Biology subjects

Kalia, S. K.

Publications and source records attributed to Kalia, S. K..

11 recordsLinked to original sources

bioRxiv2026

Inhibitory Evoked Potentials as a Spatially Dependent Intraoperative Marker of Clinical Tremor Reduction

Deep brain stimulation (DBS) of the ventral intermediate nucleus (Vim) of the thalamus may be used to treat medication refractory essential tremor. Using recordings from in vivo human Vim neurons, our previous work has suggested that evoked potentials (that we termed quasi-evoked inhibition) ~2 ms following high frequency microstimulation pulses may be related to inhibitory synapses onto the Vim. Here, we investigate whether (i) quasi-evoked inhibition is related to clinical tremor reduction, and (ii) if quasi-evoked inhibition is dependent on the stimulation location within the Vim. By developing an objective determination of the presence or absence of quasi-evoked inhibition and utilizing accelerometer recordings, we showed that recordings with quasi-evoked inhibition at 100 Hz microstimulation exhibit greater tremor reduction than those without (P < 0.05, BF > 30). The number of stimulation pulses with quasi-evoked inhibition is also correlated with tremor reduction (rho = 0.18, P < 0.05) at all stimulation frequencies >=100 Hz. Furthermore, by analyzing microelectrode trajectories reconstructed from structural MRIs, we found that proximity to the ventral caudal border (P < 0.005) and to a previously established sweet spot (P < 0.05) are anti-correlated with the number of stimulation pulses with quasi-evoked inhibition. Our findings suggest that quasi-evoked inhibition is a potential biomarker of tremor reduction by means of network inhibition, and the more posterior regions of the Vim may allow for better recruitment of inhibition. This may be useful for closed-loop stimulation design.

neuroscience↗

bioRxiv2026

Differentiating filter-induced oscillations from physiological stimulation-evoked potentials in intracranial recordings

IntroductionStimulation-evoked potentials (SEPs), recorded both during and after deep brain stimulation (DBS) surgery, have shown promise for guiding DBS targeting and programming. However, filtering protocols applied to stimulation trains produce an artifact we call a filter-induced oscillation (FIO) which closely mimics physiological SEPs. Hence, we outline the mechanistic origins of this distortion and describe a means of differentiating it from valid SEP activity. MethodsWe recorded in 18 patients undergoing DBS surgery targeting the subthalamic nucleus or globus pallidus internus. We stimulated target nuclei with cathode-first (CF) and anode-first (AF) pulses to record native SEPs, and in white matter tracts (null condition). Recordings were subsequently filtered to illustrate FIO. Next, we filtered harmonic frequencies of an artificial stimulation train to demonstrate FIO origins. Finally, FIO was deliberately generated in white matter recordings with a notch filter, and its behaviour contrasted with SEPs during AF and CF stimulation. ResultsFiltering stimulation trains produced FIOs that depended on filter order and corner frequency. We also showed that FIO emerges from filter-induced attenuations of harmonic frequencies which compose stimulation trains, producing oscillations of like frequency around pulses. Finally, FIOs reverse in polarity depending on AF or CF stimulation, whereas SEPs do not. ConclusionsGiven the potential for widespread adoption of SEPs in DBS targeting and programming, safe analytical protocols are imperative to avoid the induction of processing-related artifacts which can be misinterpreted as biological signals. Here we establish the necessary theory for identifying FIOs and tuning analytical pipelines to avoid their generation.

neuroscience↗

bioRxiv2025

Order-Selective Cells Tile Temporal Space and Predict Order Memory in Humans

Remembering the temporal order of events is critical for episodic memory, allowing us to link individual events into sequences. While the medial temporal lobe and prefrontal cortex are essential for this process, the underlying neural mechanisms remain poorly understood. Here we characterized the representation of order information at the level of single neurons and field potentials recorded from human neurosurgical patients watching naturalistic videos of everyday events and later recalling the order and content of the events depicted. We found order-selective cells (OSCs) in the human hippocampus, amygdala, and orbitofrontal cortex that responded selectively to specific event orders, independent of event content or absolute time. OSCs exhibited transient theta phase precession following their preferred order during both memory encoding and retrieval, the strength of which predicted participants order memory accuracy. During retrieval, OSC spike timing relative to theta varied with the relative position of their preferred event within the recalled event sequence, enabling selective retrieval of relevant events. These findings reveal a neural substrate for representing, encoding into and retrieving from memory absolute and relative ordinal relationships between discrete events. OSCs tile temporal space into discrete ordinal positions, thereby weaving episodic experiences into coherent temporal narratives.

neuroscience↗

bioRxiv2025

Frequency-dependent Inhibition during Deep Brain Stimulation of Thalamic Ventral Intermediate Nuclei

Deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (Vim) has been a standard therapy for essential tremor. It has been shown that high frequency ([≥]100Hz) DBS suppresses Vim neuronal firing and tremor activity, however, the underlying mechanisms are not fully understood. Here, we use in vivo recordings (single-unit) of Vim neurons (n=19, people with essential tremor) during different DBS frequencies to investigate whether neuronal suppression during high-frequency DBS occurs at synaptic/cellular levels (e.g., cell inhibition due to synaptic depression/fatigue during high-frequency DBS) or is influenced by network-level effects (e.g., recurrent inhibition). We propose a theoretical framework that explains DBS effects at both cellular and network levels, i.e., (continuous) high-frequency DBS not only depresses synapses projecting to Vim but also enables the recruitment of inhibitory neurons. A transient burst in the spiking activity of Vim during high-frequency DBS, prior to neuronal suppression, is likely providing sufficient network engagement to recruit inhibitory neurons that are silent during low-frequency DBS. Further, we detected a positive-going evoked-field potential effect, hereafter referred to as quasi-evoked inhibition, during high-frequency (100 Hz and 200 Hz) Vim-DBS in four out of 19 recording sites. Interestingly, it was observed that (i) neuronal suppression is stronger in these four neurons (P < 0.05), implying that inhibitory engagement during high-frequency DBS can further suppress neuronal firing, and (ii) quasi-evoked inhibition emerges after the transient burst (P < 1.00 x 10-7), i.e., the latter may give rise to the former. By removing DBS artifacts with a novel algorithm and characterizing the dynamics of quasi-evoked inhibitory activity, we showed that the likelihood of occurrence of this inhibitory activity negatively correlated with the instantaneous firing rate (P < 1.00 x 10-5). These results suggest that an excitatory-inhibitory balance is likely regulating Vim activities during high-frequency DBS. Our findings shed light on potential network mechanisms underlying Vim-DBS, which can provide insight for optimizing DBS by designing new stimulation patterns.

neuroscience↗

bioRxiv2023

Interrogating basal ganglia circuit function in Parkinson's disease and dystonia

BackgroundThe dichotomy between the hypo-versus hyperkinetic nature of Parkinsons disease (PD) and dystonia, respectively, is thought to be reflected in the underlying basal ganglia pathophysiology. ObjectiveInvestigate differences in globus pallidus internus (GPi) neuronal activity, and short- and long-term plasticity of direct pathway projections. ResultsGPi neurons were slower, burstier, and less regular in dystonia. In PD, symptom severity positively correlated with the power of low-beta frequency spiketrain oscillations. In dystonia, symptom severity negatively correlated with firing rate, and positively correlated with neuronal variability and the power of theta frequency spiketrain oscillations. Dystonia was moreover associated with less long-term plasticity and slower synaptic depression. ConclusionWe substantiated claims of hyper-versus hypofunctional GPi output in PD versus dystonia, and provided cellular-level validation of the pathological nature of theta and low-beta oscillations in respective disorders. Such circuit changes may be underlain by disease-related differences in plasticity of striato-pallidal synapses.

neuroscience↗

bioRxiv2023

Hippocampal Theta Phase Precession Supports Memory Formation and Retrieval of Naturalistic Experience in Humans

Linking different experiences together is a key aspect of episodic memory. A potential neural mechanism for linking sequential events over time is phase precession, which causes neurons to fire progressively earlier in time relative to theta-frequency local field potential oscillations. However, no direct link between phase precession and behaviorally assessed memory encoding or retrieval success has been established. We recorded the activity of single neurons and local field potentials in the human medial temporal lobe (MTL) while participants encoded and retrieved memories of movie clips. Transient brief theta bouts and theta phase precession were observed following cognitive boundaries during movie watching as well as following stimulus onset during memory retrieval. Phase precession was dynamic, with different neurons exhibiting phase precession in different task periods. The strength of phase precession provided information about memory encoding and retrieval success that was not available in firing rates, thereby linking the temporal code established by phase precession to behaviorally assessed memory strength. These data reveal phase precession during non spatial memory in humans and provide direct neural evidence for a functional role of phase precession in episodic memory.

neuroscience↗

bioRxiv2022

Single-neuron bursts encode pathological oscillations in Parkinson's disease and essential tremor

Deep brain stimulation procedures offer an invaluable opportunity to study disease through intracranial recordings from awake patients. Herein, we address the relationship between singleneuron and aggregate-level (local field potential; LFP) activities in the subthalamic nucleus (STN) and thalamic ventral intermediate nucleus (Vim) of patients with Parkinsons disease (n=19) and essential tremor (n=16), respectively. Both disorders have been characterized by pathologically elevated LFP oscillations, as well as an increased tendency for neuronal bursting. Our findings suggest that periodic single-neuron bursts encode both pathophysiological beta (13-33Hz; STN) and tremor (4-10Hz; Vim) LFP oscillations, evidenced by strong time-frequency and phase-coupling relationships between the bursting and LFP signals. Spiking activity occurring outside of bursts had no relationship to the LFP. In STN, bursting activity most commonly preceded the LFP oscillation, suggesting that neuronal bursting generated within STN may give rise to an aggregate-level LFP oscillation. In Vim, LFP oscillations most commonly preceded bursting activity, suggesting that neuronal firing may be entrained by periodic afferent inputs. In both STN and Vim, the phasecoupling relationship between LFP and high-frequency oscillation (HFO) signals closely resembled the relationships between the LFP and single-neuron bursting. This suggests that periodic singleneuron bursting is likely representative of a higher spatial and temporal resolution readout of periodic increases in the amplitude of HFOs, which themselves may be a higher resolution readout of aggregate-level LFP oscillations. Overall, our results may reconcile "rate" and "oscillation" models of Parkinsons disease and shed light onto the single-neuron basis and origin of pathophysiological oscillations in movement disorders. SignificanceIn surgical patients with Parkinsons disease and essential tremor, we leverage intracranial recordings to establish a link between pathophysiological phenomena across various scales of observation (spatio-temporal resolutions). We provide insights and reconcile theories about aberrant neurocircuit phenomena which underly theses debilitating, medically refractory movement disorders. Furthermore, our connectivity analyses between single-neuron and local field potential activities may shed light on the origin of the deleterious neural oscillations underlying these disorders. Ultimately, our findings may aid in the development or investigation of targeted therapies to address or correct underlying neurocircuit dysfunction, which can include neuropharmaceuticals, but also novel neuromodulatory strategies like closed-loop deep brain stimulation targeting pathophysiological oscillations and phase-dependent stimulation methods seeking to stimulate "at the right time/phase."

neuroscience↗

bioRxiv2021

A corollary discharge mediates saccade related inhibition of single units in mnemonic structures of the human brain

Despite the critical link between visual exploration and memory, little is known about how single-unit activity (SUA) in the human mesial temporal lobe (MTL) is modulated by saccadic eye movements (SEMs). Here we characterize SEM associated SUA modulations, unit-by-unit, and contrast them to image onset, and to occipital lobe SUA. We reveal evidence for a corollary discharge (CD)-like modulatory signal that accompanies SEMs, inhibiting/exciting a unique population of broad/narrow spiking units, respectively, before and during SEMs, and with directional selectivity. These findings comport well with the timing, directional nature, and inhibitory circuit implementation of a CD. Additionally, by linking SUA to event-related potentials (ERPs), which are directionally modulated following SEMs, we recontextualize the ERP associated with SEM as a proxy for both the strength of inhibition and saccade direction, providing a mechanistic underpinning for the more commonly recorded SEM-related ERP in the human brain.

neuroscience↗

bioRxiv2020

A theoretical framework for the site-specific and frequency-dependent neuronal effects of deep brain stimulation

With the growing interest in the expansion of deep brain stimulation indications, we aimed to provide experimental and computational insights into the brain-region-specific and frequency-dependent effects of extracellular stimulation on human neuronal activity. Experimentally, we demonstrated microstimulation-evoked excitatory neuronal responses in the ventral intermediate nucleus and reticular thalamus, and inhibitory responses in the subthalamic nucleus and substantia nigra pars reticulata; hypothesized to be the result of simultaneous activations of convergent afferent inputs. Higher stimulation frequencies led to a loss of site-specificity and convergence towards neuronal suppression; hypothesized to be mediated by synaptic depression. These experimental findings were reproduced by a computational framework in which relative distributions of convergent excitatory/inhibitory afferents were embedded within a model of short-term synaptic plasticity for the prediction of site-specific and frequency-dependent responses to extracellular stimulation. This theoretical framework may aid in the design of physiologically-informed stimulation paradigms in existing or prospective deep brain stimulation indications.

neuroscience↗

bioRxiv2020

The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates

Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system (UPS), and defective clearance of these protein aggregates results in proteotoxicity and cell death. Here we show that the eIF2 kinase HRI potentiates the autophagic clearance of cytosolic protein aggregates when the UPS is inhibited. In cells silenced for HRI, proteasome inhibition resulted in accumulation of aggresomes and ubiquitinated proteins, as well as cytotoxicity. Moreover, silencing of HRI resulted in cytotoxic accumulation of over-expressed -synuclein, a protein known to aggregate in Parkinsons disease, dementia with Lewy bodies, and multiple system atrophy. In agreement, protein aggregate accumulation and microglia activation were observed in the spinal cord white matter of 7-month old Hri-/- mice as compared to Hri+/+ littermates. Moreover, aged Hri-/- mice showed accumulation of misfolded -synuclein, indicative of misfolded proteins, in the lateral collateral pathway, a region of the sacral spinal cord horn that receives visceral sensory afferents from the bladder and distal colon, a pathological feature common to -synucleinopathies in humans where it may contribute to impaired micturition and/or constipation. Together, these results suggest that HRI contributes to a general cytosolic unfolded protein response (cUPR) that could be leveraged to bolster the clearance of cytotoxic protein aggregates.

cell biology↗

bioRxiv2020

Volitional Control of Individual Neurons in the Human Brain

Can the human brain, a complex interconnected structure of over 80 billion neurons learn to control itself at the most elemental scale - a single neuron. We directly linked the firing rate of a single (direct) neuron to the position of a box on a screen, which participants tried to control. Remarkably, all subjects upregulated the firing rate of the direct neuron in memory structures of their brain. Learning was accompanied by improved performance over trials, simultaneous decorrelation of the direct neuron to local neurons, and direct neuron to beta frequency oscillation phase-locking. Such previously unexplored neuroprosthetic skill learning within memory related brain structures, and associated beta frequency phase-locking implicates the ventral striatum. Our demonstration that humans can volitionally control neuronal activity in mnemonic structures, may provide new ways of probing the function and plasticity of human memory without exogenous stimulation.

neuroscience↗