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Lesion network mapping method and split half replication. Individual amnesia-causing lesions were mapped to a common brain template (a). Connectivity between each lesion location and the rest of the brain was computed using resting state functional connectivity from 1000 healthy control subjects (b). Positive correlations with the lesion location are shown in warm colors while negative correlations (anticorrelations) are shown in cool colors. Individual lesion network maps were thresholded, binarized, and overlapped to identify connections common to the lesion locations (c). Random splitting of our amnesia-causing lesion sample into two cohorts demonstrates high reproducibility of lesion network overlap (d, e). Additional iterations of random splitting were similar (Supplementary Figure 2)
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Human memory is thought to depend on a circuit of connected brain regions, but this hypothesis has not been directly tested. We derive a human memory circuit using 53 case reports of strokes causing amnesia and a map of the human connectome (n = 1000). This circuit is reproducible across discovery (n = 27) and replication (n = 26) cohorts and speci...
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Citations
... The functional connectivity of each lesion was estimated by correlating the lesion location with a normative functional connectome derived from healthy young adult subjects (n=1000) (24) ( Figure 1A,B). A sensitivity analysis found that over 75% (116/155) of the lesions' functionalconnectivity maps overlapped the posterior subiculum of the hippocampus, with each map thresholded at |T|>7 as in prior work (18,19,22,25) (Figure 1C). These results were unchanged when using T-value thresholds of 5 and 10 (spatial r>0.99, peak remained in the subiculum). ...
... The results from these analyses identified the hippocampus and retrosplenial cortex as sensitive and specific functional connections to lesions that cause psychosis. These regions have long been known to be involved in memory, and have previously been implicated in a memory circuit derived from 53 lesions that cause amnesia (25). In addition, the functional connections of lesions that cause psychosis were more similar to the functional connections of lesions that cause was not certified by peer review) is the author/funder. ...
... We first examined the 53 cases used to derive a memory circuit (25) to identify if any of them had psychotic symptoms. We also examined the 155 cases used for this psychosis circuit to identify how many had amnestic symptoms. ...
Identifying the anatomy of circuits causal of psychosis could inform treatment targets for schizophrenia. We identified 155 published case reports of brain lesions that caused new-onset psychosis. We mapped connectivity of these lesions using a normative human fMRI connectome. Lesions causing psychosis mapped to a common brain circuit defined by functional connectivity to the posterior subiculum of the hippocampus. This circuit was consistent both across individual symptoms of psychosis (delusions, hallucinations, and thought disorders), and when excluding lesions that touched the hippocampus. In an independent observational study (n=181), lesions connected to this circuit were preferentially associated with psychotic symptoms. A location in the rostromedial prefrontal cortex with high connectivity to this psychosis circuit was identified as a potential target for transcranial magnetic stimulation. Based on these results, we conclude that lesions that cause psychosis have common functional connections to the posterior subiculum of the hippocampus.
... To identify the hub region of anxiety disorders as in previous work [26], we performed a conjunction analysis between the highly overlapping regions of the sensitivity map (≥80% [13 of 16] or 75% [12 of 16] for the analysis in Supplementary Figure 2) and voxels surviving both specificity tests (random-and disorder-controlled maps). We defined the whole brain connectivity t map of the hub region as the "human anxiety network", which was computed by the same methods for computing the study-specific t maps. ...
Background. Heterogeneous findings among anxiety disorder studies have hindered elucidation of the underlying pathophysiology and the development of mechanism-based therapies. Purpose. To determine whether structural MRI findings in anxiety disorder studies converge on a common network with therapeutic significance. Materials and Methods. In this retrospective study, a systematic literature search of PubMed and Web of Science databases was performed to identify coordinates of gray matter atrophy in patients with anxiety disorder. Atrophy coordinates were then mapped to an anxiety network constructed from the resting-state functional MRI (rs-fMRI) data of 652 healthy participants using “coordinate network mapping” and validated by specificity tests. The causal association of this network to anxiety symptoms was tested in a cohort of patients with brain lesions and emergent anxiety symptoms. The potential therapeutic utility of this anxiety network was then assessed by examining the clinical efficacy of network-targeted repetitive transcranial magnetic stimulation (rTMS) among a separate anxiety disorder cohort. Statistical analyses of images were performed using nonparametric tests and corrected for family-wise error. Results. Sixteen studies comprising 453 patients with anxiety (245 females; mean age ± SD , 31.4 ± 8.71 years) and 460 healthy controls (238 females; 31.7 ± 10.08 years) were included in the analysis. Atrophy coordinates were mapped to an anxiety network with a hub region situated primarily within the superficial amygdala. Lesions associated with emergent anxiety symptoms exhibited stronger connectivity within this anxiety network than lesions not associated with anxiety ( t = 2.99 ; P = .004 ). Moreover, the connectivity strength of rTMS targets in the anxiety network was correlated with the improvements of anxiety symptom after treatment ( r = .42 , P = .02 ). Conclusions. Heterogeneous gray matter atrophy among patients with anxiety disorder localize to a common network that may serve as an effective therapeutic target.
... Intuitively, one might expect lesions and brain atrophy patterns to align and contribute to similar symptomatology in brain disorders. Given that both processes can lead to neuronal loss or reduced activity, it is reasonable to expect that they would contribute to brain disorders in similar ways (Ferguson et al., 2019). However, some studies Stubbs et al., 2023) have shown that locations of brain atrophy show negative functional connectivity with the locations of lesions that cause the same symptom -that is, when spontaneous activity is increasing in the atrophy-derived circuit, it is simultaneously decreasing in the lesion-derived circuit. ...
Understanding the neuroanatomy of schizophrenia remains elusive due to heterogenous findings across neuroimaging studies. Here, we investigated whether patterns of brain atrophy associated with schizophrenia would localize to a common brain network. Using the human connectome as a wiring diagram, we identified a connectivity pattern, a schizophrenia network, uniting heterogenous results from 90 published studies of atrophy in schizophrenia (total n>8,000). This network was specific to schizophrenia, differentiating it from atrophy in high-risk individuals (n=3038), normal aging (n=4,195), neurodegenerative disorders (n=3,707), and other psychiatric conditions (n=3,432). The network was also stable with disease progression and across different clusters of schizophrenia symptoms. Patterns of brain atrophy in schizophrenia were negatively correlated with lesions linked to psychosis-related thought processes in an independent cohort (n=181). Our results propose a unique, stable, and unified schizophrenia network, addressing a significant portion of the heterogeneity observed in prior atrophy studies.
... For example, brain lesions that cause depression and brain stimulation therapies that relieve depression can occur in spatially distinct brain regions, but map to a common brain network 15 . Similarly, lesions that cause amnesia map to a common network that aligns with neuroimaging correlates of memory, abnormalities in Alzheimer's disease, and brain stimulation sites that modulate memory 16 . This approach has been extended to integrate correlational study-level data and is termed 'coordinate network mapping' 17 . ...
... One example would be the eventual integration of predictions of behaviour and cognition. Neuroimaging-based brain-behaviour relationships are still in the process of being understood, but meta-analytic network analyses such as lesion network mapping have demonstrated that specific clinical symptoms can emerge from impairment of remote yet functionally connected areas in a vast repertoire of neurological and psychiatric disorders [291][292][293][294] . Another study found that low-dimensional representations of glucose metabolism can explain both behavioural activation patterns and neurodegenerative patterns across various diseases 295 . ...
Neurodegenerative diseases are the most common cause of dementia. Although their underlying molecular pathologies have been identified, there is substantial heterogeneity in the patterns of progressive brain alterations across and within these diseases. Recent advances in neuroimaging methods have revealed that pathological proteins accumulate along specific macroscale brain networks, implicating the network architecture of the brain in the system-level pathophysiology of neurodegenerative diseases. However, the extent to which 'network-based neurodegeneration' applies across the wide range of neurodegenerative disorders remains unclear. Here, we discuss the state-of-the-art of neuroimaging-based connectomics for the mapping and prediction of neurodegenerative processes. We review findings supporting brain networks as passive conduits through which pathological proteins spread. As an alternative view, we also discuss complementary work suggesting that network alterations actively modulate the spreading of pathological proteins between connected brain regions. We conclude this Perspective by proposing an integrative framework in which connectome-based models can be advanced along three dimensions of innovation: incorporating parameters that modulate propagation behaviour on the basis of measurable biological features; building patient-tailored models that use individual-level information and allowing model parameters to interact dynamically over time. We discuss promises and pitfalls of these strategies for improving disease insights and moving towards precision medicine.
... One advance that has helped with symptom localization in ischemic stroke is the ability to test whether different lesions causing a common symptom map to a connected brain circuit rather than a single brain region [29]. This technique, termed lesion network mapping (LNM), uses an atlas of normative brain connectivity to identify brain regions connected to each lesion location [29][30][31][32][33][34][35][36][37]. Connections associated with a specific symptom can then be identified. ...
... Connections associated with a specific symptom can then be identified. In a recent study [35], stroke lesions causing memory dysfunction occurred in many different brain locations, but they were all part of a functionally connected brain circuit centered on the hippocampus [35]. This lesion-based memory circuit aligned with neuroanatomical models of memory [38], including the classic circuit of Papez. ...
... Connections associated with a specific symptom can then be identified. In a recent study [35], stroke lesions causing memory dysfunction occurred in many different brain locations, but they were all part of a functionally connected brain circuit centered on the hippocampus [35]. This lesion-based memory circuit aligned with neuroanatomical models of memory [38], including the classic circuit of Papez. ...
Background
Nearly 1 million Americans are living with multiple sclerosis (MS) and 30–50% will experience memory dysfunction. It remains unclear whether this memory dysfunction is due to overall white matter lesion burden or damage to specific neuroanatomical structures. Here we test if MS memory dysfunction is associated with white matter lesions to a specific brain circuit.
Methods
We performed a cross-sectional analysis of standard structural images and verbal memory scores as assessed by immediate recall trials from 431 patients with MS (mean age 49.2 years, 71.9% female) enrolled at a large, academic referral center. White matter lesion locations from each patient were mapped using a validated algorithm. First, we tested for associations between memory dysfunction and total MS lesion volume. Second, we tested for associations between memory dysfunction and lesion intersection with an a priori memory circuit derived from stroke lesions. Third, we performed mediation analyses to determine which variable was most associated with memory dysfunction. Finally, we performed a data-driven analysis to derive de-novo brain circuits for MS memory dysfunction using both functional (n = 1000) and structural (n = 178) connectomes.
Results
Both total lesion volume (r = 0.31, p < 0.001) and lesion damage to our a priori memory circuit (r = 0.34, p < 0.001) were associated with memory dysfunction. However, lesion damage to the memory circuit fully mediated the association of lesion volume with memory performance. Our data-driven analysis identified multiple connections associated with memory dysfunction, including peaks in the hippocampus (T = 6.05, family-wise error p = 0.000008), parahippocampus, fornix and cingulate. Finally, the overall topography of our data-driven MS memory circuit matched our a priori stroke-derived memory circuit.
Conclusions
Lesion locations associated with memory dysfunction in MS map onto a specific brain circuit centered on the hippocampus. Lesion damage to this circuit fully mediated associations between lesion volume and memory. A circuit-based approach to mapping MS symptoms based on lesions visible on standard structural imaging may prove useful for localization and prognosis of higher order deficits in MS.
... 19 These substructures collectively comprise a previously published memory circuit where preservation is predictive of memory retention after brain injury. 20 These substructures all have a low propensity for brain metastases and therefore can be safely spared in a WBRT plan without significantly increasing the risk of intracranial relapse. 21 The aim of this phase 2 clinical trial is to determine whether sparing the amygdala, corpus callosum, fornix, and hippocampus in patients receiving WBRT improves neurocognitive preservation. ...
Purpose
Recent advances to preserve neurocognitive function in patients treated for brain metastases include stereotactic radiosurgery, hippocampal avoidance whole brain radiation therapy (WBRT), and memantine administration. The hippocampus, corpus callosum, fornix, and amygdala are key neurocognitive substructures with a low propensity for brain metastases. Herein, we report our preliminary experience using a “memory-avoidance” WBRT (MA-WBRT) approach that spares these substructures for patients with >15 brain metastases.
Methods and Materials
Ten consecutive patients treated with MA-WBRT on a phase 2 clinical trial were reviewed. In each patient, the hippocampi, amygdalae, corpus callosum, and fornix were contoured. Patients were not eligible for MA-WBRT if they had metastases in these substructures. A memory-avoidance region was created using a 5-mm volumetric expansion around these substructures. Hotspots were avoided in the hypothalamus and pituitary gland. Coverage of brain metastases was prioritized over memory avoidance dose constraints. Dose constraints for these avoidance structures included a D100% ≤ 9 Gy and D0.03 cm³ ≤ 16 Gy (variation acceptable to 20 Gy). LINAC-based volumetric modulated arc therapy plans were generated for a prescription dose of 30 Gy in 10 fractions.
Results
On average, the memory avoidance structure volume was 37.1 cm³ (range, 25.2-44.6 cm³), occupying 2.5% of the entire whole brain target volume. All treatment plans met the D100% dose constraint, and 8 of 10 plans met the D0.03 cm³ constraint, with priority given to tumor coverage for the remaining 2 cases. Target coverage (D98% > 25 Gy) and homogeneity (D2% ≤ 37.5 Gy) were achieved for all plans.
Conclusions
Modern volumetric modulated arc therapy techniques allow for sparing of the hippocampus, amygdala, corpus callosum, and fornix with good target coverage and homogeneity. After enrollment is completed, quality of life and cognitive data will be evaluated to assess the efficacy of MA-WBRT to mitigate declines in quality of life and cognition after whole brain radiation.
... This technique involves the use of a large normative database of resting-state functional connectivity MRI data to identify brain regions that are functionally connected to lesioned brain regions. This technique has been used to characterize the neuroanatomical basis of amnesia (17), delusions (18), depression (19), mania (20), and many other neuropsychiatric syndromes (16,21). In the present study, we used this technique to characterize the brain network associated with spontaneous confabulation. ...
... For 21 of the 25 patients, lesions from published figures were traced on a Montreal Neurological Institute (MNI)-152 template in the two-dimensional plane(s) in which they were displayed based on neuroanatomical landmarks to ensure accurate tracing of the lesion location. Lesion regions of interest (ROIs) were provided by one of the authors (A.G.) for the remaining patients (patients [16][17][18][19] (14) and warped to MNI152 template space by using the FMRIB Software Library (FSL) linear image registration tool ( Figure 1). Although direct lesion tracing is susceptible to error, previous studies have shown high test-retest reliability of lesion tracings (20,24). ...
... The network of functionally connected brain regions to each lesion location was identified through lesion network mapping ( Figure 2) (16,17). Briefly, this technique involves determining the resting-state functional connectivity between each lesion location and the rest of the brain based on a publicly available connectome data set from 1,000 healthy right-handed subjects (mean6SD age521.362.9 years, range 18-35; 43% were male) (25). ...
Objective:
Spontaneous confabulation is a symptom in which false memories are conveyed by the patient as true. The purpose of the study was to identify the neuroanatomical substrate of this complex symptom and evaluate the relationship to related symptoms, such as delusions and amnesia.
Methods:
Twenty-five lesion locations associated with spontaneous confabulation were identified in a systematic literature search. The network of brain regions functionally connected to each lesion location was identified with a large connectome database (N=1,000) and compared with networks derived from lesions associated with nonspecific (i.e., variable) symptoms (N=135), delusions (N=32), or amnesia (N=53).
Results:
Lesions associated with spontaneous confabulation occurred in multiple brain locations, but they were all part of a single functionally connected brain network. Specifically, 100% of lesions were connected to the mammillary bodies (familywise error rate [FWE]-corrected p<0.05). This connectivity was specific for lesions associated with confabulation compared with lesions associated with nonspecific symptoms or delusions (FWE-corrected p<0.05). Lesions associated with confabulation were more connected to the orbitofrontal cortex than those associated with amnesia (FWE-corrected p<0.05).
Conclusions:
Spontaneous confabulation maps to a common functionally connected brain network that partially overlaps, but is distinct from, networks associated with delusions or amnesia. These findings lend new insight into the neuroanatomical bases of spontaneous confabulation.
... The appropriateness of using indirect estimates of functional disconnection to predict behavioural deficits, and the methods that can be used to determine these estimates, also remains contentious (Boes, 2021;Bowren et al., 2022;Salvalaggio et al., 2021a;Umarova & Thomalla, 2020). Some studies have found that indirect measures of functional disconnection have relatively poor utility for predicting behavioural deficits post-stroke compared with measures of structural disconnection (Salvalaggio et al., 2020); our findings do not challenge this view, although other studies report more success (Cohen et al., 2021;Ferguson et al., 2019;Padmanabhan et al., 2019). Discrepancies between studies may reflect differences in data pre-processing or the methods used to estimate the accuracy of behavioural predictions (Salvalaggio et al., 2021b). ...
Semantic cognition, the basis for our understanding of the world, is supported by both the storage of semantic representations and the ability to flexibly retrieve them – semantic control. Semantic control dictates our ability to parse ambiguous information, and is supported by a distributed semantic control network (SCN). Patients with semantic aphasia (SA) experience multimodal semantic control deficits following left hemisphere stroke. Using cognitive neuropsychology and neuroimaging, this thesis further explores the neural bases of semantic retrieval and tests the relevance of semantic control to emotion, valence, and reward. Key findings were: (i) SA patients experience diffuse disconnection beyond lesion site. Lesion and structural disconnection of left-lateralised SCN nodes predict semantic impairment, while domain-general control impairment is predicted by lesion to adjacent fronto-parietal regions and by interhemispheric structural disconnection. (ii) SA patients present with impaired categorisation of facial emotion portrayals, susceptible to effects of cues and miscues. (iii) Valence congruency between words facilitates semantic matching, while semantic relatedness facilitates valence matching. SA patients present with impaired valence matching, exacerbated by semantic distractors. (iv) Impairments in the retrieval of weak associations can be facilitated in SA using cued extrinsic rewards. (v) The retrieval of both contextual and emotional associations is associated with activation in SCN, with these tasks being dissociated by default mode subnetworks. Effects of retrieval demands on the default mode network run orthogonally to effects of task. This thesis provides novel insight into the complex neural basis of retrieving meaning and emotion. It also contributes to our understanding of the impairments in SA, as well as how they can be ameliorated. Finally, this thesis supplements conceptually-focused models of emotion processing, stressing a role of semantic control. This work contributes to an increasingly clear understanding of controlled semantic retrieval and its contribution to cognition across domains.
... For example, lesions that cause depression map to a specific brain circuit with a hub in the left dorsolateral prefrontal cortex and lesions that cause memory impairment map to the circuit of Papez, including the hippocampus. 43,44 DBS sites that cause depression or cognitive impairment in patients with Parkinson's disease are connected to these same circuits. 45,46 As such, avoiding these circuits could help guide DBS programming, but could be even more important in lesion-based treatments where side effects may be irreversible. ...
Historically, pathological brain lesions provided the foundation for localization of symptoms and therapeutic lesions were used as a treatment for brain diseases. New medications, functional neuroimaging and deep brain stimulation led to a decline in lesions in the past few decades. However, recent advances have improved our ability to localize lesion-induced symptoms, including localization to brain circuits rather than individual brain regions. Improved localization can lead to more precise treatment targets, which may mitigate traditional advantages of deep brain stimulation over lesions such as reversibility and tunability. New tools for creating therapeutic brain lesions such as high intensity focused ultrasound allow for lesions to be placed without a skin incision and are already in clinical use for tremor. Although there are limitations and caution is warranted, improvements in lesion-based localization are refining our therapeutic targets and improved technology is providing new ways to create therapeutic lesions, which together may facilitate the return of the lesion.
