Electrical Stimulation publications

As pain consists of both sensory and affective components, its management by pharmaceutical agents remains difficult. Alternative forms of neuromodulation, such as electrical stimulation, have been studied in recent years as potential pain treatment options. Although electrical stimulation of the brain has shown promise, more research into stimulation frequency and targets is required to support its clinical applications. Here, we studied the effect that stimulation frequency has on pain modulation in the prefrontal cortex (PFC) and the anterior cingulate cortex (ACC) in acute pain models in rats. We found that low-frequency stimulation in the prelimbic region of the PFC (PL-PFC) provides reduction of sensory and affective pain components. Meanwhile, high-frequency stimulation of the ACC, a region involved in processing pain affect, reduces pain aversive behaviors. Our results demonstrate that frequency-dependent neuromodulation of the PFC or ACC has the potential for pain modulation.

Clinical management of auditory synaptopathies like other genetic hearing disorders is currently limited to the use of hearing aids or cochlear implants. However, future gene therapy promises restoration of hearing in selected forms of monogenic hearing impairment, in which cochlear morphology is preserved over a time window that enables intervention. This includes non-syndromic autosomal recessive hearing impairment DFNB93, caused by defects in the CABP2 gene. Calcium-binding protein 2 (CaBP2) is a potent modulator of inner hair cell (IHC) voltage-gated calcium channels Ca V 1.3. Based on disease modeling in Cabp2 –/– mice, DFNB93 hearing impairment has been ascribed to enhanced steady-state inactivation of IHC Ca V 1.3 channels, effectively limiting their availability to trigger synaptic transmission. This, however, does not seem to interfere with cochlear development and does not cause early degeneration of hair cells or their synapses. Here, we studied the potential of a gene therapeutic approach for the treatment of DFNB93. We used AAV2/1 and AAV-PHP.eB viral vectors to deliver the Cabp2 coding sequence into IHCs of early postnatal Cabp2 –/– mice and assessed the level of restoration of hair cell function and hearing. Combining in vitro and in vivo approaches, we observed high transduction efficiency, and restoration of IHC Ca V 1.3 function resulting in improved hearing of Cabp2 –/– mice. These preclinical results prove the feasibility of DFNB93 gene therapy.

Objective. Intracranial neural recordings and electrical stimulation are tools used in an increasing range of applications, including intraoperative clinical mapping and monitoring, therapeutic neuromodulation, and brain computer interface control and feedback. However, many of these applications suffer from a lack of spatial specificity and localization, both in terms of sensed neural signal and applied stimulation. This stems from limited manufacturing processes of commercial-off-the-shelf (COTS) arrays unable to accommodate increased channel density, higher channel count, and smaller contact size. Approach. Here, we describe a manufacturing and assembly approach using thin-film microfabrication for 32-channel high density subdural micro-electrocorticography ( µ ECoG) surface arrays (contacts 1.2 mm diameter, 2 mm pitch) and intracranial electroencephalography (iEEG) depth arrays (contacts 0.5 mm × 1.5 mm, pitch 0.8 mm × 2.5 mm). Crucially, we tackle the translational hurdle and test these arrays during intraoperative studies conducted in four humans under regulatory approval. Main results. We demonstrate that the higher-density contacts provide additional unique information across the recording span compared to the density of COTS arrays which typically have electrode pitch of 8 mm or greater; 4 mm in case of specially ordered arrays. Our intracranial stimulation study results reveal that refined spatial targeting of stimulation elicits evoked potentials with differing spatial spread. Significance. Thin-film, μ ECoG and iEEG depth arrays offer a promising substrate for advancing a number of clinical and research applications reliant on high-resolution neural sensing and intracranial stimulation.

Objective: To investigate the hearing protection outcomes of different drug-eluting analog electrode arrays implanted into guinea pig cochleae. Methods: Sixty guinea pigs were randomly divided into a negative control group and five experimental groups implanted separately with blank (drug carrier), dexamethasone (DXM), aracytine (Ara-C), Ara-C+DXM, and nicotinamide adenine dinucleotide (NAD+) eluting analog electrode arrays. Micro CT was used to supervise the surgical procedure. Auditory brainstem response (ABR) thresholds of the guinea pigs were measured and analyzed. Results and conclusions: Compared with the negative control, all other groups showed a significant increase in ABR threshold (p<0.001) after surgery. Among them, there was no obvious difference between the blank (0 vs 90 days: 59.70±10.57 vs 64.60±9.47 dB SPL) and the NAD+ group (0 vs 90 days: 59.90±9.87 vs 64.70±8.65 dB SPL). On the other hand, the ABR thresholds in the DXM (0 days: 58.10±10.73 dB SPL; 90 days: 51.70±9.07 dB SPL) and the Ara-C group (0 days: 59.00±10.05 dB SPL; 90 days: 51.60±8.48 dB SPL) decreased significantly compared with the former two groups (p<0.001). However, the Ara-C+DXM group showed no further benefit (p>0.05). In addition, a significantly higher survival rate of spiral ganglion neurons in cochleae was observed in the Ara-C and/or DXM groups.

This project investigated whether pediatric (5–14 years) and adult (30–60 years) cochlear implant (CI) users benefit from a target/masker sex-mismatch for speech-in-speech recognition. Speech recognition thresholds were estimated in a two-male-talker or a two-female-talker masker. Target and masker speech were either sex-matched or sex-mismatched. For both age groups, performance for sex-matched talkers was worse for male than female speech. Sex-mismatch benefit was observed for the two-male-talker masker, indicating CI users can benefit from a target/masker sex mismatch. No benefit was observed for the two-female-talker masker, suggesting this effect may depend on the relative contributions of energetic and informational masking.

The protective effect of the efferent system against acoustic trauma (AT) has been shown by several experimental approaches, including damage to one ear, sectioning of the olivocochlear bundle (OCB) in the floor of the IV ventricle, and knock-in mice overexpressing outer hair cell (OHC) cholinergic receptors, among others. Such effects have been related to changes in the regulation of the cholinergic efferent system and in cochlear amplification, which ultimately reverse upon protective hearing suppression. In addition to well-known circuits of the brainstem, the descending corticofugal pathway also regulates efferent neurons of the olivary complex. In this study, we applied our recently developed experimental paradigm of multiple sessions of electrical stimulation (ES) to activate the efferent system in combination with noise overstimulation. ABR thresholds increased 1 and 2 days after AT (8–16 kHz bandpass noise at 107 dB for 90 min) recovering at AT + 14 days. However, after multiple sessions of epidural anodal stimulation, no changes in thresholds were observed following AT. Although an inflammatory response was also observed 1 day after AT in both groups, the counts of reactive macrophages in both experimental conditions suggest decreased inflammation in the epidural stimulation group. Quantitative immunocytochemistry for choline acetyltransferase (ChAT) showed a significant decrease in the size and optical density of the efferent terminals 1 day after AT and a rebound at 14 days, suggesting depletion of the terminals followed by a long-term compensatory response. Such a synthesis recovery was significantly higher upon cortical stimulation. No significant correlation was found between ChAT optical density and size of the buttons in sham controls (SC) and ES/AT + 1day animals; however, significant negative correlations were shown in all other experimental conditions. Therefore, our comparative analysis suggests that cochleotopic cholinergic neurotransmission is also better preserved after multisession epidural stimulation.

Age-related hearing loss (ARHL) is the most common sensory disorder among older people, and yet, the treatment options are limited to medical devices such as hearing aids and cochlear implants. The high prevalence of ARHL mandates the development of treatment strategies that can prevent or rescue age-related cochlear degeneration. In this study, we investigated a novel pharmacological strategy based on inhibition of the adenosine A2A receptor (A2AR) in middle aged C57BL/6 mice prone to early onset ARHL. C57BL/6J mice were treated with weekly istradefylline (A2AR antagonist; 1 mg/kg) injections from 6 to 12 months of age. Auditory function was assessed using auditory brainstem responses (ABR) to tone pips (4–32 kHz). ABR thresholds and suprathreshold responses (wave I amplitudes and latencies) were evaluated at 6, 9, and 12 months of age. Functional outcomes were correlated with quantitative histological assessments of sensory hair cells. Cognitive function was assessed using the Morris water maze and the novel object recognition test, and the zero maze test was used to assess anxiety-like behaviour. Weekly injections of istradefylline attenuated ABR threshold shifts by approximately 20 dB at mid to high frequencies (16–32 kHz) but did not improve ABR suprathreshold responses. Istradefylline treatment improved hair cell survival in a turn-dependent manner, whilst the cognitive function was unaffected by istradefylline treatment. This study presents the first evidence for the rescue potential of istradefylline in ARHL and highlights the role of A2AR in development of age-related cochlear degeneration.

Electrical stimulation of the cervical spinal cord is gaining traction as a therapy following spinal cord injury; however, it is difficult to target the cervical motor region in a rodent using a non-penetrating stimulus compared with direct placement of intraspinal wire electrodes. Penetrating wire electrodes have been explored in rodent and pig models and, while they have proven beneficial in the injured spinal cord, the negative aspects of spinal parenchymal penetration (e.g., gliosis, neural tissue damage, and obdurate inflammation) are of concern when considering therapeutic potential. We therefore designed a novel approach for epidural stimulation of the rat spinal cord using a wireless stimulation system and ventral electrode array. Our approach allowed for preservation of mobility following surgery and was suitable for long term stimulation strategies in awake, freely functioning animals. Further, electrophysiology mapping of the ventral spinal cord revealed the ventral approach was suitable to target muscle groups of the rat forelimb and, at a single electrode lead position, different stimulation protocols could be applied to achieve unique activation patterns of the muscles of the forelimb.

Listening to speech in noise is effortful for individuals with hearing loss, even if they have received a hearing prosthesis such as a hearing aid or cochlear implant (CI). At present, little is known about the neural functions that support listening effort. One form of neural activity that has been suggested to reflect listening effort is the power of 8–12 Hz (alpha) oscillations measured by electroencephalography (EEG). Alpha power in two cortical regions has been associated with effortful listening—left inferior frontal gyrus (IFG), and parietal cortex—but these relationships have not been examined in the same listeners. Further, there are few studies available investigating neural correlates of effort in the individuals with cochlear implants. Here we tested 16 CI users in a novel effort-focused speech-in-noise listening paradigm, and confirm a relationship between alpha power and self-reported effort ratings in parietal regions, but not left IFG. The parietal relationship was not linear but quadratic, with alpha power comparatively lower when effort ratings were at the top and bottom of the effort scale, and higher when effort ratings were in the middle of the scale. Results are discussed in terms of cognitive systems that are engaged in difficult listening situations, and the implication for clinical translation.

As a promising future treatment for stroke rehabilitation, researchers have developed direct brain stimulation to manipulate the neural excitability. However, there has been less interest in energy consumption and unexpected side effect caused by electrical stimulation to bring functional recovery for stroke rehabilitation. In this study, we propose an engineering approach with subthreshold electrical stimulation (STES) to bring functional recovery. Here, we show a low level of electrical stimulation boosted causal excitation in connected neurons and strengthened the synaptic weight in a simulation study. We found that STES with motor training enhanced functional recovery after stroke in vivo. STES was shown to induce neural reconstruction, indicated by higher neurite expression in the stimulated regions and correlated changes in behavioral performance and neural spike firing pattern during the rehabilitation process. This will reduce the energy consumption of implantable devices and the side effects caused by stimulating unwanted brain regions.

Hearing depends on glutamatergic synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where inclusion of the GluA2 subunit reduces overall channel conductance and Ca 2+ permeability. Cochlear afferent synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs) contain the AMPAR subunits GluA2, 3, and 4. However, the tetrameric complement of cochlear AMPAR subunits is not known. It was recently shown in mice that chronic intracochlear delivery of IEM-1460, an antagonist selective for GluA2-lacking AMPARs [also known as Ca 2+ -permeable AMPARs (CP-AMPARs)], before, during, and after acoustic overexposure prevented both the trauma to ANF synapses and the ensuing reduction of cochlear nerve activity in response to sound. Surprisingly, baseline measurements of cochlear function before exposure were unaffected by chronic intracochlear delivery of IEM-1460. This suggested that cochlear afferent synapses contain GluA2-lacking CP-AMPARs alongside GluA2-containing Ca 2+ -impermeable AMPA receptors (CI-AMPARs), and that the former can be antagonized for protection while the latter remain conductive. Here, we investigated hearing function in the guinea pig during acute local or systemic delivery of CP-AMPAR antagonists. Acute intracochlear delivery of IEM-1460 or systemic delivery of IEM-1460 or IEM-1925 reduced the amplitude of the ANF compound action potential (CAP) significantly, for all tone levels and frequencies, by > 50% without affecting CAP thresholds or distortion product otoacoustic emissions (DPOAE). Following systemic dosing, IEM-1460 levels in cochlear perilymph were ~ 30% of blood levels, on average, consistent with pharmacokinetic properties predicting permeation of the compounds into the brain and ear. Both compounds were metabolically stable with half-lives >5 h in vitro , and elimination half-lives in vivo of 118 min (IEM-1460) and 68 min (IEM-1925). Heart rate monitoring and off-target binding assays suggest an enhanced safety profile for IEM-1925 over IEM-1460. Compound potency on CAP reduction (IC 50 ~ 73 μM IEM-1460) was consistent with a mixture of GluA2-lacking and GluA2-containing AMPARs. These data strongly imply that cochlear afferent synapses of the guinea pig contain GluA2-lacking CP-AMPARs. We propose these CP-AMPARs may be acutely antagonized with systemic dosing, to protect from glutamate excitotoxicity, while transmission at GluA2-containing AMPARs persists to mediate hearing during the protection.

Detection of low-level sounds by the mammalian cochlea requires electromechanical feedback from outer hair cells (OHCs). This feedback arises due to the electromotile response of OHCs, which is driven by the modulation of their receptor potential caused by the stimulation of mechano-sensitive ion channels. Nonlinearity in these channels distorts impinging sounds, creating distortion-products that are detectable in the ear canal as distortion-product otoacoustic emissions (DPOAEs). Ongoing efforts aim to develop DPOAEs, which reflects the ear’s health, into diagnostic tools for sensory hearing loss. These efforts are hampered by limited knowledge on the cochlear extent contributing to DPOAEs. Here, we report on intracochlear distortion products (IDPs) in OHC electrical responses and intracochlear fluid pressures. Experiments and simulations with a physiologically motivated cochlear model show that widely generated electrical IDPs lead to mechanical vibrations in a frequency-dependent manner. The local cochlear impedance restricts the region from which IDPs contribute to DPOAEs at low to moderate intensity, which suggests that DPOAEs may be used clinically to provide location-specific information about cochlear damage.

As our understanding of volitional motor function increases, it is clear that complex movements are the result of the interactions of multiple cortical regions rather than just the output properties of primary motor cortex. However, our understanding of the interactions among these regions is limited. In this study, we used the activity-dependent stimulation (ADS) technique to determine the short/long-term effects on network activity and neuroplasticity of intracortical connections. ADS uses the intrinsic neural activity of one region to trigger stimulations in a separate region of the brain and can manipulate neuronal connectivity in vivo. Our aim was to compare single-unit neuronal activity within premotor cortex (rostral forelimb area, [RFA] in rats) in response to ADS (triggered from RFA) and randomly-generated stimulation in the somatosensory area (S1) within single sessions and across 21 consecutive days of stimulation. We examined firing rate and correlation between spikes and stimuli in chronically-implanted healthy ambulatory rats during spontaneous and evoked activity. At the end of the treatment, we evaluated changes of synaptophysin expression. Our results demonstrated the ability of ADS to modulate RFA firing properties and to promote synaptogenesis in S1, strengthening the idea that this Hebbian-inspired protocol can be used to modulate cortical connectivity.

Objectives: To investigate the role of auditory cues for spatial release from masking (SRM) in children with bilateral cochlear implants (BiCIs) and compare their performance with children with normal hearing (NH). To quantify the contribution to speech intelligibility benefits from individual auditory cues: head shadow, binaural redundancy, and interaural differences; as well as from multiple cues: SRM and binaural squelch. To assess SRM using a novel approach of adaptive target-masker angular separation, which provides a more functionally relevant assessment in realistic complex auditory environments. Design: Children fitted with BiCIs (N = 11) and with NH (N = 18) were tested in virtual acoustic space that was simulated using head-related transfer functions measured from individual children with BiCIs behind the ear and from a standard head and torso simulator for all NH children. In experiment I, by comparing speech reception thresholds across 4 test conditions that varied in target-masker spatial separation (colocated versus separated at 180°) and listening conditions (monaural versus binaural/bilateral listening), intelligibility benefits were derived for individual auditory cues for SRM. In experiment II, SRM was quantified using a novel measure to find the minimum angular separation (MAS) between the target and masker to achieve a fixed 20% intelligibility improvement. Target speech was fixed at either +90 or –90° azimuth on the side closer to the better ear (+90° for all NH children) and masker locations were adaptively varied. Results: In experiment I, children with BiCIs as a group had smaller intelligibility benefits from head shadow than NH children. No group difference was observed in benefits from binaural redundancy or interaural difference cues. In both groups of children, individuals who gained a larger benefit from interaural differences relied less on monaural head shadow, and vice versa. In experiment II, all children with BiCIs demonstrated measurable MAS thresholds <180° and on average larger than that from NH children. Eight of 11 children with BiCIs and all NH children had a MAS threshold <90°, requiring interaural differences only to gain the target intelligibility benefit; whereas the other 3 children with BiCIs had a MAS between 120° and 137°, requiring monaural head shadow for SRM. Conclusions: When target and maskers were separated at 180° on opposing hemifields, children with BiCIs demonstrated greater intelligibility benefits from head shadow and interaural differences than previous literature showed with a smaller separation. Children with BiCIs demonstrated individual differences in using auditory cues for SRM. From the MAS thresholds, more than half of the children with BiCIs demonstrated robust access to interaural differences without needing additional monaural head shadow for SRM. Both experiments led to the conclusion that individualized fitting strategies in the bilateral devices may be warranted to maximize spatial hearing for children with BiCIs in complex auditory environments.

Studying the in-vivo mechanical and electrophysiological cochlear responses in several species helps us to have a comprehensive view of the sensitivity and frequency selectivity of the cochlea. Different species might use different mechanisms to achieve the sharp frequency-place map. The outer hair cells (OHC) play an important role in mediating frequency tuning. In the present work, we measured the OHC-generated local cochlear microphonic (LCM) and the motion of different layers in the organ of Corti using optical coherence tomography (OCT) in the first turn of the cochlea in guinea pig. In the best frequency (BF) band, our observations were similar to our previous measurements in gerbil: a nonlinear peak in LCM responses and in the basilar membrane (BM) and OHC-region displacements, and higher motion in the OHC region than the BM. Sub-BF the responses in the two species were different. In both species the sub-BF displacement of the BM was linear and LCM was nonlinear. Sub-BF in the OHC-region, nonlinearity was only observed in a subset of healthy guinea pig cochleae while in gerbil, robust nonlinearity was observed in all healthy cochleae. The differences suggest that gerbils and guinea pigs employ different mechanisms for filtering sub-BF OHC activity from BM responses. However, it cannot be ruled out that the differences are due to technical measurement differences across the species.

Background Cerebellar electrical stimulation has shown promise in improving motor recovery post-stroke in both rodent and human studies. Past studies have used motor evoked potentials (MEPs) to evaluate how cerebellar stimulation modulates ongoing activity in the cortex, but the underlying mechanisms are incompletely understood. Here we used invasive electrophysiological recordings from the intact and stroke-injured rodent primary motor cortex (M1) to assess how epidural cerebellar stimulation modulates neural dynamics at the level of single neurons as well as at the level of mesoscale dynamics. Methods We recorded single unit spiking and local field potentials (LFPs) in both the intact and acutely stroke-injured M1 contralateral to the stimulated cerebellum in adult Long-Evans rats under anesthesia. We analyzed changes in the firing rates of single units, the extent of synchronous spiking and power spectral density (PSD) changes in LFPs during and post-stimulation. Results Our results show that post-stimulation, the firing rates of a majority of M1 neurons changed significantly with respect to their baseline rates. These firing rate changes were diverse in character, as the firing rate of some neurons increased while others decreased. Additionally, these changes started to set in during stimulation. Furthermore, cross-correlation analysis showed a significant increase in coincident firing amongst neuronal pairs. Interestingly, this increase in synchrony was unrelated to the direction of firing rate change. We also found that neuronal ensembles derived through principal component analysis were more active post-stimulation. Lastly, these changes occurred without a significant change in the overall spectral power of LFPs post-stimulation. Conclusions Our results show that cerebellar stimulation caused significant, long-lasting changes in the activity patterns of M1 neurons by altering firing rates, boosting neural synchrony and increasing neuronal assemblies’ activation strength. Our study provides evidence that cerebellar stimulation can directly modulate cortical dynamics. Since these results are present in the perilesional cortex, our data might also help explain the facilitatory effects of cerebellar stimulation post-stroke.

The dorsal region of the bed nucleus of the stria terminalis (dBNST) receives substantial dopaminergic input which overlaps with norepinephrine input implicated in stress responses. Using ex vivo fast scan cyclic voltammetry in male C57BL6 mouse brain slices, we demonstrate that electrically stimulated dBNST catecholamine signals are of substantially lower magnitude and have slower uptake rates compared with caudate signals. Dopamine terminal autoreceptor activation inhibited roughly half of the catecholamine transient, and noradrenergic autoreceptor activation produced an ∼30% inhibition. Dopamine transporter blockade with either cocaine or GBR12909 significantly augmented catecholamine signal duration. We optogenetically targeted dopamine terminals in the dBNST of transgenic (TH:Cre) mice of either sex and, using ex vivo whole-cell electrophysiology, we demonstrate that optically stimulated dopamine release induces slow outward membrane currents and an associated hyperpolarization response in a subset of dBNST neurons. These cellular responses had a similar temporal profile to dopamine release, were significantly reduced by the D2/D3 receptor antagonist raclopride, and were potentiated by cocaine. Using in vivo fiber photometry in male C57BL/6 mice during training sessions for cocaine conditioned place preference, we show that acute cocaine administration results in a significant inhibition of calcium transient activity in dBNST neurons compared with saline administration. These data provide evidence for a mechanism of dopamine-mediated cellular inhibition in the dBNST and demonstrate that cocaine augments this inhibition while also decreasing net activity in the dBNST in a drug reinforcement paradigm.SIGNIFICANCE STATEMENT The dorsal bed nucleus of the stria terminalis (dBNST) is a region highly implicated in mediating stress responses; however, the dBNST also receives dopaminergic inputs from classically defined drug reward pathways. Here we used various techniques to demonstrate that dopamine signaling within the dBNST region has inhibitory effects on population activity. We show that cocaine, an abused psychostimulant, augments both catecholamine release and dopamine-mediated cellular inhibition in this region. We also demonstrate that cocaine administration reduces population activity in the dBNST, in vivo Together, these data support a mechanism of dopamine-mediated inhibition within the dBNST, providing a means by which drug-induced elevations in dopamine signaling may inhibit dBNST activity to promote drug reward.

Obesity remains prevalent in the US. One potential treatment is vagus nerve stimulation (VNS), which activates the sensory afferents innervating the stomach that convey stomach volume and establish satiety. However, current VNS approaches and stimulus optimization could benefit from additional understanding of the underlying neural response to stomach distension. In this study, obesity-prone Sprague Dawley rats consumed a standard, high-carbohydrate, or high-fat diet for several months, leading to diet-induced obesity in the latter two groups. Under anesthesia, the neural activity in the vagus nerve was recorded with a penetrating microelectrode array while the stomach was distended with an implanted balloon. Vagal tone during distension was compared to baseline tone prior to distension. Responses were strongly correlated with stomach distension, but the sensitivity to distension was significantly lower in animals that had been fed the nonstandard diets. The results indicate that both high fat and high carbohydrate diets impair vagus activity.

Objective. The electrode–tissue interface surrounding a deep brain stimulation (DBS) lead is known to be highly dynamic following implantation, which may have implications on the interpretation of intraoperatively recorded local field potentials (LFPs). We characterized beta-band LFP dynamics following implantation of a directional DBS lead in the sensorimotor subthalamic nucleus (STN), which is a primary target for treating Parkinson’s disease. Approach. Directional STN-DBS leads were implanted in four healthy, non-human primates. LFPs were recorded over two weeks and again 1–4 months after implantation. Impedance was measured for two weeks post-implant without stimulation to compare the reactive tissue response to changes in LFP oscillations. Beta-band (12–30 Hz) peak power was calculated from the LFP power spectra using both common average referencing (CAR) and intra-row bipolar referencing (IRBR). Results. Resting-state LFPs in two of four subjects revealed a steady increase of beta power over the initial two weeks post-implant whereas the other two subjects showed variable changes over time. Beta power variance across days was significantly larger in the first two weeks compared to 1–4 months post-implant in all three long-term subjects. Further, spatial maps of beta power several hours after implantation did not correlate with those measured two weeks or 1–4 months post-implant. CAR and IRBR beta power correlated across short- and long-term time points. However, depending on the time period, subjects showed a significant bias towards larger beta power using one referencing scheme over the other. Lastly, electrode–tissue impedance increased over the two weeks post-implant but showed no significant correlation to beta power. Significance. These results suggest that beta power in the STN may undergo significant changes following DBS lead implantation. DBS lead diameter and electrode recording configurations can affect the post-implant interpretation of oscillatory features. Such insights will be important for extrapolating results from intraoperative and externalized LFP recordings.

Neurostimulant drugs or magnetic/electrical stimulation techniques can overcome attention deficits, but these drugs or techniques are weakly beneficial in boosting the learning capabilities of healthy subjects. Here, we report a stimulation technique, mid-infrared modulation (MIM), that delivers mid-infrared light energy through the opened skull or even non-invasively through a thinned intact skull and can activate brain neurons in vivo without introducing any exogeneous gene. Using c-Fos immunohistochemistry, in vivo single-cell electrophysiology and two-photon Ca 2+ imaging in mice, we demonstrate that MIM significantly induces firing activities of neurons in the targeted cortical area. Moreover, mice that receive MIM targeting to the auditory cortex during an auditory associative learning task exhibit a faster learning speed (~50% faster) than control mice. Together, this non-invasive, opsin-free MIM technique is demonstrated with potential for modulating neuronal activity.