LFP publications

Parvalbumin-expressing inhibitory neurons (PVNs) stabilize cortical network activity, generate gamma rhythms, and regulate experience-dependent plasticity. We found that PVNs act like a volume knob in the mouse auditory cortex (ACtx), bi-directionally adjusting neural and perceptual sensitivity to sound level over a 20 dB range. PVN-based gain adjustments were "sticky," such that a single bout of PVN activation at 40 Hz-but not at 1 or 70 Hz-sustainably dampened ACtx sound responsiveness, enhanced feedforward inhibition, and behaviorally desensitized mice to loudness. We then developed a mouse model of adult-onset hyperacusis by demonstrating ACtx hyperactivity, PVN hypofunction, and loudness hypersensitivity following a restricted noise-induced cochlear lesion. We found that several minutes of 40-Hz PVN stimulation in noise-exposed mice sustainably dampened ACtx hyperactivity and restored normal loudness sensitivity for 1 week. These findings demonstrate that sensory disorders caused by permanent peripheral injuries can be reversed by patterned stimulation of cortical circuits that directly regulate perception.

Basal forebrain cholinergic neurons (BFCNs) densely innervate auditory cortex (ACtx), conveying signals linked to internal brain states and external sensory cues. Acetylcholine (ACh) is known to rapidly modulate cortical circuits through nicotinic ACh receptor (nAChR)-mediated activation of layer 1 inhibitory neurons (L1-INs). However, BFCN terminals are also abundant in deeper layers, where their functional impact has received less attention. Using multi-plex in situ labeling across cortical layers and cell types, we found that layer 6 pyramidal neurons (L6-PNs) are highly enriched in diverse transcripts for nAChR subunits and muscarinic ACh receptors (mAChRs). In vivo optogenetic activation of BFCN axons revealed persistent modulation of regular spiking units in L2-6 but a rapid phasic activation only in L6. In acute slices, optogenetic activation of BFCN axons elicited fast nAChR-mediated excitatory post-synaptic potentials in L6-PNs, comparable to responses in L1-INs, and slower mAChR-mediated inhibitory responses. These findings identify L1-INs and excitatory L6-PNs as two major hubs for BFCN modulation of cortical circuits. By recruiting distinct receptor mechanisms and circuit motifs in L1 and L6, BFCNs may engage parallel pathways of cholinergic control that couple fast, transient modulation with slower, sustained regulation to shape cortical perception and plasticity.

As part of a deep brain stimulation (DBS) procedure, direct electrophysiological recordings from thalamic and basal ganglia circuits were obtained from a pediatric participant with secondary dystonia to examine the neural mechanisms of motor timing. The participant performed a two-phase repetitive timing task that began with synchronization to a series of externally presented auditory cues, followed by a continuation phase in which the participant maintained the movement rhythm without external guidance. Simultaneous recordings from stereoelectroencephalography (sEEG) leads implanted in the globus pallidus internus (GPi), subthalamic nucleus (STN), ventral oralis (Vo), centromedian nucleus (CM), and thalamic nuclei receiving projections from the cerebellum (ventral intermediate nucleus (VIM) and centrolateral nucleus (CL)) revealed behaviorally relevant neural dynamics. Local field potentials (LFPs) from recorded nuclei exhibited strong, time-locked responses during the synchronization phase, with reduced amplitudes during the continuation phase. Time-frequency analysis showed consistent power increases around the corresponding mean of the inter-response intervals (IRIs) in both behavioral output and neural signals, suggesting frequency-specific entrainment across circuits. These findings suggest of cerebellar-thalamic and basal ganglia contributions to temporal coordination.

Introduction Deep brain stimulation (DBS) is a neuromodulation method for treatment of various neurological disorders. Research on DBS has often focused on local inhibition or excitation effects, at the site of stimulation. However, it is well-known that DBS can lead to robust evoked potentials (EP) not only at the stimulation site, representing the local effect, but also in distant brain regions, representing the effects on distant targets. While the significance of these EPs for therapeutic outcomes is not known, it appears that the electrical effects of DBS have a partial modulatory impact on downstream targets. Nonetheless, it partly remains unclear through what mechanism DBS pulses travel to the distant targets or what portion of the pulses travel along the normal pathways from the stimulation site. The possible scenarios include orthodromic or antidromic pathways, accessory pathways, normally inhibited pathways, and direct electromagnetic activation of distant sites. We hypothesize that the pathways that transmit DBS pulses include the pathways that transmit intrinsic neural signals. Methods To test this, we performed a transfer function analysis on deep brain recordings from children with dystonia, during DBS-off condition and compared its impulse response with the transmission of signals from electrical stimulation during DBS-on condition. We compared impulse responses derived from intrinsic neural signals during voluntary movement (DBS-off) to evoked potentials (EPs) recorded during electrical stimulation (DBS-on), focusing on directional transmission (orthodromic vs. antidromic). Results DBS EPs were more accurately predicted by impulse responses corresponding to direct axonal activation rather than somatic relay. Significant correlations between intrinsic signal transfer functions and EPs, particularly in orthodromic directions ( p -value < 0.01) from pallidum to thalamus and subthalamic nucleus, support our hypothesis that DBS travels along physiological pathways. Discussion These results suggest that DBS engages existing motor pathways to reach distant targets, offering mechanistic insight into its network effects. This supports future approaches that could tailor treatment plans based on individual connectivity maps to improve clinical efficacy of DBS.

In this paper we aim to examine the correlation between diffusion tensor imaging parameters of anatomical connectivity and characteristics of signal transmission obtained from patient-specific transfer function models. Here, we focused on elucidating the correlation between structural and functional neural connectivity within a cohort of pediatric patients diagnosed with dystonia. Diffusion tractography images were obtained from 12 patients with dystonia prior to the deep brain stimulation surgery. For each patient, we processed the imaging data to estimate anatomical measures including fractional anisotropy, axial diffusivity, number of fibre tracts per unit area, and fibre tract length. After the implantation of temporary depth leads for each patient as part of their treatment plan, intracranial signals were recorded. Transfer function models of local field potential recordings and the corresponding measures of functional connectivity were computed for each patient. Linear mixed effect analysis was then employed to determine the relationship between transfer function measures and diffusion tractography parameters. Our results illustrate a positive correlation between fractional anisotropy, AD, and intrinsic neural transmission measures, representing amplification and spread of intrinsic neural oscillations, obtained from the transfer functions models. However, no significant correlation was found between the functional connectivity and number of fibre tracts or fibre lengths. Our findings suggest that white matter integrity, as measured by fractional anisotropy and AD, can potentially reflect the amplification and spread of intrinsic brain signals throughout the network. This study underscores the significant relationship between structural and functional connectivity, offering valuable insights into propagation of neural activity in the brain network and potential implications for optimizing non-invasive treatments and planning for neurological disorders.

When a visual stimulus is repeated, average neuronal responses typically decrease, yet they might maintain or even increase their impact through increased synchronization. Previous work has found that many repetitions of a grating lead to increasing gamma-band synchronization. Here, we show in awake macaque area V1 that both repetition-related reductions in firing rate and increases in gamma are specific to the repeated stimulus. These effects show some persistence on the timescale of minutes. Gamma increases are specific to the presented stimulus location. Further, repetition effects on gamma and on firing rates generalize to images of natural objects. These findings support the notion that gamma-band synchronization subserves the adaptive processing of repeated stimulus encounters.

Treatment refractory Tourette syndrome has been shown to be improved with deep brain stimulation, but with multiple possible stimulation locations and variable and incomplete benefit. This study presents a single case of complete amelioration of motor and verbal tics in a patient with Tourette syndrome during placement of 12 stereo-EEG electrodes to identify optimal targets for permanent stimulating electrodes. Subsequently, substantial improvement in motor and verbal tic frequency occurred with placement and programming of permanent electrodes in bilateral globus pallidus internus and nucleus accumbens, but without the complete resolution seen during depth electrode placement. We suggest that simultaneous stimulation at multiple patient-specific targets could provide effective control of Tourette symptomatology, but further study will be needed.

Field potential (FP) oscillations are believed to coordinate brain activity over large spatiotemporal scales, with specific features (e.g., phase and power) in discrete frequency bands correlated with motor output. Furthermore, complex correlations between oscillations in distinct frequency bands (phase-amplitude, amplitude-amplitude, and phase-phase coupling) are commonly observed. However, the mechanisms underlying FP-behavior correlations and cross-frequency coupling remain unknown. The thalamus plays a central role in generating many circuit-level neural oscillations, and single-unit activity in motor thalamus (Mthal) is correlated with behavioral output. We, therefore, hypothesized that motor thalamic spiking coordinates motor system FPs and underlies FP-behavior correlations. To investigate this possibility, we recorded wideband motor thalamic (Mthal) electrophysiology as healthy rats performed a two-alternative forced-choice task. Delta (1-4 Hz), beta (13-30 Hz), low gamma (30-70 Hz), and high gamma (70-200 Hz) power were strongly modulated by task performance. As in the cortex, the delta phase was correlated with beta/low gamma power and reaction time. Most interestingly, subpopulations of Mthal neurons defined by their relationship to the behavior exhibited distinct relationships with FP features. Specifically, neurons whose activity was correlated with action selection and movement speed were entrained to delta oscillations. Furthermore, changes in their activity anticipated power fluctuations in beta/low gamma bands. These complex relationships suggest mechanisms for commonly observed FP-FP and spike-FP correlations, as well as subcortical influences on motor output.

Deep brain stimulation (DBS) for secondary (acquired, combined) dystonia does not reach the high degree of efficacy achieved in primary (genetic, isolated) dystonia. We hypothesize that this may be due to variability in the underlying injury, so that different children may require placement of electrodes in different regions of basal ganglia and thalamus. We describe a new targeting procedure in which temporary depth electrodes are placed at multiple possible targets in basal ganglia and thalamus, and probing for efficacy is performed using test stimulation and recording while children remain for one week in an inpatient Neuromodulation Monitoring Unit (NMU). Nine Children with severe secondary dystonia underwent the NMU targeting procedure. In all cases, 4 electrodes were implanted. We compared the results to 6 children who had previously had 4 electrodes implanted using standard intraoperative microelectrode targeting techniques. Results showed a significant benefit, with 80% of children with NMU targeting achieving greater than 5-point improvement on the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS), compared with 50% of children using intraoperative targeting. NMU targeting improved BFMDRS by an average of 17.1 whereas intraoperative targeting improved by an average of 10.3. These preliminary results support the use of test stimulation and recording in a Neuromodulation Monitoring Unit (NMU) as a new technique with the potential to improve outcomes following DBS in children with secondary (acquired) dystonia. A larger sample size will be needed to confirm these results.