Biology subjects

Perlmutter, J. S.

Publications and source records attributed to Perlmutter, J. S..

4 recordsLinked to original sources

bioRxiv2026

Parietal Cortex Transcriptomics Refines Parkinson Disease GWAS Nomination and Highlights STAT3 as a Putative Upstream Glial Regulator

Parkinson disease (PD) affects more than 1.1 million individuals in the United States and around 12 million worldwide. Although Genome Wide Association Studies (GWAS) have substantially advanced our understanding of PD genetic architecture, the regulatory mechanisms linking PD risk loci to disease-relevant gene expression remain incompletely characterized, limiting our ability to infer disease mechanisms from genetic associations. Here, we integrated disease-state parietal cortex transcriptomics with the International Parkinsons Disease Genomics Consortium (iPDGC) locus prioritization to refine PD gene nomination and identify biologically plausible candidates missed by GWAS-only approaches. Using bulk RNA-seq from 99 neuropathologically confirmed PD cases and 30 neuropathologically confirmed controls, we prioritized candidate genes across 78 loci and classified them according to concordance between genetic evidence and differential expression in diseased cortices. This integrative approach recovered candidate genes not captured by external GWAS-based prioritization methods and highlighted synaptic, lysosomal, and proteostasis pathways as major components of PD risk biology. Network and transcription factor analyses further suggested coordinated regulation of these genes, with STAT3 emerging as a putative upstream glial regulator. Together, these findings suggest that integrating disease-state transcriptomics with genetic prioritization can refine PD risk-gene nomination and uncover regulatory programs that may be missed by GWAS alone.

neuroscience↗

bioRxiv2025

Temporal-orbitofrontal pathway regulates choices across physical reward and visual novelty

Perceptually novel objects have profound impacts on our daily decisions. People often pay to try novel meals over familiar ones, or to see novel visual scenes at art exhibits and travel destinations. This suggests that perceptual novelty and the value of physical rewards, such as food, interact at the level of neural circuits to guide decisions, but where and how is unknown. We designed a behavioral task to study this novelty-reward interaction in animals and to uncover its neural underpinnings. Subjects chose among familiar offers associated with different expectations of novel objects and different expectations of juice rewards. Expectation of novel objects increased the preference for expected rewards. This novelty-reward interaction was reflected by neural activity in the anterior ventral temporal cortex (AVMTC) - a region previously implicated in the detection and prediction of novelty - and in the orbitofrontal cortex (OFC) - an area that receives prominent AVMTC inputs and is known for its capacity to signal subjective value of visual objects. Neural activity patterns suggested that AVMTC was upstream of OFC in the decision process. Chemogenetic disruption of the AVMTC[->]OFC circuit altered the impact of expected novelty on the valuation of physical reward. Hence, the ventral visual system impacts novelty-reward interactions during decisions through direct projections to OFC.

neuroscience↗

bioRxiv2019

Removal of high frequency contamination from motion estimates in single-band fMRI saves data without biasing functional connectivity

Denoising fMRI data requires assessment of frame-to-frame head motion and removal of the biases motion introduces. This is usually done through analysis of the parameters calculated during retrospective head motion correction (i.e., motion parameters). However, it is increasingly recognized that respiration introduces factitious head motion via perturbations of the main (B0) field. This effect appears as higher-frequency fluctuations in the motion parameters (> 0.1 Hz, here referred to as HF-motion), primarily in the phase-encoding direction. This periodicity can sometimes be obscured in standard single-band fMRI (TR 2.0 - 2.5 s.) due to aliasing. Here we examined (1) how prevalent HF-motion effects are in seven single-band datasets with TR from 2.0 - 2.5 s and (2) how HF-motion affects functional connectivity. We demonstrate that HF-motion is relatively trait-like and more common in older adults, those with higher body mass index, and those with lower cardiorespiratory fitness. We propose a low-pass filtering approach to remove the contamination of high frequency effects from motion summary measures, such as framewise displacement (FD). We demonstrate that in most datasets this filtering approach saves a substantial amount of data from FD-based frame censoring, while at the same time reducing motion biases in functional connectivity measures. These findings suggest that filtering motion parameters is an effective way to improve the fidelity of head motion estimates, even in single band datasets. Particularly large data savings may accrue in datasets acquired in older and less fit participants. Highlights- Single-band fMRI motion traces show factitious high-frequency content (HF-motion) - The magnitude of HF-motion relates to age and other demographic factors - HF-motion elevates framewise displacement (FD) and causes data loss - Substantial fMRI data can be recovered from censoring by filtering motion traces - Filtering motion traces reduces motion artifacts in functional connectivity

neuroscience↗

bioRxiv2017

Mapping Movement, Mood, Motivation, and Mentation in the Subthalamic Nucleus

The anatomical connections of the subthalamic nucleus (STN) have driven hypotheses about its functional anatomy, including the hypothesis that the precise anatomical location of STN deep brain stimulation (DBS) determines the variability of motor and non-motor responses across Parkinson disease (PD) patients. We previously tested that hypothesis using a three-dimensional (3D) statistical method to interpret the acute effects of unilateral DBS at each patients clinically optimized DBS settings and active contact. Here we report a similar analysis from a new study in which DBS parameters were standardized and DBS locations were chosen blind to clinical response. In 74 individuals with PD and STN DBS, STN contacts were selected near the dorsal and ventral border of the STN contralateral to the more affected side of the body. Participants were tested off PD medications in each of 3 conditions (ventral STN DBS, dorsal STN DBS and DBS off) for acute effects on mood, apathy, working memory, response inhibition and motor function. Voltage, frequency, and pulse width were standardized, and participants and raters were blind to condition. In a categorical analysis, both dorsal and ventral STN DBS improved mean motor function without affecting cognitive measures. Dorsal STN DBS induced greater improvement in rigidity than ventral STN DBS, whereas ventral STN DBS was more effective for improving anxiety and mood. In the 3D analysis, contact location was significant only for bradykinesia and resting tremor, with the greatest improvement occurring with DBS in dorsal STN and zona incerta. These results provide new, direct functional evidence for the anatomically-derived model of STN using the novel 3D analysis, in which motor function is most represented in dorsal STN. However, our data suggest that functional segregation between motor and non-motor areas of the STN is limited, since locations that induced improvements in motor function and mood overlapped substantially.

neuroscience↗