Electrical stimulation of the brain is a unique tool to perturb endogenous neural signals, allowing us to evaluate the necessity of given neural processes to cognitive processing. An important issue, gaining increasing interest in the literature, is whether and how stimulation can be employed to selectively improve or disrupt declarative memory processes. Here, we provide a comprehensive review of both invasive and non-invasive stimulation studies aimed at modulating memory performance. The majority of past studies suggest that invasive stimulation of the hippocampus impairs memory performance; similarly, most non-invasive studies show that disrupting frontal or parietal regions also impairs memory performance, suggesting that these regions also play necessary roles in declarative memory. On the other hand, a handful of both invasive and non-invasive studies have also suggested modest improvements in memory performance following stimulation. These studies typically target brain regions connected to the hippocampus or other memory "hubs," which may affect endogenous activity in connected areas like the hippocampus, suggesting that to augment declarative memory, altering the broader endogenous memory network activity is critical. Together, studies reporting memory improvements/impairments are consistent with the idea that a network of distinct brain "hubs" may be crucial for successful memory encoding and retrieval rather than a single primary hub such as the hippocampus. Thus, it is important to consider neurostimulation from the network perspective, rather than from a purely localizationalist viewpoint. We conclude by proposing a novel approach to neurostimulation for declarative memory modulation that aims to facilitate interactions between multiple brain "nodes" underlying memory rather than considering individual brain regions in isolation.

The medial temporal lobes, prefrontal cortex and parts of parietal cortex form the neural underpinnings of episodic memory, which includes remembering both where and when an event occurred. However, the manner in which these three regions interact during retrieval of spatial and temporal context remains untested. We employed simultaneous electrocorticographical recordings across multilobular regions in patients undergoing seizure monitoring while they retrieved spatial and temporal context associated with an episode, and we used phase synchronization as a measure of network connectivity. Successful memory retrieval was characterized by greater global connectivity compared with incorrect retrieval, with the medial temporal lobe acting as a hub for these interactions. Spatial versus temporal context retrieval resulted in prominent differences in both the spectral and temporal patterns of network interactions. These results emphasize dynamic network interactions as being central to episodic memory retrieval, providing insight into how multiple contexts underlying a single event can be recreated in the same network.

Semantic memory underpins our understanding of objects, people, places, and ideas. Anomia, a disruption of semantic memory access, is the most common residual language disturbance and is seen in dementia and following injury to temporal cortex. While such anomia has been well characterized by lesion symptom mapping studies, its pathophysiology is not well understood. We hypothesize that inputs to the semantic memory system engage a specific heteromodal network hub that integrates lexical retrieval with the appropriate semantic content. Such a network hub has been proposed by others, but has thus far eluded precise spatiotemporal delineation. This limitation in our understanding of semantic memory has impeded progress in the treatment of anomia. We evaluated the cortical structure and dynamics of the lexical semantic network in driving speech production in a large cohort of patients with epilepsy using electrocorticography (n = 64), functional MRI (n = 36), and direct cortical stimulation (n = 30) during two generative language processes that rely on semantic knowledge: visual picture naming and auditory naming to definition. Each task also featured a non-semantic control condition: scrambled pictures and reversed speech, respectively. These large-scale data of the left, language-dominant hemisphere uniquely enable convergent, high-resolution analyses of neural mechanisms characterized by rapid, transient dynamics with strong interactions between distributed cortical substrates. We observed three stages of activity during both visual picture naming and auditory naming to definition that were serially organized: sensory processing, lexical semantic processing, and articulation. Critically, the second stage was absent in both the visual and auditory control conditions. Group activity maps from both electrocorticography and functional MRI identified heteromodal responses in middle fusiform gyrus, intraparietal sulcus, and inferior frontal gyrus; furthermore, the spectrotemporal profiles of these three regions revealed coincident activity preceding articulation. Only in the middle fusiform gyrus did direct cortical stimulation disrupt both naming tasks while still preserving the ability to repeat sentences. These convergent data strongly support a model in which a distinct neuroanatomical substrate in middle fusiform gyrus provides access to object semantic information. This under-appreciated locus of semantic processing is at risk in resections for temporal lobe epilepsy as well as in trauma and strokes that affect the inferior temporal cortex-it may explain the range of anomic states seen in these conditions. Further characterization of brain network behaviour engaging this region in both healthy and diseased states will expand our understanding of semantic memory and further development of therapies directed at anomia.

Cognitive control refers to the ability to produce flexible, goal-oriented behavior in the face of changing task demands and conflicting response tendencies. A classic cognitive control experiment is the Stroop-color naming task, which requires participants to name the color in which a word is written while inhibiting the tendency to read the word. By comparing stimuli with conflicting word-color associations to congruent ones, control processes over response tendencies can be isolated. We assessed the spatial specificity and temporal dynamics in the theta and gamma bands for regions engaged in detecting and resolving conflict in a cohort of 13 patients using a combination of high-resolution surface and depth recordings. We show that cognitive control manifests as a sustained increase in gamma band power, which correlates with response time. Conflict elicits a sustained gamma power increase but a transient theta power increase, specifically localized to the left cingulate sulcus and bilateral dorsolateral prefrontal cortex (DLPFC). Additionally, activity in DLPFC is affected by trial-by-trial modulation of cognitive control (the Gratton effect). Altogether, the sustained local neural activity in dorsolateral and medial regions is what determines the timing of the correct response.

BACKGROUND: Resection of the contrast-enhancing (CE) tumor represents the standard of care in newly diagnosed glioblastoma. However, some tumors ultimately diagnosed as glioblastoma lack contrast enhancement and have a low-grade appearance on imaging (non-CE glioblastoma). We aimed to (a) volumetrically define the value of non-CE tumor resection in the absence of contrast enhancement, and to (b) delineate outcome differences between glioblastoma patients with and without contrast enhancement. METHODS: The RANO resect group retrospectively compiled a global, eight-center cohort of patients with newly diagnosed glioblastoma per WHO 2021 classification. The associations between postoperative tumor volumes and outcome were analyzed. Propensity score-matched analyses were constructed to compare glioblastomas with and without contrast enhancement. RESULTS: Among 1323 newly diagnosed IDH-wildtype glioblastomas, we identified 98 patients (7.4%) without contrast enhancement. In such patients, smaller postoperative tumor volumes were associated with more favorable outcome. There was an exponential increase in risk for death with larger residual non-CE tumor. Accordingly, extensive resection was associated with improved survival compared to lesion biopsy. These findings were retained on a multivariable analysis adjusting for demographic and clinical markers. Compared to CE glioblastoma, patients with non-CE glioblastoma had a more favorable clinical profile and superior outcome as confirmed in propensity score analyses by matching the patients with non-CE glioblastoma to patients with CE glioblastoma using a large set of clinical variables. CONCLUSIONS: The absence of contrast enhancement characterizes a less aggressive clinical phenotype of IDH-wildtype glioblastomas. Maximal resection of non-CE tumors has prognostic implications and translates into favorable outcome.

BACKGROUND: The value of re-resection in recurrent glioblastoma remains controversial as a randomized trial that specifies intentional incomplete resection cannot be justified ethically. Here, we aimed to (1) explore the prognostic role of extent of re-resection using the previously proposed Response Assessment in Neuro-Oncology (RANO) classification (based upon residual contrast-enhancing (CE) and non-CE tumor), and to (2) define factors consolidating the surgical effects on outcome. METHODS: The RANO resect group retrospectively compiled an 8-center cohort of patients with first recurrence from previously resected glioblastomas. The associations of re-resection and other clinical factors with outcome were analyzed. Propensity score-matched analyses were constructed to minimize confounding effects when comparing the different RANO classes. RESULTS: We studied 681 patients with first recurrence of Isocitrate Dehydrogenase (IDH) wild-type glioblastomas, including 310 patients who underwent re-resection. Re-resection was associated with prolonged survival even when stratifying for molecular and clinical confounders on multivariate analysis; ≤1 cm3 residual CE tumor was associated with longer survival than non-surgical management. Accordingly, maximal resection (class 2) had superior survival compared to submaximal resection (class 3). Administration of (radio-)chemotherapy in the absence of postoperative deficits augmented the survival associations of smaller residual CE tumors. Conversely, supramaximal resection of non-CE tumor (class 1) was not associated with prolonged survival but was frequently accompanied by postoperative deficits. The prognostic role of residual CE tumor was confirmed in propensity score analyses. CONCLUSIONS: The RANO resect classification serves to stratify patients with re-resection of glioblastoma. Complete resection according to RANO resect classes 1 and 2 is prognostic.

Leveraging firsthand experience, BRAIN-funded investigators conducting intracranial human neuroscience research propose two fundamental ethical commitments: (1) maintaining the integrity of clinical care and (2) ensuring voluntariness. Principles, practices, and uncertainties related to these commitments are offered for future investigation.

Background

Terminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (1) explore the prognostic utility of the classification system and (2) define how much removed non-CE tumor translates into a survival benefit.

Methods

The international RANO resect group retrospectively searched previously compiled databases from 7 neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and postoperative MRI were collected.

Results

We collected 1,008 patients with newly diagnosed IDHwt glioblastoma. 744 IDHwt glioblastomas were treated with radiochemotherapy per EORTC-26981/22981 (TMZ/RT→TMZ) following surgery. Among these homogenously treated patients, lower absolute residual tumor volumes (in cm3) were favorably associated with outcome: patients with "maximal CE resection" (class 2) had superior outcome compared to patients with "submaximal CE resection" (class 3) or "biopsy" (class 4). Extensive resection of non-CE tumor (≤5 cm3 residual non-CE tumor) was associated with better survival among patients with complete CE resection, thus defining class 1 ("supramaximal CE resection"). The prognostic value of the resection classes was retained on multivariate analysis when adjusting for molecular and clinical markers.

Conclusions

The proposed "RANO categories for extent of resection in glioblastoma" are highly prognostic and may serve for stratification within clinical trials. Removal of non-CE tumor beyond the CE tumor borders may translate into additional survival benefit, providing a rationale to explicitly denominate such "supramaximal CE resection."