Dystonia is a chronic and often disabling hyperkinetic movement disorder arising from dysfunction within the basal ganglia thalamo cortical circuits [1]. It is clinically heterogeneous, encompassing focal, segmental, and generalized subtypes. The disorder manifests as sustained or intermittent muscle contractions, abnormal postures, and repetitive movements, often associated with pain and functional loss [2]. The prevalence of primary dystonia ranges from 15 to 30 per 100,000 individuals, while secondary dystonia associated with genetic mutations or neurodegenerative conditions is much rarer [3]. Among these, PTEN-induced kinase 1 (PINK1) mutations, typically associated with autosomal recessive early-onset Parkinsonism, have been linked to segmental dystonia through mitochondrial dysfunction and dopaminergic neurodegeneration [4]. Conventional therapies for dystonia include oral medications such as anticholinergics, benzodiazepines, or dopamine agonists; focal botulinum toxin injections; and, in severe cases, deep brain stimulation (DBS) [5,6]. However, many patients remain refractory to these treatments. Repetitive Transcranial Magnetic Stimulation (rTMS) represents an emerging non-invasive neuromodulatory approach capable of modulating cortical excitability and neural network connectivity [7]. Low-frequency (≤1 Hz) stimulation can reduce cortical hyperexcitability, whereas high-frequency (>5 Hz) rTMS may enhance excitatory plasticity [8]. Previous studies have demonstrated symptom reduction in focal dystonia, writer’s cramp, and cervical dystonia with rTMS applied over the premotor or motor cortex [9,10]. This case report presents a unique scenario of PINK1-related dystonia treated with dual-phase

Patient Demographics and History A 22-year-old married female, a third-year Bachelor of Science student, presented to Asha Hospital, Hyderabad, accompanied by her father, with complaints of: • Involuntary contractions of fingers of the left hand and toes of the left foot for 10 years, • Pain and stiffness in the left limbs for the same duration, and • Neck pain persisting for three years. She belonged to a semi-urban background, with no history of consanguinity, head trauma, or toxin exposure. Past Medical and Treatment History Her illness began insidiously in 2012, with progressive muscle contractions on the left side. She consulted approximately 10–12 physicians over a decade, receiving various symptomatic medications. • First prescription: Tetrabenazine 25 mg daily – transient benefit for 3 months. • Subsequent regimen: Syndopa Plus (carbidopa/levodopa combination), providing partial relief. • Medication cessation: June 2022, followed by symptom relapse within 5 months. In July 2021, after neurogenetic evaluation, she tested positive for PINK1 mutation, suggestive of autosomal recessive Parkinsonism with segmental dystonia. No deletion or duplication was found on MLPA analysis. The patient experienced emotional distress due to persistent symptoms, leading to secondary dysthymia with somatic complaints. Clinical Examination On examination, she was alert, oriented, and cooperative. • Motor findings: Sustained flexion of the left fingers and toes, mild dystonic tremor, and rigidity over the left forearm and calf. • Pain: Reported as severe (PEG = 27/30). • Reflexes: Normal. • Gait: Stable but limited by pain. • Mental status: Mild depressive affect, no psychotic features, intact memory. Diagnostic Assessment Scale Pre-treatment Score Post-treatment Score % Improvement Fahn-Marsden Movement Scale 22 2 91% Dystonia Disability Scale 7 3 57% Global Dystonia Severity Rating Scale 31 7 77% PEG Pain Scale 27 8 70% These results indicated a marked reduction in dystonia severity, disability, and pain perception following the rTMS protocol. Therapeutic Intervention The patient was admitted on 15th November 2022. After informed consent and baseline neuropsychiatric evaluation, she underwent combined Deep rTMS and conventional rTMS therapy. Deep rTMS Protocol (Brainsway Device) The Parkinson’s Protocol (Italy) was administered in two consecutive parts: Part 1: Low-frequency stimulation (1 Hz) targeting bilateral primary motor cortex (M1). Part 2: High-frequency stimulation (10 Hz) targeting bilateral prefrontal cortex (PFC). Stimulation Parameters Phase MT % Target Area Frequency (Hz) Train Duration (s) No. of Trains Total Pulses Session Duration 1 55 % (90 % MT) Bilateral M1 1 Hz 1 s 900 900 ~15 min 2 55 % (100 % MT) Bilateral PFC 10 Hz 2 s 40 800 ~14 min After a 2-hour rest, a conventional rTMS session using a figure-of-8 coil (MagVenture device) was delivered at 1 Hz over the right dorsolateral prefrontal cortex (DLPFC) to address associated mood symptoms and augment cortical inhibition. Adjunct Therapy • Medication: Desvenlafaxine 50 mg HS, increased to twice daily for dysthymic symptoms. • Physiotherapy: Stretching and relaxation exercises. • Psychotherapy: Supportive and behavioral activation sessions. Clinical Course and Outcome By Day 5 of treatment, the patient demonstrated: • Reduction in muscle rigidity and frequency of contractions. • Restoration of normal finger extension and improved grip strength. • Pain reduction from 9/10 to 3/10 on numerical rating scale. • Improved mood, energy, and engagement in self-care activities. • Sleep quality and concentration improved markedly. At one-month follow-up, her functional gains persisted without relapse, and no adverse effects (e.g., headache, seizure, cognitive changes) were observed.

Pathophysiology and Rationale Dystonia arises from impaired sensorimotor integration and abnormal plasticity within the basal ganglia and cortical circuits [11]. rTMS, by modulating excitatory and inhibitory pathways, can normalize cortical hyperexcitability and restore interhemispheric balance [12]. In this patient, low-frequency rTMS over the motor cortex likely induced inhibitory effects on overactive cortical regions, reducing dystonic contractions [13]. Meanwhile, high-frequency stimulation over the PFC may have improved executive control and emotional regulation, indirectly reducing dystonic exacerbation related to stress or anxiety [14]. Mechanistic Insights rTMS exerts its therapeutic effects via: • Synaptic plasticity modulation: Long-term depression (LTD) in hyperactive cortical circuits. • Thalamo-cortical feedback regulation: Balancing inhibitory GABAergic and excitatory glutamatergic signals. • Neurotransmitter modulation: Increased dopamine release in striatal circuits, enhancing motor control [15]. • Network reorganization: Functional MRI studies show normalization of sensorimotor connectivity post-rTMS [16]. Comparison with Literature Multiple studies have demonstrated benefits of rTMS in focal and generalized dystonia: • Murase et al. [7] found that 1 Hz stimulation over premotor cortex improved writer’s cramp. • Koch et al. [9] reported significant symptom reduction in cervical dystonia after rTMS to the supplementary motor area. • Lefaucheur et al. [10] summarized over 30 controlled studies confirming transient but clinically meaningful relief in various dystonias. However, combining Deep TMS and surface rTMS, as in this case, has rarely been documented. The dual-protocol approach targeting both cortical and subcortical loops may explain the rapid and robust clinical improvement. Genetic Implications The presence of PINK1 mutation adds pathophysiological complexity. PINK1 encodes a mitochondrial kinase involved in mitophagy and neuronal survival [17]. Its dysfunction leads to dopaminergic neuronal vulnerability, contributing to dystonic and parkinsonian phenotypes. rTMS might enhance mitochondrial function indirectly through neurotrophic factor upregulation, as shown in preclinical models [18]. Clinical Learning Points 1. rTMS provides measurable improvement in motor and pain symptoms even after short-duration therapy. 2. Dual-site stimulation (motor + prefrontal cortex) yields synergistic benefits addressing both physical and affective components. 3. Genetic dystonias, previously considered refractory, may respond to non-invasive neuromodulation. 4. Regular multimodal assessment scales are essential for monitoring progress and objective evaluation. Limitations • Single-case report; generalizability limited. • Short follow-up duration (one month). • Mechanistic inferences are theoretical; neuroimaging correlation not performed. Future work should include randomized controlled studies assessing durability, dosage optimization, and integration with pharmacological and physiotherapeutic modalities.

This case demonstrates that repetitive transcranial magnetic stimulation particularly when combining deep and surface coil modalities can produce substantial improvements in motor function, pain, and emotional wellbeing in patients with dystonia. The findings highlight rTMS as a promising adjunctive therapy in complex movement disorders, especially those with genetic underpinnings such as PINK1-related dystonia. Integration of neuropsychiatric, rehabilitative, and neuromodulatory strategies may redefine the treatment paradigm for refractory dystonias, offering hope for improved quality of life and functional recovery.

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