Ventral Tegmental Area deep brain stimulation for cluster headache

• Deep brain stimulation for chronic refractory cluster headache: A case series about long-term outcomes and connectivity analysis
• Association of Clinical and Neuroanatomic Factors With Response to Ventral Tegmental Area DBS in Chronic Cluster Headache
• The sensitivity to change of the cluster headache quality of life scale assessed before and after deep brain stimulation of the ventral tegmental area
• Deep brain stimulation of the brainstem
• Deep brain stimulation of chronic cluster headaches: Posterior hypothalamus, ventral tegmentum and beyond
• Ventral tegmental area deep brain stimulation for chronic cluster headache: Effects on cognition, mood, pain report behaviour and quality of life
• Deep Brain Stimulation for Chronic Cluster Headache: A Review
• Defective functional connectivity between posterior hypothalamus and regions of the diencephalic-mesencephalic junction in chronic cluster headache

The Ventral Tegmental Area (VTA) is an emerging target for Deep Brain Stimulation (DBS) in the treatment of chronic cluster headaches (CCH), particularly in patients who are refractory to conventional therapies.

• The VTA is a key region in the brain's reward and pain modulation circuits.
• It plays a significant role in nociceptive processing and the regulation of emotional and pain responses, which is relevant for the affective aspects of cluster headaches.
• DBS targeting the VTA aims to modulate pain pathways and reduce headache frequency and severity by influencing the brain's pain-processing mechanisms.

• Refractory Chronic Cluster Headache:
  • Patients who have not responded to standard treatments such as triptans, verapamil, lithium, or corticosteroids.
  • Patients who have also failed other neuromodulation treatments like occipital nerve stimulation or posterior hypothalamus DBS.
• Severe, Disabling Attacks:
  • Cluster headaches significantly impair daily activities and quality of life.
  • Frequent attacks (2–3 attacks per day) that cause severe pain.
• Psychologically Stable and Medically Suitable Patients:
  • Patients who are medically stable and psychologically fit for surgery and long-term follow-up.

• Pre-surgical Planning:
  • Imaging: Stereotactic MRI or CT scans are used to identify the precise location of the VTA.
  • Targeting: The VTA is typically located near the midbrain and can be precisely targeted through deep brain mapping.
• Electrode Implantation:
  • Bilateral or unilateral electrode implantation depending on patient factors.
  • The implantation is performed under general anesthesia using stereotactic guidance.
• Post-surgical Stimulation:
  • Initial stimulation settings are conservative to minimize side effects.
  • Stimulation parameters are adjusted over time based on patient response.

• Frequency: 130–160 Hz.
• Pulse Width: 60–90 μs.
• Amplitude: 2–4 V, adjusted according to patient feedback.
• Programmed Adjustments: Parameters are fine-tuned during follow-up visits to balance efficacy and side effects.

• Headache Reduction:
  • Patients have reported significant reductions in both the frequency and intensity of cluster headaches after VTA DBS.
  • Some studies show up to 70% of patients experiencing relief, with effects sustained over the long term.
• Quality of Life Improvement:
  • Many patients report improved quality of life post-DBS, with fewer disabling attacks and better overall well-being.
• Long-Term Data:
  • Long-term follow-up shows that VTA DBS can offer sustained improvement, though more studies are needed to confirm its long-term benefits.

• Mood Changes:
  • Patients may experience emotional changes, such as euphoria or depressive symptoms, especially in the initial stages of stimulation.
• Autonomic Symptoms:
  • Some patients report mild autonomic disturbances such as dizziness or changes in blood pressure.
• Other Risks:
  • As with any DBS procedure, there are risks related to the surgery itself, including infection, bleeding, and hardware complications.
  • Stimulation-related side effects may include transient vertigo or gait instability, which can be managed by adjusting stimulation parameters.

• Alternative Mechanism:
  • Provides an alternative to other DBS targets (posterior hypothalamus) for patients who do not respond to standard therapies.
• Pain Modulation:
  • Modulates pain pathways through the brain's reward system, offering a unique approach for cluster headache management.

• Limited Clinical Evidence:
  • The VTA is a relatively new target for DBS in cluster headaches, and the evidence is still emerging.
  • More clinical trials and long-term studies are needed to establish its effectiveness and safety profile.
• Technical Challenges:
  • Precise targeting of the VTA is crucial due to its proximity to other midbrain structures, requiring highly skilled surgical teams.

Ventral Tegmental Area (VTA) DBS is a promising treatment option for patients with chronic, refractory cluster headaches who have not responded to conventional therapies. It targets pain-modulating pathways and offers a novel approach for managing this debilitating condition. However, its use should be reserved for carefully selected patients in specialized centers with expertise in neuromodulation.

Cheema et al. examines consecutive patients with refractory CCH treated with VTA DBS by a multidisciplinary team in a single tertiary neuroscience center as part of usual care. Headache diaries and validated questionnaires were completed at baseline and regular follow-up intervals. All patients underwent T1-weighted structural MRI before surgery. We compared clinical features using multivariable logistic regression and neuroanatomic differences using voxel-based morphometry (VBM) between responders and nonresponders.

Results: Over a 10-year period, 43 patients (mean age 53 years, SD 11.9), including 29 male patients, with a mean duration of CCH 12 years (SD 7.4), were treated and followed up for at least 1 year (mean follow-up duration 5.6 years). Overall, there was a statistically significant improvement in median attack frequency from 140 to 56 per month (Z = -4.95, p < 0.001), attack severity from 10/10 to 8/10 (Z = -4.83, p < 0.001), and duration from 110 to 60 minutes (Z = -3.48, p < 0.001). Twenty-nine (67.4%) patients experienced ≥50% improvement in attack frequency and were therefore classed as responders. There were no serious adverse events. The most common side effects were discomfort or pain around the battery site (7 patients) and transient diplopia and/or oscillopsia (6 patients). There were no differences in demographics, headache characteristics, or comorbidities between responders and nonresponders. VBM identified increased neural density in nonresponders in several brain regions, including the orbitofrontal cortex, anterior cingulate cortex, anterior insula, and amygdala, which were statistically significant (p < 0.001).

Discussion: VTA DBS showed no serious adverse events, and, although there was no placebo control, was effective in approximately two-thirds of patients at long-term follow-up. This study did not reveal any reliable clinical predictors of response. However, nonresponders had increased neural density in brain regions linked to processing of pain and autonomic function, both of which are prominent in the pathophysiology of CCH ¹⁾.

Cheema et al.’s study is a meaningful contribution to the field of neurology, demonstrating the potential of VTA DBS for refractory CCH. While the safety and long-term efficacy results are promising, the study’s limitations, particularly the lack of placebo control and clinical predictors, underscore the need for further research. Nonetheless, it provides a valuable foundation for advancing the use of DBS in headache disorders.

Cappon et al. study aimed to test the sensitivity to change of the CH-QoL in CH. Specifically we aimed to (i) assess the sensitivity of CH-QoL to change before and following deep brain stimulation of the ventral tegmental area (VTA-DBS), (ii) evaluate the relationship of changes on CH-QoL with changes in other generic measures of quality of life, as well as indices of mood and pain. Ten consecutive CH patients completed the CH-QoL and underwent neuropsychological assessment before and after VTA-DBS. The patients were evaluated on headache frequency, severity, and load (HAL) as well as on tests of generic quality of life (Short Form-36 (SF-36)), mood (Beck Depression Inventory, Hospital Anxiety and Depression Rating Scale), and pain (McGill Pain Questionnaire, Headache Impact Test, Pain Behaviour Checklist).

Results: The CH-QoL total score was significantly reduced after compared to before VTA-DBS. Changes in the CH-QoL total score correlated significantly and negatively with changes in HAL, the SF-36, and positively and significantly with depression and the evaluative domain on the McGill Pain Questionnaire.

Conclusions: Our findings demonstrate that changes after VTA-DBS in CH-QoL total scores are associated with the reduction of frequency, duration, and severity of headache attacks after surgery. Moreover, post VTA-DBS improvement in CH-QoL scores is associated with an amelioration in quality of life assessed with generic measures, a reduction of depressive symptoms, and evaluative pain experience after VTA-DBS. These results support the sensitivity to change of the CH-QoL and further demonstrate the validity and applicability of CH-QoL as a disease specific measure of quality of life for CH ²⁾.

Cappon et al. successfully demonstrate that the CH-QoL is a sensitive and valid tool for capturing QoL changes following VTA-DBS in CCH patients. Despite limitations in sample size and methodology, this study represents a significant step in addressing the unique QoL challenges faced by CCH patients. Future research should aim to refine and expand the use of CH-QoL, ensuring its integration into comprehensive patient care.