# Biological Basis of the Computational Model The provided code implements a computational model aimed at simulating essential tremor (ET) and exploring the effect of transcranial alternating current stimulation (tACS). Below is a breakdown of the biological relevance of the components modeled in the code: ## Essential Tremor Essential tremor is a movement disorder characterized by rhythmic, involuntary shaking. It commonly affects the hands but can also impact other areas of the body. The pathophysiology of essential tremor is not fully understood, but it is believed to involve oscillatory activity in specific neural circuits. ## Neural Circuits Modeled The code models several neurons and their synaptic connections, which are significant in the context of essential tremor: - **Inferior Olive (ION) Cells:** These neurons can produce intrinsic oscillations, which are thought to play a role in the generation of tremor. The model emulates these oscillations and their contribution to tremor. - **Purkinje Cells (PC):** These are inhibitory neurons located in the cerebellar cortex that form a crucial part of the output pathway of the cerebellum. They project to the deep cerebellar nuclei (DCN) and are involved in coordination and precision of movement. - **Deep Cerebellar Nuclei (DCN) Cells:** These are the main output structures of the cerebellum, receiving inhibitory input from Purkinje cells and playing a role in motor execution and feedback. - **Thalamocortical (TC) Cells:** These neurons are part of the thalamus and are involved in relaying motor signals to the cortex. They transmit the synchronized output of the cerebellum to the motor cortex. - **Motor Cortex (MC) Cells:** These neurons are part of the cerebral cortex and are responsible for generating neural impulses that control movement. The code emulates these cells through `hoc` files, suggesting that the neurons' electrophysiological properties (i.e., membrane potential and synaptic currents) are modeled based on known biological dynamics. ## Synaptic Connections The model includes synaptic connections between various types of cells to mimic the interactions within and between different regions of the brain that are involved in the generation of tremor: - **ION-PC, PC-DCN, DCN-ION, DCN-TC, and TC-MC connections:** These connections replicate the transmission of signals through the relevant circuits. The delays and weights of these synapses can be tuned to influence the dynamics and simulate tremor. ## Modulatory Intervention: tACS The primary biological feature of interest here is the implementation of real-time phase-locked tACS: - **SinClamp Stimulation** is applied to Purkinje cells, simulating a neuromodulation technique that applies sinusoidal electric currents transcranially. This type of stimulation is theorized to modulate oscillatory activity in neurons, potentially stabilizing or reducing tremor by disrupting the pathological synchronization. - **Amplitude and Phase Parameters:** These are read from a configuration file and applied to adjust the parameters for the SinClamp stimulation on a cycle-by-cycle basis, reflecting the real-time nature of the modulation. ## Noise and Variability Randomized elements in synaptic and neuronal properties (e.g., variability in synaptic conductances and time constants) are included to mimic the biological variability seen across different neurons and synapses. In summary, the model simulates the neural circuit dynamics implicated in essential tremor and investigates the impact of tACS as a potential therapeutic intervention. It incorporates biologically inspired architecture and dynamics to reflect both the intrinsic properties of neurons and their interactions.