Posts Tagged low-frequency oscillations

[ARTICLE] Large-scale changes in cortical dynamics triggered by repetitive somatosensory electrical stimulation – Full Text

Abstract

Background

Repetitive somatosensory electrical stimulation (SES) of forelimb peripheral nerves is a promising therapy; studies have shown that SES can improve motor function in stroke subjects with chronic deficits. However, little is known about how SES can directly modulate neural dynamics. Past studies using SES have primarily used noninvasive methods in human subjects. Here we used electrophysiological recordings from the rodent primary motor cortex (M1) to assess how SES affects neural dynamics at the level of single neurons as well as at the level of mesoscale dynamics.

Methods

We performed acute extracellular recordings in 7 intact adult Long Evans rats under ketamine-xylazine anesthesia while they received transcutaneous SES. We recorded single unit spiking and local field potentials (LFP) in the M1 contralateral to the stimulated arm. We then compared neural firing rate, spike-field coherence (SFC), and power spectral density (PSD) before and after stimulation.

Results

Following SES, the firing rate of a majority of neurons changed significantly from their respective baseline values. There was, however, a diversity of responses; some neurons increased while others decreased their firing rates. Interestingly, SFC, a measure of how a neuron’s firing is coupled to mesoscale oscillatory dynamics, increased specifically in the δ-band, also known as the low frequency band (0.3- 4 Hz). This increase appeared to be driven by a change in the phase-locking of broad-spiking, putative pyramidal neurons. These changes in the low frequency range occurred without a significant change in the overall PSD.

Conclusions

Repetitive SES significantly and persistently altered the local cortical dynamics of M1 neurons, changing both firing rates as well as the SFC magnitude in the δ-band. Thus, SES altered the neural firing and coupling to ongoing mesoscale dynamics. Our study provides evidence that SES can directly modulate cortical dynamics.

Background

Somatosensory input is essential for skilled movements [1,2,3]; this is particularly true for dexterous movements [14,5,6]. Interestingly, the somatosensory system has been shown to experience relatively rapid bidirectional changes in organization as a result of repetitive manipulations of peripheral inputs. Consistent with this notion are seminal studies in both animals and humans which demonstrated that reductions in sensory feedback, either by denervation or ischemic nerve block, induced changes in motor representations [78].

Studies have also shown that increases in afferent input by stimulating peripheral pathways (i.e. repetitive somatosensory electrical stimulation or SES) can alter sensorimotor representations of the stimulated body part [910]. One of the first studies examining this neuromodulation method found that sensory stimulation of oral structures resulted in prolonged changes in excitability as well as an increase in the area of representation determined using functional imaging [11]. Consistent with these results are studies demonstrating that altered patterns of physical contacts to the fingers can also persistently reorganize sensory maps [1213]. Importantly, repetitive SES has also proven to be a promising therapeutic tool for motor rehabilitation [1014,15,16].

In both humans and rodents, SES can increase excitability as measured by responses to transcranial magnetic stimulation (TMS) pulses [917]. Past studies have used non-invasive measures to examine cortical excitability such as motor evoked potentials (MEPs) with TMS [917] and cortical reorganization using blood oxygenation signals [11]. It remains unclear what are the precise mechanisms underlying these changes. For example, the observed change in the evoked MEPs following SES may occur without changes in brainstem electrical stimulation-evoked potentials or spinal reflexes [91819]. This suggests the possibility that the cortex may be an important site of plasticity. While our recent study showed that SES can also modify low-frequency dynamics as measured using electroencephalogram (EEG) [20], it remains unclear if these changes are local to cortex. Invasive electrophysiology offers one method to assess if SES can directly alter local motor cortical dynamics.

While the body of literature summarized above has provided important mechanistic insight, little is known about how SES interacts with ongoing cortical dynamics at the level of single neurons and groups of neurons, or neural ensembles. Single neurons are a fundamental unit of the nervous system. The coordinated firing of neural ensembles, e.g. co-firing of neurons in a temporally coupled manner, is now also recognized as an important module for information processing [21,22,23,24,25,26]. In addition, oscillations may provide a mechanism for dynamic coordination of ensembles across motor and sensory areas [21,22,23,24,2527]. Oscillations likely reflect synchronized rhythmic excitability linked to coordinated firing of neurons [28]. Our collective understanding of both single neuron and ensemble firing patterns has greatly improved our understanding of how neural activity patterns underlie complex sensory and motor behaviors. Similarly, it is likely that such activity may play an important role in driving neural plasticity after injury and during neuromodulation using methods such as SES.

The goal of this study was to develop a model of the cortical effects of SES using high-resolution, invasive recording of neurons. We were particularly interested in understanding the diversity of single neuron responses to SES. It is unlikely that all neurons respond identically to a given perturbation. This may be, in part, the result of the multiple cell-types in a given region and the diversity of network connectivity for single neurons [29]. We also wanted to compare changes in neural activity related to larger scale network oscillatory activity. More specifically, we examined the effects of SES on primary motor cortex (M1) at the level of single neuron firing rates as well as the neural coupling to ongoing spontaneous oscillations. We found that SES could independently change both the firing rate and the phase locking, i.e. the consistency of the neural firing relative to oscillatory dynamics. Together, our results provide evidence that SES can directly modulate neural dynamics in M1.

Methods

Animal and surgery preparation

All animal procedures were in accordance with protocols approved by the Institutional Animal Care and Use Committee at the San Francisco Veterans Affairs Medical Center. Adult male Long Evans rats (n = 8, 250-400 g, ~ 8 weeks old, Charles River Laboratories) were housed in a 12 h light:12 h dark cycle with lights out at 6:00 AM and were kept under controlled temperature. One animal was excluded from the study due to significant recording drift and electrical noise in the recording, thus n = 7 animals were used for the analysis shown. Animals were initially anesthetized using a ketamine/xylazine cocktail (85 mg/kg ketamine, and 10 mg/kg xylazine), with supplemental ketamine (at half of the induction dose) given every 40–60 min as needed to maintain a stable anesthetic level, and also to maintain anesthesia at stage III characterized by predominantly slow oscillations. Moreover, 0.05 mg/kg of atropine was given separately to counter respiratory and cardiac depression, and decrease secretion. Animals were sacrificed at the end of the recordings.

Somatosensory electrical stimulation and electrophysiology

After anesthesia induction, transcutaneous stimulation electrodes were clipped near forelimb peripheral nerves (medial, ulnar, and radial nerve), in the configuration noted in Fig. 1a. These copper metal clips were wrapped around the forelimb and then connected to a Multi-Channel Systems Stimulus Generator (MCS STG4000 series) to deliver transcutaneous stimulation. SES current parameters were set by determining the maximum amount of current where no evoked movement in the forelimb was seen (typically 300–750 μA currents).

 

figure1

Fig. 1 Schematic of the Experiment. a, Somatosensory electrical stimulation was applied directly to the distal forelimb while neural activity was recorded under anesthesia. b, Schematic of the stimulation paradigm. c, Averaged evoked potential in the local field potential during SES

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[WEB SITE] Electrically stimulating the brain may restore movement after stroke

June 18, 2018, University of California, San Francisco
stroke

Micrograph showing cortical pseudolaminar necrosis, a finding seen in strokes on medical imaging and at autopsy. H&E-LFB stain. Credit: Nephron/Wikipedia

UC San Francisco scientists have improved mobility in rats that had experienced debilitating strokes by using electrical stimulation to restore a distinctive pattern of brain cell activity associated with efficient movement. The researchers say they plan to use the new findings to help develop brain implants that might one day restore motor function in human stroke patients.

After a , roughly one-third of  recover fully, one-third have significant lingering  problems, and one-third remain virtually paralyzed, said senior author Karunesh Ganguly, MD, Ph.D., associate professor of neurology and a member of the UCSF Weill Institute for Neurosciences. Even patients who experience partial recovery often continue to struggle with “goal-directed” movements of the arms and hands, such as reaching and manipulating objects, which can be crucial in the workplace and in daily living.

“Our main impetus was to understand how we can develop implantable neurotechnology to help stroke patients,” said Ganguly, who conducts research at the San Francisco VA Health Care System. “There’s an enormous field growing around the idea of neural implants that can help neural circuits recover and improve function. We were interested in trying to understand the circuit properties of an injured brain relative to a healthy brain and to use this information to tailor neural implants to improve  after stroke.”

Over the past 20 years, neuroscientists have presented evidence that coordinated patterns of neural activity known as oscillations are important for efficient brain function. More recently, low-frequency oscillations (LFOs)—which were first identified in studies of sleep—have been specifically found to help organize the firing of neurons in the brain’s primary motor cortex. The motor cortex controls voluntary movement, and LFOs chunk the cells’ activity together to ensure that goal-directed movements are smooth and efficient.

In the new study, published in the June 18, 2018 issue of Nature Medicine, the researchers first measured neural activity in rats while the animals reached out to grab a small food pellet, a task designed to emulate human goal-directed movements. They detected LFOs immediately before and during the action, which inspired the researchers to investigate how these activity patterns might change after stroke and during recovery.

To explore these questions, they caused a stroke in the rats that impaired the animals’ movement ability, and found that LFOs diminished. In rats that were able to recover, gradually making faster and more precise movements, the LFOs also returned. There was a strong correlation between recovery of function and the reemergence of LFOs. Animals that fully recovered had stronger low-frequency activity than those that partially recovered, and those that didn’t recover had virtually no low-frequency activity.

To try to boost recovery, the researchers used electrodes to both record activity and deliver a mild electrical current to the rats’ brains, stimulating the area immediately surrounding the center of the . This stimulation consistently enhanced LFOs in the damaged area and appeared to improve motor function: when the researchers delivered a burst of electricity right before a rat made a movement, the rat was up to 60 percent more accurate at reaching and grasping for a food pellet.

“Interestingly, we observed this augmentation of LFOs only on the trials where stimulation was applied,” said Tanuj Gulati, Ph.D., a postdoctoral researcher in the Ganguly lab who is co-first author of the study, along with Dhakshin Ramanathan, MD, Ph.D., now assistant professor of psychiatry at UC San Diego, and Ling Guo, a neuroscience graduate student at UCSF.

“We are not creating a new frequency, we are amplifying the existing frequency,” added Ganguly. “By amplifying the weak low-frequency oscillations, we are able to help organize the task-related . When we delivered the electrical current in step with their intended actions, motor control actually got better.”

The researchers wanted to know whether their findings might also apply to humans, so they analyzed recordings made from the surface of the brain of an epilepsy patient who had suffered a stroke that had impaired the patient’s arm and hand movements. The recordings revealed significantly fewer LFOs than recordings made in two epilepsy patients who hadn’t had a stroke. These findings suggest that, just as in rats, the stroke had caused a loss of low-frequency  that impaired the patient’s movement.

Physical therapy is the only treatment currently available to aid stroke patients in their recovery. It can help people who are able to recover neurologically get back to being fully functional more quickly, but not those whose stroke damage is too extensive. Ganguly hopes that electrical brain stimulation can offer a much-needed alternative for these latter patients, helping their brain circuits to gain better control of motor neurons that are still functional. Electrical  stimulation is already widely used to help patients with Parkinson’s disease and epilepsy, and Ganguly believes stroke patients may be the next to benefit.

 Explore further: Electrical nerve stimulation could help patients regain motor functions sooner

More information: Low-frequency cortical activity is a neuromodulatory target that tracks recovery after stroke, Nature Medicine (2018). www.nature.com/articles/s41591-018-0058-y

via Electrically stimulating the brain may restore movement after stroke

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[WEB SITE] Electrically Stimulating the Brain May Restore Movement after a Stroke

electrical-stimulation
by SONDRA FORSYTH

University of California – San Francisco scientists have improved mobility in rats that had experienced debilitating strokes by using electrical stimulation to restore a distinctive pattern of brain cell activity associated with efficient movement. The researchers say they plan to use the 2018 findings to help develop brain implants that might one day restore motor function in human stroke patients.

A release from the university explains that after a stroke, roughly one-third of patients recover fully, one-third have significant lingering movement problems, and one-third remain virtually paralyzed, according to senior author Karunesh Ganguly, MD, PhD, associate professor of neurology and a member of the UCSF Weill Institute for Neurosciences. Even patients who experience partial recovery often continue to struggle with “goal-directed” movements of the arms and hands, such as reaching and manipulating objects, which can be crucial in the workplace and in daily living.

The release quotes Ganguly, who conducts research at the San Francisco VA Health Care System, as saying, “Our main impetus was to understand how we can develop implantable neurotechnology to help stroke patients. There’s an enormous field growing around the idea of neural implants that can help neural circuits recover and improve function. We were interested in trying to understand the circuit properties of an injured brain relative to a healthy brain and to use this information to tailor neural implants to improve motor function after stroke.”

Over the past 20 years, neuroscientists have presented evidence that coordinated patterns of neural activity known as oscillations are important for efficient brain function. More recently, low-frequency oscillations (LFOs)–which were first identified in studies of sleep–have been specifically found to help organize the firing of neurons in the brain’s primary motor cortex. The motor cortex controls voluntary movement, and LFOs chunk the cells’ activity together to ensure that goal-directed movements are smooth and efficient.

In the new study, published in the June 18, 2018 issue of Nature Medicine, the researchers first measured neural activity in rats while the animals reached out to grab a small food pellet, a task designed to emulate human goal-directed movements. They detected LFOs immediately before and during the action, which inspired the researchers to investigate how these activity patterns might change after stroke and during recovery.

To explore these questions, they caused a stroke in the rats that impaired the animals’ movement ability, and found that LFOs diminished. In rats that were able to recover, gradually making faster and more precise movements, the LFOs also returned. There was a strong correlation between recovery of function and the reemergence of LFOs. Animals that fully recovered had stronger low-frequency activity than those that partially recovered, and those that didn’t recover had virtually no low-frequency activity.

To try to boost recovery, the researchers used electrodes to both record activity and deliver a mild electrical current to the rats’ brains, stimulating the area immediately surrounding the center of the stroke damage. This stimulation consistently enhanced LFOs in the damaged area and appeared to improve motor function: when the researchers delivered a burst of electricity right before a rat made a movement, the rat was up to 60 percent more accurate at reaching and grasping for a food pellet.

“Interestingly, we observed this augmentation of LFOs only on the trials where stimulation was applied,” said Tanuj Gulati, PhD, a postdoctoral researcher in the Ganguly lab who is co-first author of the study, along with Dhakshin Ramanathan, MD, PhD, now assistant professor of psychiatry at UC San Diego, and Ling Guo, a neuroscience graduate student at UCSF.

“We are not creating a new frequency, we are amplifying the existing frequency,” added Ganguly. “By amplifying the weak low-frequency oscillations, we are able to help organize the task-related neural activity. When we delivered the electrical current in step with their intended actions, motor control actually got better.”

The researchers wanted to know whether their findings might also apply to humans, so they analyzed recordings made from the surface of the brain of an epilepsy patient who had suffered a stroke that had impaired the patient’s arm and hand movements. The recordings revealed significantly fewer LFOs than recordings made in two epilepsy patients who hadn’t had a stroke. These findings suggest that, just as in rats, the stroke had caused a loss of low-frequency activity that impaired the patient’s movement.

Physical therapy is the only treatment currently available to aid stroke patients in their recovery. It can help people who are able to recover neurologically get back to being fully functional more quickly, but not those whose stroke damage is too extensive. Ganguly hopes that electrical brain stimulation can offer a much-needed alternative for these latter patients, helping their brain circuits to gain better control of motor neurons that are still functional. Electrical brain stimulation is already widely used to help patients with Parkinson’s disease and epilepsy, and Ganguly believes stroke patients may be the next to benefit.

via Electrically Stimulation the Brain May Restore Movement followin a Stroke | thirdAGE

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[WEB SITE] Electrically Stimulating the Brain May Restore Movement After Stroke

Findings Suggest Potential for Brain Implants to Treat Stroke Patients

UC San Francisco scientists have improved mobility in rats that had experienced debilitating strokes by using electrical stimulation to restore a distinctive pattern of brain cell activity associated with efficient movement. The researchers say they plan to use the new findings to help develop brain implants that might one day restore motor function in human stroke patients.

After a stroke, roughly one-third of patients recover fully, one-third have significant lingering movement problems, and one-third remain virtually paralyzed, said senior author Karunesh Ganguly, MD, PhD, associate professor of neurology and a member of the UCSF Weill Institute for Neurosciences. Even patients who experience partial recovery often continue to struggle with “goal-directed” movements of the arms and hands, such as reaching and manipulating objects, which can be crucial in the workplace and in daily living.

Headshot of Karunesh Ganguly, MD, PhD, associate professor of neurology, study's senior author.
Karunesh Ganguly, MD, PhD, associate professor of neurology, study’s senior author.

 

“Our main impetus was to understand how we can develop implantable neurotechnology to help stroke patients,” said Ganguly, who conducts research at the San Francisco VA Health Care System. “There’s an enormous field growing around the idea of neural implants that can help neural circuits recover and improve function. We were interested in trying to understand the circuit properties of an injured brain relative to a healthy brain and to use this information to tailor neural implants to improve motor function after stroke.”

Over the past 20 years, neuroscientists have presented evidence that coordinated patterns of neural activity known as oscillations are important for efficient brain function.  More recently, low-frequency oscillations (LFOs)—which were first identified in studies of sleep—have been specifically found to help organize the firing of neurons in the brain’s primary motor cortex. The motor cortex controls voluntary movement, and LFOs chunking the cells’ activity together to ensure that goal-directed movements are smooth and efficient.

In the new study, published in the June 18, 2018 issue of Nature Medicine, the researchers first measured neural activity in rats while the animals reached out to grab a small food pellet, a task designed to emulate human goal-directed movements. They detected LFOs immediately before and during the action, which inspired the researchers to investigate how these activity patterns might change after stroke and during recovery.

To explore these questions, they caused a stroke in the rats that impaired the animals’ movement ability, and found that LFOs diminished. In rats that were able to recover, gradually making faster and more precise movements, the LFOs also returned. There was a strong correlation between recovery of function and the reemergence of LFOs: animals that fully recovered had stronger low-frequency activity than those that partially recovered, and those that didn’t recover had virtually no low-frequency activity at all.

To try to boost recovery, the researchers used electrodes to both record activity and to deliver a mild electrical current to the rats’ brains, stimulating the area immediately surrounding the center of the stroke damage. This stimulation consistently enhanced LFOs in the damaged area and appeared to improve motor function: when the researchers delivered a burst of electricity right before a rat made a movement, the rat was up to 60 percent more accurate at reaching and grasping for a food pellet.

“Interestingly, we observed this augmentation of LFOs only on the trials where stimulation was applied,” said Tanuj Gulati, PhD, a postdoctoral researcher in the Ganguly lab who is co-first author of the study, along with Dhakshin Ramanathan, MD, PhD, now assistant professor of psychiatry at UC San Diego, and Ling Guo, a neuroscience graduate student at UCSF.

“We are not creating a new frequency, we are amplifying the existing frequency,” added Ganguly. “By amplifying the weak low-frequency oscillations, we are able to help organize the task-related neural activity. When we delivered the electrical current in step with their intended actions, motor control actually got better.”

The researchers wanted to know whether their findings might also apply to humans, so they analyzed recordings made from the surface of the brain of an epilepsy patient who had suffered a stroke that had impaired the patient’s arm and hand movements. The recordings revealed significantly fewer LFOs than recordings made in two epilepsy patients who hadn’t had a stroke. These findings suggest that, just like in rats, the stroke had caused a loss of low-frequency activity that impaired the patient’s movement.

Physical therapy is the only treatment currently available to aid stroke patients in their recovery. It can help people who are able to recover neurologically get back to being fully functional more quickly, but not those whose stroke damage is too extensive. Ganguly hopes that electrical brain stimulation can offer a much-needed alternative for these latter patients, helping their brain circuits to gain better control of motor neurons that are still functional. Electrical brain stimulation is already widely used to help patients with Parkinson’s disease and epilepsy, and Ganguly believes stroke patients may be the next to benefit.

Other UCSF contributors to the work included Gray Davidson; April Hishinuma; Seok-Joon Won, PhD, associate adjunct professor of neurology; Edward Chang, MD, professor of neurosurgery and William K. Bowes Jr. Biomedical Investigator; and Raymond Swanson, MD, professor of neurology. They were joined by Robert T. Knight, MD, professor of psychology and neuroscience at UC Berkeley.

The research was supported in part by funding from the National Institute of Neurological Disorders and Stroke; the National Institute of Mental Health; the Agency for Science, Technology, and Research (A*STAR), in Singapore; the U.S. Department of Veterans Affairs, and the Burroughs Wellcome Fund.

 

via Electrically Stimulating the Brain May Restore Movement After Stroke | UC San Francisco

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