Michelle M. McCarthy

Striatal origin of the pathologic beta oscillations in Parkinson's disease

Enhanced oscillations at beta frequencies (8–30 Hz) are a signature neural dynamic pathology in the basal ganglia and cortex of Parkinsons disease patients. The mechanisms underlying these pathological beta oscillations remain elusive. Here, using mathematical models, we find that robust beta oscillations can emerge from inhibitory interactions between striatal medium spiny neurons. The interaction of the synaptic GABAa currents and the intrinsic membrane M-current promotes population oscillations in the beta frequency range. Increased levels of cholinergic drive, a condition relevant to the parkinsonian striatum, lead to enhanced beta oscillations in the striatal model. We show experimentally that direct infusion of the cholinergic agonist carbachol into the striatum, but not into the neighboring cortex, of the awake, normal rodent induces prominent beta frequency oscillations in the local field potential. These results provide evidence for amplification of normal striatal network dynamics as a mechanism responsible for the enhanced beta frequency oscillations in Parkinsons disease.

Potential network mechanisms mediating electroencephalographic beta rhythm changes during propofol-induced paradoxical excitation

Propofol, like most general anesthetic drugs, can induce both behavioral and electroencephalographic (EEG) manifestations of excitation, rather than sedation, at low doses. Neuronal excitation is unexpected in the presence of this GABAA-potentiating drug. We construct a series of network models to understand this paradox. Individual neurons have ion channel conductances with Hodgkin–Huxley-type formulations. Propofol increases the maximal conductance and time constant of decay of the synaptic GABAA current. Networks range in size from 2 to 230 neurons. Population output is measured as a function of pyramidal cell activity, with the electroencephalogram approximated by the sum of population AMPA activity between pyramidal cells. These model networks suggest propofol-induced paradoxical excitation may result from a membrane level interaction between the GABAA current and an intrinsic membrane slow potassium current (M-current). This membrane level interaction has consequences at the level of multicellular networks enabling a switch from baseline interneuron synchrony to propofol-induced interneuron antisynchrony. Large network models reproduce the clinical EEG changes characteristic of propofol-induced paradoxical excitation. The EEG changes coincide with the emergence of antisynchronous interneuron clusters in the model networks. Our findings suggest interneuron antisynchrony as a potential network mechanism underlying the generation of propofol-induced paradoxical excitation. As correlates of behavioral phenomenology, these networks may refine our understanding of the specific behavioral states associated with general anesthesia.

Neurosystems: brain rhythms and cognitive processing.

Neuronal rhythms are ubiquitous features of brain dynamics, and are highly correlated with cognitive processing. However, the relationship between the physiological mechanisms producing these rhythms and the functions associated with the rhythms remains mysterious. This article investigates the contributions of rhythms to basic cognitive computations (such as filtering signals by coherence and/or frequency) and to major cognitive functions (such as attention and multi‐modal coordination). We offer support to the premise that the physiology underlying brain rhythms plays an essential role in how these rhythms facilitate some cognitive operations.

Therapeutic mechanisms of high-frequency stimulation in Parkinson’s disease and neural restoration via loop-based reinforcement

Significance We investigated the therapeutic mechanisms of high-frequency stimulation (HFS) in Parkinson’s disease by developing a computational model of the cortico-basal ganglia-thalamo-cortical loop in normal and parkinsonian conditions under the effects of stimulation at several frequencies. We found that the stimulation injected in the loop elicits neural perturbations that travel along multiple pathways with different latencies and rendezvous in striatum (one of the basal ganglia). If the stimulation frequency is high enough, these perturbations overlap (reinforcement) and cause more regular, stimulus-locked firing patterns in striatum. Overlap is maximal at clinically relevant HFS and restores more normal activity in the remaining structures of the loop. This suggests that neural restoration and striatal reinforcement may be a therapeutic merit and mechanism of HFS, respectively. High-frequency deep brain stimulation (HFS) is clinically recognized to treat parkinsonian movement disorders, but its mechanisms remain elusive. Current hypotheses suggest that the therapeutic merit of HFS stems from increasing the regularity of the firing patterns in the basal ganglia (BG). Although this is consistent with experiments in humans and animal models of Parkinsonism, it is unclear how the pattern regularization would originate from HFS. To address this question, we built a computational model of the cortico-BG-thalamo-cortical loop in normal and parkinsonian conditions. We simulated the effects of subthalamic deep brain stimulation both proximally to the stimulation site and distally through orthodromic and antidromic mechanisms for several stimulation frequencies (20–180 Hz) and, correspondingly, we studied the evolution of the firing patterns in the loop. The model closely reproduced experimental evidence for each structure in the loop and showed that neither the proximal effects nor the distal effects individually account for the observed pattern changes, whereas the combined impact of these effects increases with the stimulation frequency and becomes significant for HFS. Perturbations evoked proximally and distally propagate along the loop, rendezvous in the striatum, and, for HFS, positively overlap (reinforcement), thus causing larger poststimulus activation and more regular patterns in striatum. Reinforcement is maximal for the clinically relevant 130-Hz stimulation and restores a more normal activity in the nuclei downstream. These results suggest that reinforcement may be pivotal to achieve pattern regularization and restore the neural activity in the nuclei downstream and may stem from frequency-selective resonant properties of the loop.

Excitable Neurons, Firing Threshold Manifolds and Canards

We investigate firing threshold manifolds in a mathematical model of an excitable neuron. The model analyzed investigates the phenomenon of post-inhibitory rebound spiking due to propofol anesthesia and is adapted from McCarthy et al. (SIAM J. Appl. Dyn. Syst. 11(4):1674–1697, [2012]). Propofol modulates the decay time-scale of an inhibitory GABAa synaptic current. Interestingly, this system gives rise to rebound spiking within a specific range of propofol doses. Using techniques from geometric singular perturbation theory, we identify geometric structures, known as canards of folded saddle-type, which form the firing threshold manifolds. We find that the position and orientation of the canard separatrix is propofol dependent. Thus, the speeds of relevant slow synaptic processes are encoded within this geometric structure. We show that this behavior cannot be understood using a static, inhibitory current step protocol, which can provide a single threshold for rebound spiking but cannot explain the observed cessation of spiking for higher propofol doses. We then compare the analyses of dynamic and static synaptic inhibition, showing how the firing threshold manifolds of each relate, and why a current step approach is unable to fully capture the behavior of this model.

Dynamical changes in neurological diseases and anesthesia

Dynamics of neuronal networks can be altered in at least two ways: by changes in connectivity, that is, the physical architecture of the network, or changes in the amplitudes and kinetics of the intrinsic and synaptic currents within and between the elements making up a network. We argue that the latter changes are often overlooked as sources of alterations in network behavior when there are also structural (connectivity) abnormalities present; indeed, they may even give rise to the structural changes observed in these states. Here we look at two clinically relevant states (Parkinsons disease and schizophrenia) and argue that non-structural changes are important in the development of abnormal dynamics within the networks known to be relevant to each disorder. We also discuss anesthesia, since it is entirely acute, thus illustrating the potent effects of changes in synaptic and intrinsic membrane currents in the absence of structural alteration. In each of these, we focus on the role of changes in GABAergic function within microcircuits, stressing literature within the last few years.

Striatal cholinergic interneurons generate beta and gamma oscillations in the corticostriatal circuit and produce motor deficits

Significance Exaggerated beta oscillations within the cortico-basal ganglia-thalamic (CBT) network are putative electrophysiological signatures of bradykinesia and rigidity in Parkinson’s disease (PD). However, it is unclear how exaggerated beta oscillations emerge and how such oscillation patterns are related to PD motor deficits. In this study, we demonstrate that a single cell type, the striatal cholinergic interneuron, mediates the emergence of exaggerated beta oscillations within CBT circuits of normal mice and induces parkinsonian-like motor deficits. Because the striatal cholinergic system is uninhibited by loss of dopamine, these results provide mechanistic insights into the therapeutic effects of anticholinergic drugs in the treatment of PD and highlight the potential for developing beta oscillation-based biomakers for PD. Cortico-basal ganglia-thalamic (CBT) neural circuits are critical modulators of cognitive and motor function. When compromised, these circuits contribute to neurological and psychiatric disorders, such as Parkinson’s disease (PD). In PD, motor deficits correlate with the emergence of exaggerated beta frequency (15–30 Hz) oscillations throughout the CBT network. However, little is known about how specific cell types within individual CBT brain regions support the generation, propagation, and interaction of oscillatory dynamics throughout the CBT circuit or how specific oscillatory dynamics are related to motor function. Here, we investigated the role of striatal cholinergic interneurons (SChIs) in generating beta and gamma oscillations in cortical-striatal circuits and in influencing movement behavior. We found that selective stimulation of SChIs via optogenetics in normal mice robustly and reversibly amplified beta and gamma oscillations that are supported by distinct mechanisms within striatal-cortical circuits. Whereas beta oscillations are supported robustly in the striatum and all layers of primary motor cortex (M1) through a muscarinic-receptor mediated mechanism, gamma oscillations are largely restricted to the striatum and the deeper layers of M1. Finally, SChI activation led to parkinsonian-like motor deficits in otherwise normal mice. These results highlight the important role of striatal cholinergic interneurons in supporting oscillations in the CBT network that are closely related to movement and parkinsonian motor symptoms.

The Effect of Propofol Anesthesia on Rebound Spiking

The anesthetic propofol potentiates GABAa (inhibitory) receptors in the central nervous system. Paradoxically, low doses of propofol create manifestations of excitation rather than sedation. Previous computational modeling work suggests that postinhibitory rebound spiking may be responsible for this paradoxical excitation. In our models, postinhibitory rebound spiking emerges from an interaction between the inhibitory GABAa current and a slow potassium current (M-current). In contrast to previous studies of postinhibitory rebound spiking, the inhibition is not required to be strong or long. Rather, rebound spiking happens only when the time-constant of inhibition is within a specific range, including relatively fast time-constants. To better understand this phenomenon, we examine rebound spiking in a single model neuron. Fast/slow dynamics are analyzed using techniques from geometric singular perturbation theory. For the transition when the inhibitory time-constant is on the same time scale as the M-curre...

Striatal cholinergic receptor activation causes a rapid, selective and state-dependent rise in cortico-striatal β activity

Cortico‐basal ganglia‐thalamic (CBT) β oscillations (15–30 Hz) are elevated in Parkinsons disease and correlated with movement disability. To date, no experimental paradigm outside of loss of dopamine has been able to specifically elevate β oscillations in the CBT loop. Here, we show that activation of striatal cholinergic receptors selectively increased β oscillations in mouse striatum and motor cortex. In individuals showing simultaneous β increases in both striatum and M1, β partial directed coherence (PDC) increased from striatum to M1 (but not in the reverse direction). In individuals that did not show simultaneous β increases, β PDC increased from M1 to striatum (but not in the reverse direction), and M1 was characterized by persistent β‐high frequency oscillation phase–amplitude coupling. Finally, the direction of β PDC distinguished between β sub‐bands. This suggests that (1) striatal cholinergic tone exerts state‐dependent and frequency‐selective control over CBT β power and coordination; (2) ongoing rhythmic dynamics can determine whether elevated β oscillations are expressed in striatum and M1; and (3) altered striatal cholinergic tone differentially modulates distinct β sub‐bands.

Biased competition in the absence of input bias: predictions from corticostriatal computation

Classical accounts of biased competition (BC) require an input bias to resolve the competition between neuronal ensembles driving downstream processing. However, flexible and reliable selection of behaviorally-relevant ensembles can occur with unbiased stimulation: striatal D1 and D2 spiny projecting neurons (SPNs) receive balanced cortical input, yet their activity determines the choice between GO and NO-GO pathways in the basal ganglia. We present a corticostriatal model identifying three mechanisms that rely on physiological asymmetries to effect rate- and time-coded BC in the presence of balanced inputs. First, tonic input strength determines which SPN phenotype exhibit higher mean firing rate (FR). Second, low strength oscillatory inputs induce higher FR in D2 SPNs but higher coherence between D1 SPNs. Third, high strength inputs oscillating at distinct frequencies preferentially activate D1 or D2 SPN populations. Of these mechanisms, the latter accommodates observed rhythmic activity supporting rule-based decision making in prefrontal cortex.