular neurons and does not appear in cortical regions. These results support the existence of a rapid subcortical pathway independent of cortical pathways to the human amygdala.

Two stages of speech envelope tracking in human auditory cortex modulated by speech intelligibility.

The envelope is essential for speech perception. Recent studies have shown that cortical activity can track the acoustic envelope. However, whether the tracking strength reflects the extent of speech intelligibility processing remains controversial. Here, using stereo-electroencephalogram technology, we directly recorded the activity in human auditory cortex while subjects listened to either natural or noise-vocoded speech. These 2 stimuli have approximately identical envelopes, but the noise-vocoded speech does not have speech intelligibility. According to the tracking lags, we revealed 2 stages of envelope tracking: an early high-γ (60-140 Hz) power stage that preferred the noise-vocoded speech and a late θ (4-8 Hz) phase stage that preferred the natural speech. Furthermore, the decoding performance of high-γ power was better in primary auditory cortex than in nonprimary auditory cortex, consistent with its short tracking delay, while θ phase showed better decoding performance in right auditory cortex. In addition, high-γ responses with sustained temporal profiles in nonprimary auditory cortex were dominant in both envelope tracking and decoding. In sum, we suggested a functional dissociation between high-γ power and θ phase: the former reflects fast and automatic processing of brief acoustic features, while the latter correlates to slow build-up processing facilitated by speech intelligibility.

Periventricular nodular heterotopia is coupled with the neocortex during resting and task states.

Periventricular nodular heterotopia (PVNH) is a well-defined developmental disorder characterized by failed neuronal migration, which forms ectopic neuronal nodules along the ventricular walls. Previous studies mainly focus on clinical symptoms caused by the PVNH tissue, such as seizures. However, little is known about whether and how neurons in the PVNH tissue functionally communicate with neurons in the neocortex. To probe this, we applied magnetoencephalography (MEG) and stereo-electroencephalography (sEEG) recordings to patients with PVNH during resting and task states. By estimating frequency-resolved phase coupling strength of the source-reconstructed neural activities, we found that the PVNH tissue was spontaneously coupled with the neocortex in the α-ß frequency range, which was consistent with the synchronization pattern within the neocortical network. Furthermore, the coupling strength between PVNH and sensory areas effectively modulated the local neural activity in sensory areas. In both MEG and sEEG visual experiments, the PVNH tissue exhibited visual-evoked responses, with a similar pattern and latency as the ipsilateral visual cortex. These findings demonstrate that PVNH is functionally integrated into cognition-related cortical circuits, suggesting a co-development perspective of ectopic neurons after their migration failure.

Long-term ANT-DBS effects in pilocarpine-induced epileptic rats: A combined 9.4T MRI and histological study.

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) appears to be effective against seizures in animals and humans however, its therapeutic mechanisms remain elusive. This study aimed to combine 9.4T multimodal magnetic resonance imaging (MRI) with histology to investigate the longitudinal effects of long-term ANT-DBS in pilocarpine-induced epileptic rats. Status epilepsy (SE) was induced by LiCl-pilocarpine injection in 11 adult male Sprague-Dawley rats. Four weeks after SE, chronic epileptic rats underwent either ANT-DBS (n = 6) or sham-DBS (n = 5) surgery. Electroencephalography (EEG) and spontaneous recurrent seizures (SRS) were recorded for 1 week. The T2-weighted image and images from resting-state functional MRI (rs-fMRI) were acquired at three states: before SE, at 4 weeks post-SE, and at 5 weeks post-DBS. Volumes of the hippocampal subregions and hippocampal-related functional connectivity (FC) were compared longitudinally. Finally, antibodies against neuronal nuclei (NeuN) and glial fibrillary acidic proteins were used to evaluate neuronal loss and astrogliosis in the hippocampus. Long-term ANT-DBS significantly reduced seizure generalization in pilocarpine-induced epileptic rats. By analyzing the gray matter volume using T2-weighted images, long-term ANT-DBS displayed morphometric restoration of the hippocampal subregions. Neuronal protection of the hippocampal subregions and inhibition of astrogliosis in the hippocampal subregions were observed in the ANT-DBS group. ANT-DBS caused reversible regulation of FC in the insula-hippocampus and subthalamic nucleus-hippocampus. Long-term ANT-DBS provides comprehensive protection of hippocampal histology, hippocampal morphometrics, and hippocampal-related functional networks.

Ectopic expression of neuronal adenosine kinase, a biomarker in mesial temporal lobe epilepsy without hippocampal sclerosis.

AIMS: Mesial temporal lobe epilepsy without hippocampal sclerosis (no-HS MTLE) refers to those MTLE patients who have neither magnetic resonance imaging (MRI) lesions nor definite pathological evidence of hippocampal sclerosis. They usually have resistance to antiepileptic drugs, difficulties in precise seizure location and poor surgical outcomes. Adenosine is a neuroprotective neuromodulator that acts as a seizure terminator in the brain. The role of adenosine in no-HS MTLE is still unclear. Further research to explore the aetiology and pathogenesis of no-HS MTLE may help to find new therapeutic targets. METHODS: In surgically resected hippocampal specimens, we examined the maladaptive changes of the adenosine system of patients with no-HS MTLE. In order to better understand the dysregulation of the adenosine pathway in no-HS MTLE, we developed a rat model based on the induction of focal cortical lesions through a prenatal freeze injury. RESULTS: We first examined the adenosine system in no-HS MTLE patients who lack hippocampal neuronal loss and found ectopic expression of the astrocytic adenosine metabolising enzyme adenosine kinase (ADK) in hippocampal pyramidal neurons, as well as downregulation of neuronal A1 receptors (A1 Rs) in the hippocampus. In the no-HS MTLE model rats, the transition of ADK from neuronal expression to an adult pattern of glial expression in the hippocampus was significantly delayed. CONCLUSIONS: Ectopic expression of neuronal ADK might be a pathological hallmark of no-HS MTLE. Maladaptive changes in adenosine metabolism might be a novel target for therapeutic intervention in no-HS MTLE.

Characteristics, surgical outcomes, and influential factors of epilepsy in Sturge-Weber syndrome.

Few studies have reported the clinical presentation, surgical treatment, outcomes and influential factors for patients with epilepsy and Sturge-Weber syndrome. This large-scale retrospective study continuously enrolled 132 patients with Sturge-Weber syndrome and epilepsy from January 2008 to December 2018 at our hospital to analyse their characteristics. Among these patients, 90 underwent epilepsy surgery, and their postoperative 2-year follow-up seizure, cognitive and motor functional outcomes were assessed and analysed. Univariable and multivariable logistic analyses were conducted to explore the influential factors. Among the patients with Sturge-Weber syndrome for whom characteristics were analysed (n = 132), 76.52% of patients had their first epileptic seizures within their first year of life. The risk factors for cognitive decline were seizure history ≥ 2 years [adjusted odds ratio (aOR) = 3.829, 95% confidence interval (CI): 1.810-9.021, P = 0.008)], bilateral leptomeningeal angiomas (aOR = 3.173, 95% CI: 1.970-48.194, P = 0.013), age at onset <1 year (aOR = 2.903, 95% CI: 1.230-6.514, P = 0.013), brain calcification (aOR = 2.375, 95% CI: 1.396-5.201, P = 0.021) and left leptomeningeal angiomas (aOR = 2.228, 95% CI: 1.351-32.571, P = 0.030). Of the patients who underwent epilepsy surgery (n = 90), 44 were subject to focal resection, and 46 underwent hemisphere surgery (19 anatomical hemispherectomies and 27 modified hemispherotomies). A postoperative seizure-free status, favourable cognitive outcomes, and favourable motor outcomes were achieved in 83.33%, 44.44% and 43.33% of surgical patients, respectively. The modified hemispherotomy group had similar surgical outcomes, less intraoperative blood loss and shorter postoperative hospital stays than the anatomical hemispherectomy group. Regarding seizure outcomes, full resection (aOR = 11.115, 95% CI: 1.260-98.067, P = 0.020) and age at surgery < 2 years (aOR = 6.040, 95% CI: 1.444-73.367, P = 0.031) were positive influential factors for focal resection. Age at surgery < 2 years (aOR = 15.053, 95% CI: 1.050-215.899, P = 0.036) and infrequent seizures (aOR = 8.426, 95% CI: 1.086-87.442, P = 0.042; monthly versus weekly) were positive influential factors for hemisphere surgery. In conclusion, epilepsy surgery resulted in a good postoperative seizure-free rate and favourable cognitive and motor functional outcomes and showed acceptable safety for patients with epilepsy and Sturge-Weber syndrome. Modified hemispherotomy is a less invasive and safer type of hemisphere surgery than traditional anatomic hemispherectomy with similar surgical outcomes. Early surgery may be helpful to achieve better seizure outcomes and cognitive protection, while the risk of surgery for young children should also be considered.

Rasmussen's encephalitis is characterized by relatively lower production of IFN-ß and activated cytotoxic T cell upon herpes viruses infection.

BACKGROUND: The etiology of Rasmussen's encephalitis (RE), a rare chronic neurological disorder characterized by CD8+ T cell infiltration and unihemispheric brain atrophy, is still unknown. Various human herpes viruses (HHVs) have been detected in RE brain, but their contribution to RE pathogenesis is unclear. METHODS: HHVs infection and relevant immune response were compared among brain tissues from RE, temporal lobe epilepsy (TLE) and traumatic brain injury (TBI) patients. Viral antigen or genome, CD8+ T cells, microglia and innate immunity molecules were analyzed by immunohistochemical staining, DNA dot blot assay or immunofluorescence double staining. Cytokines were measured by multiplex flow cytometry. Cell apoptosis was visualized by TUNEL staining. Viral infection, immune response and the severity of unihemispheric atrophy were subjected to correlation analysis. RESULTS: Antigens of various HHVs were prevalent in RE and TLE brains, and the cumulative viral score of HHVs positively correlated with the unihemispheric atrophy in RE patients. CD8+ T cells infiltration were observed in both RE and TLE brains and showed co-localization with HHV antigens, but their activation, as revealed by Granzyme B (GZMB) release and apoptosis, was found only in RE. In comparison to TLE, RE brain tissues contained higher level of inflammatory cytokines, but the interferon-ß level, which was negatively correlated with cumulative viral score, was relatively lower. In line with this, the DNA sensor STING and IFI16, rather than other innate immunity signaling molecules, were insufficiently activated in RE. CONCLUSIONS: Compared with TBI, both RE and TLE had prevalently HHV infection and immune response in brain tissues. However, in comparison to TLE, RE showed insufficient activation of antiviral innate immunity but overactivation of cytotoxic T cells. Our results show the relatively lower level of antiviral innate immunity and overactivation of cytotoxic T cells in RE cases upon HHV infection, the overactivated T cells might be a compensate to the innate immunity but the causative evidence is lack in our study and need more investigation in the future.

Comparative Effectiveness of Stereotactic Electroencephalography Versus Subdural Grids in Epilepsy Surgery.

OBJECTIVE: The aim was to compare the outcomes of subdural electrode (SDE) implantations versus stereotactic electroencephalography (SEEG), the 2 predominant methods of intracranial electroencephalography (iEEG) performed in difficult-to-localize drug-resistant focal epilepsy. METHODS: The Surgical Therapies Commission of the International League Against Epilepsy created an international registry of iEEG patients implanted between 2005 and 2019 with ≥1 year of follow-up. We used propensity score matching to control exposure selection bias and generate comparable cohorts. Study endpoints were: (1) likelihood of resection after iEEG; (2) seizure freedom at last follow-up; and (3) complications (composite of postoperative infection, symptomatic intracranial hemorrhage, or permanent neurological deficit). RESULTS: Ten study sites from 7 countries and 3 continents contributed 2,012 patients, including 1,468 (73%) eligible for analysis (526 SDE and 942 SEEG), of whom 988 (67%) underwent subsequent resection. Propensity score matching improved covariate balance between exposure groups for all analyses. Propensity-matched patients who underwent SDE had higher odds of subsequent resective surgery (odds ratio [OR] = 1.4, 95% confidence interval [CI] 1.05, 1.84) and higher odds of complications (OR = 2.24, 95% CI 1.34, 3.74; unadjusted: 9.6% after SDE vs 3.3% after SEEG). Odds of seizure freedom in propensity-matched resected patients were 1.66 times higher (95% CI 1.21, 2.26) for SEEG compared with SDE (unadjusted: 55% seizure free after SEEG-guided resections vs 41% after SDE). INTERPRETATION: In comparison to SEEG, SDE evaluations are more likely to lead to brain surgery in patients with drug-resistant epilepsy but have more surgical complications and lower probability of seizure freedom. This comparative-effectiveness study provides the highest feasible evidence level to guide decisions on iEEG. ANN NEUROL 2021;90:927-939.

Timing of referral to evaluate for epilepsy surgery: Expert Consensus Recommendations from the Surgical Therapies Commission of the International League Against Epilepsy.

Epilepsy surgery is the treatment of choice for patients with drug-resistant seizures. A timely evaluation for surgical candidacy can be life-saving for patients who are identified as appropriate surgical candidates, and may also enhance the care of nonsurgical candidates through improvement in diagnosis, optimization of therapy, and treatment of comorbidities. Yet, referral for surgical evaluations is often delayed while palliative options are pursued, with significant adverse consequences due to increased morbidity and mortality associated with intractable epilepsy. The Surgical Therapies Commission of the International League Against Epilepsy (ILAE) sought to address these clinical gaps and clarify when to initiate a surgical evaluation. We conducted a Delphi consensus process with 61 epileptologists, epilepsy neurosurgeons, neurologists, neuropsychiatrists, and neuropsychologists with a median of 22 years in practice, from 28 countries in all six ILAE world regions. After three rounds of Delphi surveys, evaluating 51 unique scenarios, we reached the following Expert Consensus Recommendations: (1) Referral for a surgical evaluation should be offered to every patient with drug-resistant epilepsy (up to 70 years of age), as soon as drug resistance is ascertained, regardless of epilepsy duration, sex, socioeconomic status, seizure type, epilepsy type (including epileptic encephalopathies), localization, and comorbidities (including severe psychiatric comorbidity like psychogenic nonepileptic seizures [PNES] or substance abuse) if patients are cooperative with management; (2) A surgical referral should be considered for older patients with drug-resistant epilepsy who have no surgical contraindication, and for patients (adults and children) who are seizure-free on 1-2 antiseizure medications (ASMs) but have a brain lesion in noneloquent cortex; and (3) referral for surgery should not be offered to patients with active substance abuse who are noncooperative with management. We present the Delphi consensus results leading up to these Expert Consensus Recommendations and discuss the data supporting our conclusions. High level evidence will be required to permit creation of clinical practice guidelines.

The cognitive functions and seizure outcomes of patients with low-grade epilepsy-associated neuroepithelial tumors.

PURPOSE: The aim of the study was to evaluate the cognitive functions and seizure outcomes of patients with low-grade epilepsy-associated neuroepithelial tumors (LEATs). METHODS: We retrospectively reviewed the clinical data of patients who underwent preoperative neuropsychological evaluations and subsequent epilepsy surgery for LEATs. The neuropsychological results of full-scaled intelligence quotient (FSIQ) and full-scaled memory quotient (FSMQ) were analyzed, as well as the postoperative seizure outcomes. RESULTS: Of the 138 patients included in the study, 59 patients (40.4%) were female and 47 (36.6%) patients were children. Preoperatively, 138 patients received FSIQ assessments and 30 patients (21.7%) had an intellectual deficit (FSIQ < 80 scores); 124 patients received FSMQ assessments and 32 patients (25.8%) had a memory deficit (FSMQ < 80 scores). Younger age at seizure onset (OR 0.93; P = 0.035) and discordant ictal electroencephalography (EEG) findings (OR 5.26; P = 0.001) were found to predict intellectual deficits, while abnormal hippocampus (OR 2.36; P = 0.051) as well as discordant ictal EEG findings (OR 4.03; P = 0.007) tended to cause memory deficits. During postoperative follow-up, 123 patients (90.7%) were followed up at least 12 months, and among them, 105 patients (85.4%) got seizure-free (Engel class I), while 18 patients (14.6%) were not (Engel class II-IV); longer duration of epilepsy (OR 1.01; P < 0.001) and discordant interictal EEG findings (OR 5.91; P = 0.005) were found to be related to poor seizure outcomes in patients with LEATs. CONCLUSION: Cognitive deficits commonly occur in patients with LEATs, especially in patients with early or childhood seizures. Early surgical intervention, however, could prevent most of patients from repeated seizure onsets and thus cognitive impairments.

Progress in pathogenesis and therapy of Rasmussen's encephalitis.

Rasmussen's encephalitis (RE) is a rare condition of unknown etiology that causes a severe chronically neurological disorder with mostly affecting children. The main clinical feature of RE includes frequent seizures with drug-resistant, unilateral hemispheric atrophy, and progressive neurological deficits. In this review, we summarized five pathogenesis on the basis of the current research including virus infection, antibody-mediated degeneration, cell-mediated immunity, microglia-induced degeneration, and genetic mutations. So far, no exact virus in RE brain tissue or definite antigen in humoral immune system was confirmed as the determined etiology. The importance of cytotoxic CD8+ T lymphocytes and activated microglial and the role of their immune mechanism in RE development are gradually emerging with the deep study. Genetic researches support the notion that the pathogenesis of RE is probably associated with single nucleotide polymorphisms on immune-related genes, which is driven by affecting inherent antiretroviral innate immunity. Recent advances in treatment suggest immunotherapy could partially slows down the progression of RE according to the histopathology and clinical presentation, which aimed at the initial damage to the brain by T cells and microglia in the early stage. However, the cerebral hemispherectomy is an effective means to controlling the intractable seizure, which is accompanied by neurological complications inevitably. So, the optimal timing for surgical intervention is still a challenge for RE patient. On the contrary, exploration on other aspects of pathogenesis such as dysfunction of adenosine system may offer a new therapeutic option for the treatment of RE in future.

Vagus nerve stimulation for drug-resistant epilepsy induced by tuberous sclerosis complex.

OBJECTIVE: This study investigated the dynamic and long-term efficacy of vagus nerve stimulation (VNS) in patients with drug-resistant epilepsy (DRE) induced by tuberous sclerosis complex (TSC). In addition, the impact of VNS on cognition and emotion after a one-year follow-up was evaluated. METHODS: A total of 17 patients diagnosed with DRE induced by TSC were retrospectively recruited between 2008 and 2019. Dynamic changes in seizure frequency were observed in the responders (≥50% reduction of seizure frequency at last follow-up) and non-responders. Clinical characteristics and seizure outcomes were comprehensively analyzed to determine factors associated with seizure outcomes. The Wechsler intelligence scale was applied in a subgroup of six pediatric patients, whereas the Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) were assessed in a subgroup of nine patients to determine the impact of VNS therapy on cognitive performance and emotional state. RESULTS: The follow-up duration for the 17 patients who underwent VNS treatment ranged from 0.5 to 10 years (mean ±â€¯SD: 4.1 ±â€¯3.2 years). Monthly seizures decreased significantly from three months to four years post-treatment (p < 0.05). At the last follow-up, 70.6% of the patients achieved at least a 50% reduction in seizure frequency, and three patients were completely seizure free. Comparatively, non-responder patients experienced deterioration of seizure frequency after the first year. Notably, after one-year follow-up the mean standard score of full-scale intelligence quotient increased from 67.33 to 69.5 (p = 0.078) while the mean, standard score of SDS decreased from 49.22 to 45.67 (p = 0.003) compared to preoperative neuropsychological evaluation results. CONCLUSION: VNS is a safe and effective treatment for patients with DRE caused by TSC. Although early outcomes were encouraging, a follow-up of at least one-year was required to predict long-term outcomes in patients receiving VNS treatment. Moreover, VNS may improve depressive mood in patients with DRE caused by TSC. Further investigations are needed to validate the present results.

Individual Variability in Functional Organization of the Human and Monkey Auditory Cortex.

Accumulating evidence shows that auditory cortex (AC) of humans, and other primates, is involved in more complex cognitive processes than feature segregation only, which are shaped by experience-dependent plasticity and thus likely show substantial individual variability. However, thus far, individual variability of ACs has been considered a methodological impediment rather than a phenomenon of theoretical importance. Here, we examined the variability of ACs using intrinsic functional connectivity patterns in humans and macaques. Our results demonstrate that in humans, interindividual variability is greater near the nonprimary than primary ACs, indicating that variability dramatically increases across the processing hierarchy. ACs are also more variable than comparable visual areas and show higher variability in the left than in the right hemisphere, which may be related to the left lateralization of auditory-related functions such as language. Intriguingly, remarkably similar modality differences and lateralization of variability were also observed in macaques. These connectivity-based findings are consistent with a confirmatory task-based functional magnetic resonance imaging analysis. The quantification of variability in auditory function, and the similar findings in both humans and macaques, will have strong implications for understanding the evolution of advanced auditory functions in humans.

Dissociable Auditory Cortico-Cerebellar Pathways in the Human Brain Estimated by Intrinsic Functional Connectivity.

The cerebellum, a structure historically associated with motor control, has more recently been implicated in several higher-order auditory-cognitive functions. However, the exact functional pathways that mediate cerebellar influences on auditory cortex (AC) remain unclear. Here, we sought to identify auditory cortico-cerebellar pathways based on intrinsic functional connectivity magnetic resonance imaging. In contrast to previous connectivity studies that principally consider the AC as a single functionally homogenous unit, we mapped the cerebellar connectivity across different parts of the AC. Our results reveal that auditory subareas demonstrating different levels of interindividual functional variability are functionally coupled with distinct cerebellar regions. Moreover, auditory and sensorimotor areas show divergent cortico-cerebellar connectivity patterns, although sensorimotor areas proximal to the AC are often functionally grouped with the AC in previous connectivity-based network analyses. Lastly, we found that the AC can be functionally segmented into highly similar subareas based on either cortico-cerebellar or cortico-cortical functional connectivity, suggesting the existence of multiple parallel auditory cortico-cerebellar circuits that involve different subareas of the AC. Overall, the present study revealed multiple auditory cortico-cerebellar pathways and provided a fine-grained map of AC subareas, indicative of the critical role of the cerebellum in auditory processing and multisensory integration.

Co-activation patterns across multiple tasks reveal robust anti-correlated functional networks.

Whether antagonistic brain states constitute a fundamental principle of human brain organization has been debated over the past decade. Some argue that intrinsically anti-correlated brain networks in resting-state functional connectivity are an artifact of preprocessing. Others argue that anti-correlations are biologically meaningful predictors of how the brain will respond to different stimuli. Here, we investigated the co-activation patterns across the whole brain in various tasks and test whether brain regions demonstrate anti-correlated activity similar to those observed at rest. We examined brain activity in 47 task contrasts from the Human Connectome Project (N = 680) and found robust antagonistic interactions between networks. Regions of the default network exhibited the highest degree of cortex-wide negative connectivity. The negative co-activation patterns across tasks showed good correspondence to that derived from resting-state data processed with global signal regression (GSR). Interestingly, GSR-processed resting-state data was a significantly better predictor of task-induced modulation than data processed without GSR. Finally, in a cohort of 25 patients with depression, we found that task-based anti-correlations between the dorsolateral prefrontal cortex (DLPFC) and subgenual anterior cingulate cortex were associated with clinical efficacy of transcranial magnetic stimulation therapy targeting the DLPFC. Overall, our findings indicate that anti-correlations are a biologically meaningful phenomenon and may reflect an important principle of functional brain organization.

Scalp-HFO indexes are biomarkers for the lateralization and localization of the epileptogenic zone in preoperative assessment.

During the noninvasive evaluation phase for refractory epilepsy, the localization of the epileptogenic zone (EZ) is essential for the surgical protocols. Confirmation of laterality is required when the preoperative evaluation limits the EZ to bilateral anterior temporal lobes or bilateral frontal lobes. High-frequency oscillations (HFOs) are considered to be promising biological markers for the EZ. However, a large number of studies on HFOs stem from intracranial research. There were few quantitative measures for scalp HFOs, so we proposed a new method to quantify and analyze scalp HFOs. This method was called the "scalp-HFO index" (HI) and calculated in both the EZ and non-EZ. The calculation was based on the numbers and spectral power of scalp HFOs automatically detected. We labeled the brain lobes involved in the EZ as regions of interest (ROIs). The HIs based on the ripple numbers (n-HI) and spectral power (s-HI) were significantly higher in the ROI than in the contra-ROI (P = 0.012, P = 0.003), indicating that HIs contributed to the lateralization of EZ. The sensitivity and specificity of n-HI for the localization of the EZ were 90% and 79.58%, respectively, suggesting that n-HI was valuable in localizing the EZ. HI may contribute to the implantation strategy of invasive electrodes. However, few scalp HFOs were recorded when the EZ was located in the medial cortex region.NEW & NOTEWORTHY We proposed the scalp-high-frequency oscillation (HFO) index (HI) as a quantitative assessment method for scalp HFOs to locate the epileptogenic zone (EZ). Our results showed that the HI in regions of interest (ROIs) was significantly higher than in contra-ROIs. Sensitivity and specificity of HI based on ripple rates (n-HI) for EZ localization were 90% and 79.58%, respectively. If the n-HI of the brain region was >1.35, it was more likely to be an epileptogenic region. Clinical application of HIs as an indicator may facilitate localization of the EZ.

A concordance study determining language dominance between navigated transcranial magnetic stimulation and the Wada test in patients with drug-resistant epilepsy.

OBJECTIVE: It remains unclear whether transcranial magnetic stimulation (TMS) can replace the Wada test to determine language hemisphere dominance (HD). Using the Wada test as the gold standard, this study aimed to investigate the accuracy of navigated TMS (nTMS) in determining language HD. METHODS: This study enrolled nine right-handed patients with drug-resistant epilepsy. We hypothesized that application of nTMS to language-related areas of the language-dominant hemisphere would induce positive manifestation of language dysfunction (LD). To test our hypothesis, the patients were instructed to perform a visual object-naming task while nTMS was applied to the anterior (e.g., Broca's area) and posterior (e.g., Wernicke's area) regions, which are closely related to language processing. The Wada test result was used as the gold standard, and the diagnostic value of nTMS was assessed using the Kappa consistency test. RESULTS: The nTMS-induced LD positive rate for the bilateral anterior language areas (85.7%) was higher than that for the posterior language areas (57.1%). There was high consistency between nTMS stimulation of the left anterior and posterior language areas and the Wada test results for determining language HD. In contrast, the consistency of stimulation of the right anterior and posterior transfer sites was moderate (Kappa value = 0.545, P = 0.171) and low, respectively. For the latter, no statistical calculation was performed because stimulation of the right posterior speech area was negative in all patients compared with the Wada test results. CONCLUSIONS: Our findings revealed that using nTMS to stimulate language-related left anterior and posterior areas could predict language HD with high accuracy. When the stimulation performance of these areas is positive, nTMS and the Wada test are equally accurate. Observing only negative performance may indicate that language HD has been transferred to the right side.

Regulation of TWIK-related K+ channel 1 in the anterior hippocampus of patients with temporal lobe epilepsy with comorbid depression.

Epilepsy with comorbid depression has recently attracted increasing attention. Temporal lobe epilepsy (TLE) may represent an increased risk of developing depression, especially if the seizures do not generalize. The two-pore domain potassium channel-TWIK-related K+ channel (TREK-1) plays important roles in both epilepsy and depression. However, the changes in its expression in patients with epilepsy with comorbid depression remain unclear. In the present study, we analyzed depressive symptoms using neuropsychiatric scales in forty-two patients with drug-resistant TLE, who also underwent EEG in waking and sleeping states, as well as 3.0 T brain MRI. We tested for TREK-1 positive neurons and microglial cells in the anterior hippocampi of patients with drug-resistant TLE with and without comorbid depression (n=5/group). Approximately 31% of patients with TLE had comorbid depression (13/42). Meanwhile, the patients who had hippocampal sclerosis had much higher scores on the depression rating scale. The results indicated the contribution of hippocampal sclerosis to the development of depression. Immunostaining of TREK-1 channels was observed in neurons and glia in the anterior hippocampus. Increased immunoreactivity of TREK-1 neurons was observed in the hippocampi of patients with TLE with comorbid depression compared with nondepressed patients with TLE. TREK-1 was expressed in almost all microglia. Curiously, more activated TREK-1-positive microglia were observed in patients with TLE with depression than in those without depression. The results suggested that a change in TREK-1 immunoreactivity was involved, at least partly, in the development of depression as a comorbidity of TLE. Imbalance of the TREK-1 channel may be a potential target for the treatment of patients with epilepsy with comorbid depression.

Long-term efficacy and cognitive effects of bilateral hippocampal deep brain stimulation in patients with drug-resistant temporal lobe epilepsy.

PURPOSE: Temporal lobe epilepsy patients treated with hippocampal deep brain stimulation (Hip-DBS) have rarely been reported before. Preoperative and postoperative cognitive function is seldom analyzed. METHODS: Seven patients with drug-resistant temporal lobe epilepsy were included in this study. Bilateral Hip-DBS was performed in these patients. The stimulator was activated 1 month after the implantation. Then, the patients returned for further adjustments 4 months after the surgery and reprogramming every year. The seizure frequency, Wechsler Adult Intelligence Scale-IV, and Wechsler memory scale-IV were assessed blindly as the outcomes at each follow-up. RESULTS: After a mean 48-month follow-up, the mean seizure frequency significantly decreased (p = 0.011, paired t test; decrease of 78.1%). One patient (14.3%) was seizure-free by the last follow-up; six of seven (85.7%) patients had reductions in seizure frequency of at least 50%; one patient (14.3%) who did not comply with the antiepileptic drug instructions had a less than 50% reduction in seizure frequency. In addition, there were no significant decreases in intelligence or verbal and visual memory from baseline to the last follow-up (p = 0.736, paired t test; p = 0.380, paired t test, respectively). CONCLUSION: Hip-DBS could provide acceptable long-term efficacy and safety. For patients with drug-resistant temporal lobe epilepsy who are not suitable for resective surgery, Hip-DBS could become a potential therapeutic option.