Stiff Person Syndrom

The study uses transcranial direct current stimulation (tDCS) to investigate the effect of GAD65 autoantibodies (GAD65-Ab) in stiff person syndrome (SPS) and cerebellar ataxia (CA). Here are the key findings and effect of tDCS:

tDCS mechanism of action in the study:

• tDCS on the motor cortex:
  • tDCS modulates neuronal excitability by applying a weak electric field.
  • In this study, tDCS was used to evaluate dysregulation of motor control caused by GAD65 antibodies.

Effects of tDCS:

1. Disinhibition of the motor cortex in CA:
   • In GAD65 antibodies from patients with cerebellar ataxia (Ab CA), tDCS showed a strong disinhibition of the motor cortex.
   • This suggests that Ab CA impairs neuronal inhibition by GABA (mediated via GAD65), which was enhanced by tDCS.
2. Differences between SPS and CA:
   • No comparable disinhibition by tDCS was observed with SPS antibodies (Ab SPS).
   • Ab CA appears to specifically impair cerebellar control of inhibition, which was illustrated by the results of tDCS.
3. Increased glutamate release with specific antibodies:
   • Monoclonal antibodies (b78) led to increased glutamate concentration and a stronger disinhibition of the motor cortex after tDCS.
   • SPS antibodies (Ab SPS) showed similar effects to b78 in terms of their epitope properties and GABA inhibition.

Summary:

• tDCS made functional disorders visible: It enhanced the disinhibition of the motor cortex by CA antibodies.
• Different epitopes and effects: SPS and CA antibodies affect GABA and neuronal functions differently, which became clear through tDCS effects.
• Potential of tDCS: It could play a role in the diagnosis or therapy of GAD65-mediated neurological disorders by making specific dysregulations visible or modulating them.

The Study highlights how tDCS can be used as a tool to investigate and potentially treat disorders of neuronal inhibition.

SPS is an autoimmune disease

The mechanism of Stiff Person Syndrome (SPS) in the brain primarily revolves around disruptions in GABAergic neurotransmission, which is critical for maintaining the balance between excitatory and inhibitory signals in the central nervous system. Here are the key mechanisms:

1. Autoantibodies Against GAD65:
   • SPS is strongly associated with autoantibodies against glutamic acid decarboxylase (GAD65), an enzyme critical for converting glutamate to GABA.
   • Reduced GAD65 activity leads to lower GABA levels, impairing inhibitory neurotransmission.
2. Hyperexcitability of the Motor Cortex:
   • Impaired GABAergic function results in a loss of intracortical inhibition.
   • This creates a hyperexcitable state in the motor cortex, leading to excessive corticospinal responses and continuous motor activity.
3. Dysregulated Corticospinal Pathways:
   • The imbalance between excitatory (glutamate-driven) and inhibitory (GABAergic) signals results in stimuli-induced spasms and rigidity characteristic of SPS.
4. Immune-Mediated Pathology:
   • Intrathecal synthesis of GAD antibodies suggests central nervous system-specific immune activation.
   • It remains unclear whether these antibodies are directly pathogenic or markers of immune dysregulation.
5. Supraspinal Impairment:
   • Dysfunction in supraspinal GABAergic neurons disrupts the inhibitory-excitatory circuitry across the brain and spinal cord, amplifying motor responses to stimuli.

This mechanistic understanding helps explain why therapies targeting GABAergic pathways, such as benzodiazepines or immunotherapy, can mitigate symptoms. Experimental neuromodulation techniques like non-invasive brain stimulation (NIBS) also aim to address motor cortex hyperexcitability and enhance inhibitory control【24†source】.