scholarly journals Biophysical modeling of VIM to assess contributions of oscillatory activity to essential tremor

2018 ◽  
Author(s):  
Shane Lee ◽  
David J Segar ◽  
Wael F Asaad ◽  
Stephanie R Jones
Keyword(s):  
Computational Model ◽  
Movement Disorder ◽  
Essential Tremor ◽  
Treatment Strategies ◽  
Thalamic Reticular Nucleus ◽  
Oscillatory Activity ◽  
Reticular Nucleus ◽  
Biophysical Modeling ◽  
Tremor Frequency ◽  
A Site

AbstractEssential tremor (ET) is the most common movement disorder, in which the primary symptom is a prominent, involuntary 4–10 Hz rhythmic movement. The presence of tremor frequency oscillations (TFOs) in the ventral intermediate nucleus of the thalamus (VIM) is well-established, but it is often assumed that it is driven by cerebellar tremor frequency activity, while the role of intrinsic oscillatory activity in VIM is not clear. An improved understanding of the mechanisms of tremor and non-tremor frequency activity in VIM is critical to the development of improved pharmacological and neuromodulatory therapies. Starting from a canonical model of thalamus, we developed a biophysically-principled computational model of tremor field activity in the VIM, coupled with the thalamic reticular nucleus (TRN). We simulated TFOs in the model generated either by extrinsic tremor-periodic drive or intrinsic VIM-TRN interaction to understand whether these networks exhibited distinct biophysical properties, which may impact the efficacy of pharmacological or stimulation treatment for TFOs. Extrinsic and intrinsic TFOs in the model depended on T-type Ca2+channels in different ways. Each also depended on GABA modulation in a site- and type-specific manner. These results suggested that efficacy of pharmacological manipulations may depend upon the mechanisms generating TFOs in VIM. Simulated non-tremor-related motor activity from cerebellum decreased extrinsic but increased intrinsic TFOs. Our results suggest that both mechanisms may be important to understand the emergence and cessation of TFOs in VIM and lead to experimentally testable predictions on how to modulate tremor frequency activity to improve treatment strategies for ET.Significance StatementEssential Tremor (ET) is a movement disorder in which the primary symptom is a prominent, involuntary, and rhythmic shaking, often of the hands. Electrical activity in many areas of the brain exhibit rhythmicity related to the patient’s tremor. One such area resides in a structure called the thalamus, but it is not fully known what gives rise to tremor-related activity. We created a computational model of this activity, which suggested how to differentiate tremor mechanisms and how these differences may contribute to other impairments in ET. Knowledge of the biophysical mechanisms contributing to tremor can ultimately lead to improvements in treatments to alleviate symptoms of ET.

scholarly journals Propagation of cortical activity via open-loop intrathalamic architectures: a computational analysis

2019 ◽  
Author(s):  
Jeffrey W. Brown ◽  
Aynaz Taheri ◽  
Robert V. Kenyon ◽  
Tanya Berger-Wolf ◽  
Daniel A. Llano
Keyword(s):  
Closed Loop ◽  
Neural Model ◽  
Signal Propagation ◽  
Open Loop ◽  
Thalamic Reticular Nucleus ◽  
Oscillatory Activity ◽  
Reticular Nucleus ◽  
Dorsal Thalamus ◽  
In Series ◽  
Intracortical Connectivity

AbstractPropagation of signals across the cerebral cortex is a core component of many cognitive processes and is generally thought to be mediated by direct intracortical connectivity. The thalamus, by contrast, is considered to be devoid of internal connections and organized as a collection of parallel inputs to the cortex. Here, we provide evidence that “open-loop” intrathalamic connections involving the thalamic reticular nucleus (TRN) can support propagation of oscillatory activity across the cortex. Recent studies support the existence of open-loop thalamo-reticulo-thalamic (TC-TRN-TC) synaptic motifs in addition to traditional closed-loop architectures. We hypothesized that open-loop structural modules, when connected in series, might underlie thalamic and, therefore cortical, signal propagation. Using a supercomputing platform to simulate thousands of permutations of a thalamo-reticular-cortical network and allowing select synapses to vary both by class and individually, we evaluated the relative capacities of closed- and open-loop TC-TRN-TC synaptic configurations to support both propagation and oscillation. We observed that 1) signal propagation was best supported in networks possessing strong open-loop TC-TRN-TC connectivity; 2) intrareticular synapses were neither primary substrates of propagation nor oscillation; and 3) heterogeneous synaptic networks supported more robust propagation of oscillation than their homogeneous counterparts. These findings suggest that open-loop heterogeneous intrathalamic architectures complement direct intracortical connectivity to facilitate cortical signal propagation.Significance StatementInteractions between the dorsal thalamus and thalamic reticular nucleus (TRN) are speculated to contribute to phenomena such as arousal, attention, sleep, and seizures. Despite the importance of the TRN, the synaptic microarchitectures forming the basis for dorsal thalamus-TRN interactions are not fully understood. The computational neural model we present incorporates “open-loop” thalamo-reticular-thalamic (TC-TRN-TC) synaptic motifs, which have been experimentally observed. We elucidate how open-loop motifs possess the capacity to shape the propagative properties of signals intrinsic to the thalamus and evaluate the wave dynamics they support relative to closed-loop TC-TRN-TC pathways and intrareticular synaptic connections. Our model also generates predictions regarding how different spatial distributions of reticulothalamic and intrareticular synapses affect these signaling properties.

Characterizing rare mis-sense variations of CACNA1I identified in a Swedish schizophrenia cohort

2016 ◽  
Vol 33 (S1) ◽  
pp. S182-S183
Author(s):  
J. Pan ◽  
A. Allen ◽  
L. huang ◽  
D. Daez
Keyword(s):  
Calcium Influx ◽  
Association Studies ◽  
Expression System ◽  
Single Copy ◽  
Thalamic Reticular Nucleus ◽  
Oscillatory Activity ◽  
Reticular Nucleus ◽  
Patient Specific ◽  
Genome Wide Association Studies ◽  
The Impact

CACNA1I (hCaV3.3) encodes the α1 pore-forming subunit of human voltage-gated T-type calcium channels. CaV3.3 is expressed in a limited subset of neurons including GABAergic neurons of the thalamic reticular nucleus (TRN) where they support oscillatory activity essential for sleep spindle generation. CACNA1I is implicated in schizophrenia risk by emerging genetics including genome-wide association studies (PGC, 2014), and exome sequencing of trio samples (Gulsuner et al., 2013). In order to understand the impact of disease-associated sequence variation on the function of CaV3.3, we set out to analyze a complete set of rare mis-sense coding variations in CACNA1I in a Swedish cohort, including 15 variations identified in patients, 20 identified in control subjects, and 23 in both. We established a heterologous expression system of isogenic cell lines, each carrying single-copy inducible cDNA variants of hCaV3.3, and evaluated their functional impact on channel function by electrophysiology, calcium imaging, and biochemistry. We found at least five coding variations impaired overall channel protein abundance, as well as whole cell current density. In addition, we identified hCaV3.3 variants with altered voltage-dependence of channel activation and inactivation. Overall, we found that reduced calcium influx through hCaV3.3 is associated with the group of variants identified in patients, compared to those in both patients and controls. Our findings suggest that patient-specific rare variations of CACNA1I may influence channel-dependent functions, including rebound bursting in TRN neurons, with potential implications for schizophrenia pathophysiology.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Modeling mechanisms of tremor reduction for essential tremor using symmetric biphasic DBS

2019 ◽  
Author(s):  
Shane Lee ◽  
Wael F Asaad ◽  
Stephanie R Jones
Keyword(s):  
Deep Brain Stimulation ◽  
Side Effects ◽  
Movement Disorder ◽  
Essential Tremor ◽  
Brain Stimulation ◽  
Future Studies ◽  
Tremor Frequency ◽  
Ventral Intermediate Nucleus ◽  
Different Shapes ◽  
Deep Brain

AbstractEssential tremor (ET) is the most common movement disorder, in which the primary symptom is a prominent, involuntary 4–10 Hz movement. For severe, medication refractory cases, deep brain stimulation (DBS) targeting the ventral intermediate nucleus of the thalamus (VIM) can be an effective treatment for cessation of tremor and is thought to work in part by disrupting tremor frequency oscillations (TFOs) in VIM. However, DBS is not universally effective and may be further disrupting cerebellar-mediated activity in the VIM. Here, we applied biophysically detailed computational modeling to investigate whether the efficacy of DBS is affected by the mechanism of generation of TFOs or by the pattern of stimulation. We simulated the effects of DBS using standard, asymmetric pulses as well as biphasic, symmetric pulses to understand biophysical mechanisms of how DBS disrupts TFOs generated either extrinsically or intrinsically. The model results suggested that the efficacy of DBS in the VIM is affected by the mechanism of generation of TFOs. Symmetric biphasic DBS reduced TFOs more than standard DBS in both networks, and these effects were stronger in the intrinsic network. For intrinsic tremor frequency activity, symmetric biphasic DBS was more effective at reducing TFOs. Simulated non-tremor signals were also transmitted during symmetric biphasic DBS, suggesting that this type of DBS may help to reduce side effects caused by disruption of the cerebellothalamocortical pathway. Biophysical details in the model provided a mechanistic interpretation of the cellular and network dynamics contributing to these effects that can be empirically tested in future studies.Significance StatementEssential tremor (ET) is a common movement disorder, whose primary symptom is an involuntary rhythmic movement of the limbs or head. An area of the human tha-lamus demonstrates electrical activity that oscillates at the frequencies of tremor, and deep brain stimulation (DBS) in this area can reduce tremor. It is not fully understood how DBS affects tremor frequency activity in the thalamus, and studying different patterns of DBS stimulation may help to clarify these mechanisms. We created a computational model of different shapes of DBS and studied how they reduce different hypothesized generators of tremor frequency activity. A greater understanding of how DBS affects the thalamus may lead to improved treatments to reduce tremor and alleviate side effects in patients with ET.

Posture-Related Oscillations in Human Cerebellar Thalamus in Essential Tremor Are Enabled by Voluntary Motor Circuits

2005 ◽  
Vol 93 (1) ◽  
pp. 117-127 ◽  
Author(s):  
Sherwin E. Hua ◽  
Frederick A. Lenz
Keyword(s):  
Essential Tremor ◽  
Thalamic Nucleus ◽  
Oscillatory Activity ◽  
Active Movement ◽  
Thalamic Nuclei ◽  
Motor Circuits ◽  
Cross Correlation Analysis ◽  
Tremor Frequency ◽  
Sensory Nucleus ◽  
Proprioceptive Inputs

The mechanism of essential tremor (ET) is unclear. Animal models of tremor and functional imaging studies in ET predict that the cerebellum and a cerebellar recipient thalamic nucleus ( ventral intermediate, Vim) should exhibit oscillatory activity during rest and during tremor due to abnormal olivo-cerebellar activity. Physiologic responses of 152 single neurons were recorded during awake mapping of the ventral thalamus in seven patients with ET prior to thalamotomy. During postural tremor, spectral cross-correlation analysis demonstrated that 51% of the neurons studied exhibited a concentration of power at tremor frequency that was correlated with electromyography, i.e., tremor neurons. During rest, thalamic neurons did not exhibit tremor-frequency activity. Among the three thalamic nuclei surveyed, Vim had a significantly higher proportion of tremor neurons than did the principal somatic sensory nucleus ( ventral caudal, Vc) or a pallidal recipient thalamic nucleus ( ventral oral posterior, Vop). Neurons related to active movement (voluntary neurons) had significantly greater tremor-related activity than did nonvoluntary neurons. These findings are not consistent with a model of continuous olivo-cerebellar driving of the motor cortex through thalamic connections. Instead ET may be facilitated by motor circuits that enable tremor-related thalamic activity during voluntary movement. Additionally, a subgroup of tremor neurons with proprioceptive inputs were identified that may allow sensory feedback to access the central tremor network.

scholarly journals Role of cerebellar GABAergic dysfunctions in the origins of essential tremor

2019 ◽  
Vol 116 (27) ◽  
pp. 13592-13601 ◽  
Author(s):  
Xu Zhang ◽  
Sabato Santaniello
Keyword(s):  
Essential Tremor ◽  
Dentate Nucleus ◽  
Oscillatory Activity ◽  
High Frequency Stimulation ◽  
Inferior Olivary Nucleus ◽  
Functional Changes ◽  
Decay Times ◽  
Tremor Frequency ◽  
Frequency Stimulation ◽  
Inferior Olivary

Essential tremor (ET) is among the most prevalent movement disorders, but its origins are elusive. The inferior olivary nucleus (ION) has been hypothesized as the prime generator of tremor because of the pacemaker properties of ION neurons, but structural and functional changes in ION are unlikely under ET. Abnormalities have instead been reported in the cerebello-thalamo-cortical network, including dysfunctions of the GABAergic projections from the cerebellar cortex to the dentate nucleus. It remains unclear, though, how tremor would relate to a dysfunction of cerebellar connectivity. To address this question, we built a computational model of the cortico-cerebello-thalamo-cortical loop. We simulated the effects of a progressive loss of GABAA α1-receptor subunits and up-regulation of α2/3-receptor subunits in the dentate nucleus, and correspondingly, we studied the evolution of the firing patterns along the loop. The model closely reproduced experimental evidence for each structure in the loop. It showed that an alteration of amplitudes and decay times of the GABAergic currents to the dentate nucleus can facilitate sustained oscillatory activity at tremor frequency throughout the network as well as a robust bursting activity in the thalamus, which is consistent with observations of thalamic tremor cells in ET patients. Tremor-related oscillations initiated in small neural populations and spread to a larger network as the synaptic dysfunction increased, while thalamic high-frequency stimulation suppressed tremor-related activity in thalamus but increased the oscillation frequency in the olivocerebellar loop. These results suggest a mechanism for tremor generation under cerebellar dysfunction, which may explain the origin of ET.

scholarly journals TRPM4 conductances in thalamic reticular nucleus neurons generate persistent firing during slow oscillations

2020 ◽  
Author(s):  
John J. O’Malley ◽  
Frederik Seibt ◽  
Jeannie Chin ◽  
Michael Beierlein
Keyword(s):  
Rhythmic Activity ◽  
Thalamic Reticular Nucleus ◽  
Oscillatory Activity ◽  
Reticular Nucleus ◽  
Plateau Potentials ◽  
Slow Oscillations ◽  
Synaptic Circuits ◽  
Ventrobasal Thalamus ◽  
Persistent Firing

AbstractDuring sleep, neurons in the thalamic reticular nucleus (TRN) participate in distinct types of oscillatory activity. While the reciprocal synaptic circuits between TRN and sensory relay nuclei are known to underlie the generation of sleep spindles, the mechanisms regulating slow (<1 Hz) forms of thalamic oscillations are not well understood. Under in vitro conditions, TRN neurons can generate slow oscillations in a cell-intrinsic manner, with postsynaptic Group 1 metabotropic glutamate receptor (mGluR) activation leading to the generation of plateau potentials mediated by both T-type Ca2+ currents and Ca2+ -activated nonselective cation currents (ICAN). However, the identity of ICAN and the possible contribution of thalamic circuits to slow rhythmic activity remain unclear. Using thalamic slices derived from adult mice of either sex, we recorded slow forms of rhythmic activity in TRN neurons, which were mediated by fast glutamatergic thalamoreticular inputs but did not require postsynaptic mGluR activation. For a significant fraction of TRN neurons, synaptic inputs or brief depolarizing current steps led to long-lasting plateau potentials and persistent firing (PF), and in turn, resulted in sustained synaptic inhibition in postsynaptic relay neurons of the ventrobasal thalamus (VB). Pharmacological approaches indicated that plateau potentials were triggered by Ca2+ influx through T-type Ca2+ channels and mediated by Ca2+ and voltage-dependent transient receptor potential melastatin 4 (TRPM4) channels. Taken together, our results suggest that thalamic circuits can generate slow oscillatory activity, mediated by an interplay of TRN-VB synaptic circuits that generate rhythmicity and TRN cell-intrinsic mechanisms that control PF and oscillation frequency.Significance StatementSlow forms of thalamocortical rhythmic activity are thought to be essential for memory consolidation during sleep and the efficient removal of potentially toxic metabolites. In vivo, thalamic slow oscillations are regulated by strong bidirectional synaptic pathways linking neocortex and thalamus. Therefore, in vitro studies in the isolated thalamus can offer important insights about the ability of individual neurons and local circuits to generate different forms of rhythmic activity. We found that circuits formed by GABAergic neurons in the thalamic reticular nucleus (TRN) and glutamatergic relay neurons in the ventrobasal thalamus generated slow oscillatory activity, which was accompanied by persistent firing in TRN neurons. Our results identify both cell-intrinsic and synaptic mechanisms that mediate slow forms of rhythmic activity in thalamic circuits.

A model of spindle rhythmicity in the isolated thalamic reticular nucleus

1994 ◽  
Vol 72 (2) ◽  
pp. 803-818 ◽  
Author(s):  
A. Destexhe ◽  
D. Contreras ◽  
T. J. Sejnowski ◽  
M. Steriade
Keyword(s):  
Ionic Channels ◽  
Thalamic Reticular Nucleus ◽  
Oscillatory Activity ◽  
Inhibitory Synapses ◽  
Reticular Nucleus ◽  
Two Dimensional ◽  
Gamma Aminobutyric Acid ◽  
Spatiotemporal Behavior ◽  
Synchronous Oscillations

1. The oscillatory properties of the isolated reticular (RE) thalamus were modeled with the use of compartmental models of RE cells. Hodgkin-Huxley type kinetic models of ionic channels were derived from voltage- and current-clamp data from RE cells. Interactions between interconnected RE cells were simulated with the use of a kinetic model of gamma-aminobutyric acid (GABA) inhibitory synapses. 2. The intrinsic bursting properties of RE cells in the model were due to the presence of a low-threshold Ca2+ current and two Ca(2+)-activated currents. The properties of these model RE cells were compared with RE neurons recorded intracellularly in vivo in cats. 3. Model RE cells densely interconnected with GABAA synapses produced synchronous oscillations at a frequency close to that of spindles (7–14 Hz). Networks of RE neurons organized in a two-dimensional array with only proximal connectivity also exhibited synchronized oscillations in the spindle range. In addition, the proximally connected network showed periods of high and low synchronicity, giving rise to waxing and waning oscillations in the population of RE cells. 4. The spatiotemporal behavior of the network was investigated during waxing and waning oscillations. The waxing and waning emerged as an alternation between periods of desynchronized and synchronized activity, corresponding to periods of irregular and coherent spatial activity. During synchronized periods, the network displayed propagating coherent waves of synchronous activity that had a tendency to form spirals. 5. Networks of model RE neurons fully connected through GABAB synapses exhibited perfectly synchronous oscillations at lower frequencies (0.5–1 Hz), but two-dimensional networks with proximal GABAB connectivity failed to synchronize. 6. These simulations demonstrate that networks of model neurons that include the main intrinsic currents found in RE cells can generate waxing and waning oscillatory activity similar to the spindle rhythmicity observed in the isolated RE nucleus in vivo. The model reveals the interplay between the intrinsic rhythmic properties of RE cells and the fast synaptic interactions in organizing synchronized rhythmicity.

Short-term deep brain stimulation of the thalamic reticular nucleus modifies aberrant oscillatory activity in a neurodevelopment model of schizophrenia

Neuroscience ◽  
2017 ◽  
Vol 357 ◽  
pp. 99-109 ◽  
Author(s):  
Víctor Manuel Magdaleno-Madrigal ◽  
Gerardo Contreras-Murillo ◽  
Israel Camacho-Abrego ◽  
José Vicente Negrete-Díaz ◽  
Alejandro Valdés-Cruz ◽  
...  
Keyword(s):  
Deep Brain Stimulation ◽  
Brain Stimulation ◽  
Thalamic Reticular Nucleus ◽  
Oscillatory Activity ◽  
Reticular Nucleus ◽  
Short Term ◽  
Deep Brain ◽  
Stimulation Of

scholarly journals Volatile Anesthetic Action in a Computational Model of the Thalamic Reticular Nucleus

2009 ◽  
Vol 110 (5) ◽  
pp. 996-1010 ◽  
Author(s):  
Allan Gottschalk ◽  
Sam A. Miotke
Keyword(s):  
Ion Channels ◽  
Computational Model ◽  
Type A ◽  
Aminobutyric Acid ◽  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Gamma Aminobutyric Acid ◽  
Network Behavior ◽  
Acid Type ◽  
Network Synchrony

Background Although volatile anesthetics (VAs) modulate the activity of multiple ion channels, the process whereby one or more of these effects are integrated to produce components of the general anesthetic state remains enigmatic. Computer models offer the opportunity to examine systems level effects of VA action at one or more sites. Motivated by the role of the thalamus in consciousness and sensory processing, a computational model of the thalamic reticular nucleus was used to determine the collective impact on model behavior of VA action at multiple sites. Methods A computational model of the thalamic reticular nucleus was modified to permit VA modulation of its ion channels. Isobolographic analysis was used to determine how multiple sites interact. Results VA modulation of either T-type Ca(2+) channels or gamma-aminobutyric acid type A receptors led to increased network synchrony. VA modulation of both further increased network synchronization. VA-induced decrements in Ca(2+) current permitted greater impact of inhibitory currents on membrane potential, but at higher VA concentrations the decrease in Ca(2+) current led to a decreased number of spikes in the burst generating the inhibitory signal. MAC-awake (the minimum alveolar concentration at which 50% of subjects will recover consciousness) concentrations of both isoflurane and halothane led to similar levels of network synchrony in the model. Conclusions Relatively modest VA effects at both T-type Ca(2+) channels and gamma-aminobutyric acid type A receptors can substantially alter network behavior in a computational model of a thalamic nucleus. The similarity of network behavior at MAC-awake concentrations of different VAs is consistent with a contribution of the thalamus to VA-induced unconsciousness through action at these channels.

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