V Srinivasa Chakravarthy

Parkinson's disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (akinesia and bradykinesia, tremor and rigidity), PD patients show additional motor deficits, including: gait disturbance, impaired handwriting, grip force and speech deficits, among others. Some of these motor symptoms (e.g., deficits of gait, speech, and handwriting) have similar clinical profiles, neural substrates, and respond similarly to dopaminergic medication and deep brain stimulation (DBS). Here, we provide an extensive review of the clinical characteristics and neural substrates of each of these motor symptoms, to highlight precisely how PD and its medical and surgical treatments impact motor symptoms. In conclusion, we offer a unified framework for understanding the range of motor symptoms in PD. We argue that various motor symptoms in PD reflect dysfunction of neural structures responsible for action selection, motor sequencing, and coordination and execution of movement.

Parkinson's disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (tremor, bradykinesia/akinesia, and rigidity), PD patients also show other motor deficits, including gait disturbance, speech deficits, and impaired handwriting. However, along with these key motor symptoms, PD patients also experience cognitive deficits in attention, executive function, working memory, and learning. Recent evidence suggests that these motor and cognitive deficits of PD are not completely dissociable, as aspects of cognitive dysfunction can impact motor performance in PD. In this article, we provide a review of behavioral and neural studies on the associations between motor symptoms and cognitive deficits in PD, specifically akinesia/bradykinesia, tremor, gait, handwriting, precision grip, and speech production. This review paves the way for providing a framework for understanding how treatment of cognitive dysfunction, for example cognitive rehabilitation programs, may in turn influence the motor symptoms of PD.

Although empirical and neural studies show that serotonin (5HT) plays many functional roles in the brain, prior computational models mostly focus on its role in behavioral inhibition. In this study, we present a model of risk based decision making in a modified Reinforcement Learning (RL)-framework. The model depicts the roles of dopamine (DA) and serotonin (5HT) in Basal Ganglia (BG). In this model, the DA signal is represented by the temporal difference error (δ), while the 5HT signal is represented by a parameter (α) that controls risk prediction error. This formulation that accommodates both 5HT and DA reconciles some of the diverse roles of 5HT particularly in connection with the BG system. We apply the model to different experimental paradigms used to study the role of 5HT: (1) Risk-sensitive decision making, where 5HT controls risk assessment, (2) Temporal reward prediction, where 5HT controls time-scale of reward prediction, and (3) Reward/Punishment sensitivity, in which the punishment prediction error depends on 5HT levels. Thus the proposed integrated RL model reconciles several existing theories of 5HT and DA in the BG. © 2014 Balasubramani, Chakravarthy, Ravindran and Moustafa.

Many computational models of the basal ganglia (BG) have been proposed over the past twenty-five years. While computational neuroscience models have focused on closely matching the neurobiology of the BG, computational cognitive neuroscience (CCN) models have focused on how the BG can be used to implement cognitive and motor functions. This review article focuses on CCN models of the BG and how they use the neuroanatomy of the BG to account for cognitive and motor functions such as categorization, instrumental conditioning, probabilistic learning, working memory, sequence learning, automaticity, reaching, handwriting, and eye saccades. A total of 19 BG models accounting for one or more of these functions are reviewed and compared. The review concludes with a discussion of the limitations of existing CCN models of the BG and prescriptions for future modeling, including the need for computational models of the BG that can simultaneously account for cognitive and motor functions, and the need for a more complete specification of the role of the BG in behavioral functions. © 2013 Helie, Chakravarthy and Moustafa.

Experimental data show that perceptual cues can either exacerbate or ameliorate freezing of gait (FOG) in Parkinson’s Disease (PD). For example, simple visual stimuli like stripes on the floor can alleviate freezing whereas complex stimuli like narrow doorways can trigger it. We present a computational model of the cognitive and motor cortico-basal ganglia loops that explains the effects of sensory and cognitive processes on FOG. The model simulates strong causative factors of FOG including decision conflict (a disagreement of various sensory stimuli in their association with a response) and cognitive load (complexity of coupling a stimulus with downstream mechanisms that control gait execution). Specifically, the model simulates gait of PD patients (freezers and non-freezers) as they navigate a series of doorways while simultaneously responding to several Stroop word cues in a virtual reality setup. The model is based on an actor-critic architecture of Reinforcement Learning involving Utility-based decision making, where Utility is a weighted sum of Value and Risk functions. The model accounts for the following experimental data: (a) the increased foot-step latency seen in relation to high conflict cues, (b) the high number of motor arrests seen in PD freezers when faced with a complex cue compared to the simple cue, and (c) the effect of dopamine medication on these motor arrests. The freezing behavior arises as a result of addition of task parameters (doorways and cues) and not due to inherent differences in the subject group. The model predicts a differential role of risk sensitivity in PD freezers and non-freezers in the cognitive and motor loops. Additionally this first-of-its-kind model provides a plausible framework for understanding the influence of cognition on automatic motor actions in controls and Parkinson’s Disease.

We present a computational model of altered gait velocity patterns in Parkinson's Disease (PD) patients. PD gait is characterized by short shuffling steps, reduced walking speed, increased double support time and sometimes increased cadence. The most debilitating symptom of PD gait is the context dependent cessation in gait known as freezing of gait (FOG). Cowie et al. (2010) and Almeida and Lebold (2010) investigated FOG as the changes in velocity profiles of PD gait, as patients walked through a doorway with variable width. The former reported a sharp dip in velocity, a short distance from the doorway that was greater for narrower doorways. They compared the gait performance in PD freezers at ON and OFF dopaminergic medication. In keeping with this finding, the latter also reported the same for ON medicated PD freezers and non-freezers. In the current study, we sought to simulate these gait changes using a computational model of Basal Ganglia based on Reinforcement Learning, coupled with a spinal rhythm mimicking central pattern generator (CPG) model. In the model, a simulated agent was trained to learn a value profile over a corridor leading to the doorway by repeatedly attempting to pass through the doorway. Temporal difference error in value, associated with dopamine signal, was appropriately constrained in order to reflect the dopamine-deficient conditions of PD. Simulated gait under PD conditions exhibited a sharp dip in velocity close to the doorway, with PD OFF freezers showing the largest decrease in velocity compared to PD ON freezers and controls. PD ON and PD OFF freezers both showed sensitivity to the doorway width, with narrow door producing the least velocity/ stride length. Step length variations were also captured with PD freezers producing smaller steps and larger step-variability than PD non-freezers and controls. In addition this model is the first to explain the non-dopamine dependence for FOG giving rise to several other possibilities for its etiology. © 2014 Muralidharan, Balasubramani, Chakravarthy, Lewisand Moustafa.

Freezing of gait (FOG) is a mysterious clinical phenomenon seen in Parkinson’s disease (PD) patients, a neurodegenerative disorder of the basal ganglia (BG), where there is cessation of locomotion under specific contexts. These contexts could include motor initiation, i.e., when starting movement, passing through narrow passages and corridors, while making a turn and as they are about to reach a destination. We have developed computational models of the BG which explains the freezing behavior seen in PD. The model uses reinforcement learning framework, incorporating Actor–Critic architecture, to aid learning of a virtual subject to navigate through these specific contexts. The model captures the velocity changes (slowing down) seen in PD freezers upon encountering a doorway, turns, and under the influence of cognitive load compared to PD non-freezers and healthy controls. The model throws interesting predictions about the pathology of freezing suggesting that dopamine, a key neurochemical deficient in PD, might not be the only reason for the occurrences of such freeze episodes. Other neuromodulators which are involved in action exploration and risk sensitivity influence these motor arrests. Finally, we have incorporated a network model of the BG to understand the network level parameters which influence contextual motor freezing.

In neuroscience literature, dopamine is often considered as a pleasure chemical of the brain. Dopaminergic neurons respond to rewarding stimuli which include primary rewards like opioids or food, or more abstract forms of reward like cash rewards or pictures of pretty faces. It is this reward-related aspect of dopamine, particularly its association with reward prediction error, that is highlighted by a large class of computational models of dopamine signaling. Dopamine is also a neuromodulator, controlling synaptic plasticity in several cortical and subcortical areas. But dopamine's influence is not limited to the nervous system; its effects are also found in other physiological systems, particularly the circulatory system. Importantly, dopamine agonists have been used as a drug to control blood pressure. Is there a theoretical, conceptual connection that reconciles dopamine's effects in the nervous system with those in the circulatory system? This perspective article integrates the diverse physiological roles of dopamine and provides a simple theoretical framework arguing that its reward related function regulates the processes of energy consumption and acquisition in the body. We conclude by suggesting that energy-related book-keeping of the body at the physiological level is the common motif that links the many facets of dopamine and its functions.

There is significant evidence that in addition to reward-punishment based decision making, the Basal Ganglia (BG) contributes to risk-based decision making (Balasubramani et al., 2014). Despite this evidence, little is known about the computational principles and neural correlates of risk computation in this subcortical system. We have previously proposed a reinforcement learning (RL)-based model of the BG that simulates the interactions between dopamine (DA) and serotonin (5HT) in a diverse set of experimental studies including reward, punishment and risk based decision making (Balasubramani et al., 2014). Starting with the classical idea that the activity of mesencephalic DA represents reward prediction error, the model posits that serotoninergic activity in the striatum controls risk-prediction error. Our prior model of the BG was an abstract model that did not incorporate anatomical and cellular-level data. In this work, we expand the earlier model into a detailed network model of the BG and demonstrate the joint contributions of DA-5HT in risk and reward-punishment sensitivity. At the core of the proposed network model is the following insight regarding cellular correlates of value and risk computation. Just as DA D1 receptor (D1R) expressing medium spiny neurons (MSNs) of the striatum were thought to be the neural substrates for value computation, we propose that DA D1R and D2R co-expressing MSNs are capable of computing risk. Though the existence of MSNs that co-express D1R and D2R are reported by various experimental studies, prior existing computational models did not include them. Ours is the first model that accounts for the computational possibilities of these co-expressing D1R-D2R MSNs, and describes how DA and 5HT mediate activity in these classes of neurons (D1R-, D2R-, D1R-D2R- MSNs). Starting from the assumption that 5HT modulates all MSNs, our study predicts significant modulatory effects of 5HT on D2R and co-expressing D1R-D2R MSNs which in turn explains the multifarious functions of 5HT in the BG. The experiments simulated in the present study relates 5HT to risk sensitivity and reward-punishment learning. Furthermore, our model is shown to capture reward-punishment and risk based decision making impairment in Parkinson's Disease (PD). The model predicts that optimizing 5HT levels along with DA medications might be essential for improving the patients' reward-punishment learning deficits.

Impulsivity, i.e. irresistibility in the execution of actions, may be prominent in Parkinson's disease (PD) patients who are treated with dopamine precursors or dopamine receptor agonists. In this study, we combine clinical investigations with computational modeling to explore whether impulsivity in PD patients on medication may arise as a result of abnormalities in risk, reward and punishment learning. In order to empirically assess learning outcomes involving risk, reward and punishment, four subject groups were examined: healthy controls, ON medication PD patients with impulse control disorder (PD-ON ICD) or without ICD (PD-ON non- ICD), and OFF medication PD patients (PD-OFF). A neural network model of the Basal Ganglia (BG) that has the capacity to predict the dysfunction of both the dopaminergic (DA) and the serotonergic (5HT) neuromodulator systems was developed and used to facilitate the interpretation of experimental results. In the model, the BG action selection dynamics were mimicked using a utility function based decision making framework, with DA controlling reward prediction and 5HT controlling punishment and risk predictions. The striatal model included three pools of Medium Spiny Neurons (MSNs), with D1 receptor (R) alone, D2R alone and co-expressing D1R-D2R. Empirical studies showed that reward optimality was increased in PD-ON ICD patients while punishment optimality was increased in PD-OFF patients. Empirical studies also revealed that PD-ON ICD subjects had lower reaction times (RT) compared to that of the PD-ON non-ICD patients. Computational modeling suggested that PD-OFF patients have higher punishment sensitivity, while healthy controls showed comparatively higher risk sensitivity. A significant decrease in sensitivity to punishment and risk was crucial for explaining behavioral changes observed in PD-ON ICD patients. Our results highlight the power of computational modelling for identifying neuronal circuitry implicated in learning, and its impairment in PD. The results presented here not only show that computational modelling can be used as a valuable tool for understanding and interpreting clinical data, but they also show that computational modeling has the potential to become an invaluable tool to predict the onset of behavioral changes during disease progression.