Biology subjects

Cohen, A. L.

Publications and source records attributed to Cohen, A. L..

6 recordsLinked to original sources

bioRxiv2026

The methodological foundations of lesion network mapping remain sound

Lesion network mapping (LNM) and related techniques have been used in over 200 studies, primarily to test whether anatomically distributed lesions that cause the same symptom fall within a common brain network. A recent article1 challenges the specificity and validity of this technique, suggesting that lesion network maps primarily reflect intrinsic properties of the normative connectome rather than lesion-symptom relationships. However, the data and procedures in van den Heuvel et al. do not reflect those used in most LNM studies. Further, the main conclusions were based on similarity between maps, but similarity does not imply the absence of meaningful differences. In contrast, LNM provides evidence for meaningful differences using specificity testing. Exemplary analyses of 1090 lesion locations from 34 prior LNM studies do not support van den Heuvels concerns and confirm the lesion-deficit specificity of LNM. While we encourage further methodological investigation, the analyses of van den Heuvel et al. do not invalidate prior LNM findings or future applications.

neuroscience↗

bioRxiv2024

Lesions that Cause Psychosis Map to a Common Brain Circuit in the Hippocampus

ImportanceIdentifying anatomy causally involved in psychosis could inform therapeutic neuromodulation targets for schizophrenia. ObjectiveTo assess whether lesions that cause secondary psychosis have functional connections to a common brain circuit. DesignThis case-control study mapped functional connections of published cases of lesions causing secondary psychosis compared with control lesions unassociated with psychosis. SettingThis study was conducted in a computational laboratory. ParticipantsPublished cases of lesion-induced psychosis were analyzed. Included subjects had documented brain lesions associated with new-onset psychotic symptoms without prior history of psychosis. Control cases included 1156 patients with lesions not associated with psychosis. Generalizability across lesional datasets was assessed using an independent cohort of 181 patients with brain lesions who subsequently underwent neurobehavioral testing. ExposuresLesions causing secondary psychosis. Main Outcomes and MeasuresPsychosis or no psychosis. Results153 lesions from published cases were determined to be causal of psychosis (65 [42%] male; mean [SD] age, 50.0 [20.8] years), 42 of which were described as "schizophrenia" or "schizophrenia-like". Lesions that caused secondary psychosis mapped to a common brain circuit defined by functional connectivity to the posterior subiculum of the hippocampus (84% functional overlap, pFWE<5 x 10-5). At a lower statistical threshold (75%> overlap, pFWE<5 x 10-4), this circuit included the ventral tegmental area, retrosplenial cortex, lobule IX and dentate nucleus of the cerebellum, and the mediodorsal and midline nuclei of the thalamus. This circuit was consistent when derived from "schizophrenia-like" cases (spatial r=0.98). We repeated these analyses after excluding lesions intersecting the hippocampus (n=47) and found a consistent functional connectivity profile (spatial r=0.98) with the posterior subiculum remaining the center of connectivity (>75% overlap, pFWE<5x10-5), demonstrating a circuit-level effect. In an independent observational cohort of patients with penetrating head trauma (n=181), lesions associated with symptoms of psychosis exhibited significantly similar connectivity profiles to the lesion-derived psychosis circuit (suspiciousness, p=0.025; unusual thought content, p=0.046). Voxels in the rostromedial prefrontal cortex (rmPFC) are highly correlated with this psychosis circuit (spatial r=0.82), suggesting the rmPFC as a promising TMS target for psychosis. Conclusions and RelevanceLesions that cause secondary psychosis affect a common brain circuit in the hippocampus. These results can help inform therapeutic neuromodulation targeting. Key PointsO_ST_ABSQuestionC_ST_ABSDo lesions that cause psychosis affect a common brain circuit? FindingsThis case-control study found that lesions causing psychosis specifically affected a common functional circuit aligning with the posterior subiculum of the hippocampus. This functional circuit was consistent across different psychotic symptoms, suggesting a shared neural substrate for psychosis. A similar circuit was derived when excluding lesions directly intersecting the hippocampus, indicating a circuit-level effect. MeaningIdentifying a common brain circuit causally involved in psychotic symptoms suggests that the hippocampus may be pivotal in the pathophysiology and treatment targeting of psychotic disorders.

neuroscience↗

bioRxiv2023

Lesion Network Localization of a Stable Personality Trait

ObjectiveTo identify a convergent neuroanatomical substrate for novelty seeking (NS), a stable personality trait, which could serve as a therapeutic target for transcranial magnetic stimulation (TMS). MethodsWe analyzed two independent datasets (total n=136) in which the Temperament and Character Inventory (TCI) was used to document alterations across 7 stable personality traits before and after brain lesions surgically induced by glioma resection. Using lesion network mapping, we examined whether alterations in NS were causally associated with lesions to specific brain networks. We assessed for strength of replication across datasets and specificity against other personality traits. ResultsLesion locations that are linked to NS map to a common brain with its largest cluster in the dorsal cingulate. This map was specific to NS relative to other personality traits and overlapped with prior published neuroimaging findings related to the term "novelty". Utilizing a pre-computed connectome, we also derived a map highlighting potential targets for non-invasive brain stimulation that may alter this stable personality trait. ConclusionsWe derived and cross-validated a brain network that is functionally connected to lesions that are causally responsible for the stable personality trait "novelty seeking". Lesions to this network were associated with changes in NS. This includes a superficial node within the dorsolateral prefrontal cortex that may serve as a promising TMS target to modulate or protect against abnormal NS.

neuroscience↗

bioRxiv2021

Novel temporal and spatial patterns of metastatic colonization from rapid-autopsy tumor biopsies

BackgroundMetastatic breast cancer is a deadly disease with a low 5-year survival rate. Tracking metastatic spread in living patients is difficult, and thus poorly understood. ResultsVia rapid autopsy, we have collected 30 tumor samples over 3 timepoints and across 8 organs from a triple-negative metastatic breast cancer patient. The large number of sites sampled, together with deep whole genome sequencing and advanced computational analysis, allowed us to comprehensively reconstruct the tumors evolution at subclonal resolution. The most unique, previously not reported aspect of the tumors evolution we observed in this patient was the presence of "subclone incubators", i.e. already metastatic sites where substantial tumor evolution occurred before colonization of additional sites and organs by subclones that evolved at the incubator site. Overall, we identified four discrete waves of metastatic expansions, each of which resulted in a number of new, genetically similar metastasis sites that also enriched for particular organs (e.g. abdominal vs bone and brain). The lung played a critical role in facilitating metastatic spread in this patient: the lung was the first site of metastatic escape from the primary breast lesion; subclones at this site were the source of all four subsequent metastatic waves; and multiple sites in the lung acted as subclone incubators. Finally, functional annotation revealed that many known driver or metastasis-promoting tumor mutations in this patient were shared by some, but not all metastatic sites, highlighting the need for more comprehensive surveys of a patients metastases for effective clinical intervention. ConclusionsOur analysis revealed the presence of substantial tumor evolution at metastatic incubator sites, with potentially important clinical implications. Our study demonstrated that sampling of a large number of metastatic sites affords unprecedented detail for studying metastatic evolution.

cancer biology↗

bioRxiv2021

Convergent evolution of resistance pathways during early stage breast cancer treatment with combination cell cycle (CDK) and endocrine inhibitors

Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+), HER2 negative, breast cancer patients. However, the value of this combination in potentially curable earlier stage patients is not clear. Using single cell transcriptomic profiling, we examined the evolutionary trajectories of early stage breast cancer tumors using serial tumor biopsies from a clinical trial of preoperative endocrine therapy (letrozole) alone or in combination with the cell cycle inhibitor ribociclib. Applying hierarchical regression and Gaussian process mathematical modelling, we classified each tumor by whether it shrinks or persists with therapy and determined cancer phenotypes related to evolution of resistance and cell cycle transcriptional rewiring. We found that all patients tumors undergo subclonal evolution during therapy, irrespective of the clinical response. However, tumors subjected to endocrine therapy alone showed reduced diversity over time, while those facing combination therapy exhibited increased diversity. Despite different subclonal diversity, single nuclei RNA sequencing uncovered common phenotypic changes in tumor cells that persist following treatment. In these tumors, cancer cells with accelerated loss of estrogen signaling have convergent up-regulation of the JNK pathway, while cells that maintain estrogen signaling during therapy show potentiation of CDK4/6 activation consistent with ERBB4 and ERK signaling up-regulation. These convergent phenotypes were associated with growing tumors resistant to combination therapy. Cell cycle reconstruction identified that these tumors can rebound during combination therapy treatment, indicating stronger selection and promotion of a proliferative state. These results indicate that combination therapy in early stage ER+ breast cancers with ER and CDK inhibition drives rapid evolution of resistance via a shift from estrogen signaling to alternative growth factor receptor mediated proliferation and JNK signaling activation, concordant with a bypass in the G1 checkpoint.

cancer biology↗

bioRxiv2018

Comparison of stimulus-evoked BOLD responses in human and monkey visual cortex

We characterized the blood oxygenation level dependent (BOLD) signal in humans and macaque monkeys by comparing the response in visual cortex to a single checkerboard or two checkerboards, spaced 1.5, 3.0, or 4.5 s apart. We found that the magnitude and shape of the BOLD response to a single checkerboard was similar in the two species. In addition, we found that the BOLD responses summed similarly, and that at an inter-stimulus interval (ISI) of 4.5 sec BOLD summation was nearly linear in both species. When comparing the ratio of the amplitude of the response to the second checkerboard at the 4.5 sec ISI with that of the single checkerboard between subjects in both species, the results from both monkey subjects fell within one standard deviation of the mean human results (human mean (n=12): .95 +/- .31 second/single response amplitude; monkey 1: 1.16; monkey 2: .86). At the shorter ISIs, both species demonstrated increased suppression of the BOLD response to the second checkerboard. These findings indicate that the magnitude of the BOLD response to events separated by 4.5 seconds can be accurately measured in and compared between human and monkey visual cortex.

neuroscience↗