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Neuromodulation Therapies to Treat Neuroinflammation in Anxiety & Depression (2023 Research)

The intersection of neuromodulation, neuroinflammation, and their roles in mood disorders like anxiety and depression represents a significant stride in mental health research.

This complex interplay underscores the potential of novel therapeutic strategies targeting the brain’s inflammatory pathways, offering new hope for effective management of these pervasive conditions.


  • Link Between Neuroinflammation and Mood Disorders: Emerging research establishes a strong connection between elevated neuroinflammation levels and the severity of mood disorders, as evidenced through clinical and animal studies.
  • Neuromodulation Therapies as a Treatment: Techniques like Transcranial Magnetic Stimulation (TMS), Transcranial Electrical Stimulation (TES), and Electroconvulsive Therapy (ECT) are being investigated for their ability to modulate neural activities and potentially alleviate symptoms of these disorders.
  • Individual Variability in Therapy Efficacy: Findings suggest that the effectiveness of neuromodulation therapies can vary significantly among individuals, underscoring the importance of developing personalized treatment approaches.
  • Potential of Inflammatory Biomarkers: Monitoring inflammatory biomarkers is gaining attention as a promising method for assessing pathological conditions and guiding treatment options in anxiety and depression.

Source: Translational Psychiatry (2023)

Neuromodulation to Treat Psychiatric Disorders & Neuroinflammation

Guo et al. published a paper in Translational Psychiatry (2023) highlighting the interplay between neuroinflammation and psychiatric disorders – and the therapeutic potential of neuromodulation to treat these disorders by targeting inflammation.

Neuromodulation therapies targeting dysfunctional brain regions offer promising adjunct treatments for refractory psychiatric disorders.

Advances in understanding neuroanatomical networks and stimulation mechanisms, coupled with technological developments, are enhancing the efficacy of these therapies.

Neuromodulation & Neuroinflammation

  • Link to Mental Illness: Mental illness is closely associated with the body’s inflammatory response, affecting both peripheral and central neural circuits.
  • Modulation of Inflammation: Neuromodulation methods, including TMS, TES, ECT, DBS, and VNS, have shown the potential to influence the body’s inflammatory response.

Biomarkers in Neuromodulation Therapy

  • TSPO-PET Imaging: The use of TSPO as a neuroimaging biomarker for microglia activation and neuroinflammation is gaining prominence. Elevated TSPO binding in MDD patients suggests its potential to predict treatment response.
  • Challenges and Prospects: The heterogeneity of psychiatric disorders and variability in TSPO radioligands present challenges in the broad application of TSPO-PET. However, newer radioligands offer improved accuracy, making TSPO-PET a promising tool.

Inflammatory Markers in Depression and Anxiety

  • Elevated Inflammatory Factors: Studies indicate increased levels of inflammatory markers like IL-1β, IL-6, TNF-α, and CRP in depression and anxiety, correlating with symptom severity and disease duration.
  • Antidepressant Effects on Inflammation: Antidepressants have been shown to downregulate peripheral biomarkers and reduce brain inflammation.

Peripheral Cytokines & Central Inflammation

  • Interaction Channels: Peripheral cytokines can influence central inflammation through several pathways, including crossing the blood-brain barrier and activation of cerebrovascular endothelial cells.
  • Correlation with Central Inflammation: Peripheral inflammatory factors have been found to correlate with central inflammation in depression, offering potential clinical trial markers.

Inflammations in Brain Regions of Threat & Fear Circuits (Anxiety)

Recent advancements in neuroscience have elucidated the critical role of inflammation in specific brain regions associated with the threat-fear circuit.

These circuits are crucial in anxiety disorders and encompass various brain areas like the dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (mPFC), amygdala, hippocampus, and insula.

Amygdala and its Role in Anxiety

  • Central to Emotion Regulation: The amygdala is pivotal in regulating emotions, particularly fear and anxiety.
  • Impact of Stress and Social Pressure: Studies have shown that stress can trigger inflammation in the amygdala, further aggravating anxiety symptoms.
  • Bi-directional Relationship with Inflammation: Inflammatory activity can enhance amygdala activity, creating a feedback loop that exacerbates anxiety.
  • Microglial Activation and Neuroinflammation: Research indicates a correlation between microglial activation in the amygdala and increased anxiety and depressive-like behaviors.

Medial Prefrontal and Dorsal Anterior Cingulate Cortices

  • Emotion Regulation and Anxiety: These regions are known for their extensive connections with the amygdala, playing a significant role in emotion regulation.
  • Altered Activation Due to Inflammation: Elevated pro-inflammatory factors are shown to modify the activation of the mPFC and dACC.
  • Clinical Evidence of Inflammation’s Impact: Neuroimaging studies in various contexts (bereavement, vaccinations, chronic illnesses) reveal altered activities in these regions correlated with inflammation levels.

Hippocampus: Inflammation & Anxiety

  • Cognitive Functions and Emotional Regulation: The hippocampus, part of the limbic system, is crucial for cognitive functions and emotion regulation.
  • Chronic Stress and Inflammatory Response: Persistent stress results in increased pro-inflammatory factors in the hippocampus.
  • Neurogenesis Inhibition and Neuronal Apoptosis: Inflammation in the hippocampus can impede neurogenesis and promote neuronal apoptosis, contributing to anxiety behaviors.
  • Microglial Activation: Evidence from animal models and neuroimaging studies demonstrates heightened microglial activation in the hippocampus associated with anxiety-like behaviors.

Insula: Inflammation & Emotional Processing

  • Role in Fearful Situations: The insula shows increased activity in anxious individuals and in fearful contexts.
  • Inflammation’s Effect on Metabolism and Connectivity: Inflammatory processes affect the insula’s metabolism and its connectivity with other anxiety-related brain regions like the amygdala and ACC.

Inflammation in Brain Regions Associated with Reward Circuit & Depression

The neural circuits implicated in depression, primarily the reward circuit and aversion center, demonstrate significant changes in response to neuroinflammation.

Key areas involved include the anterior cingulate cortex (ACC), ventral tegmental area (VTA), ventral striatum, including the nucleus accumbens (NAc) and ventral pallidum (VP), the raphe nucleus, and the orbital prefrontal cortex (OFC).

Neuroinflammation in Depression-Related Brain Regions

  • Prefrontal Cortex and Anterior Cingulate Cortex (ACC): Studies suggest that neuroinflammation alters the functionality of these regions. Autopsies of depressed patients have shown variations in microglia densities and types, indicating persistent neuroinflammation.
  • Ventral Striatum: Central to the brain’s reward system, the ventral striatum’s connectivity and function are affected by inflammation, influencing depressive symptoms and responses to rewards and punishments.
  • Dorsal Raphe Nucleus (DRN): Inflammatory factors activate microglia in the DRN, affecting serotonin synthesis and contributing to psychiatric symptoms like anhedonia and depression.
  • Lateral Habenula (LHb): The LHb, which is associated with negative emotions, demonstrates increased inflammatory responses under stress, contributing to depressive behaviors.

Specific Findings & Implications

  • Microglial Activation: A consistent finding is the activation of microglia in these regions in response to inflammatory stimuli, varying with the course and treatment of the disease.
  • Neuroimaging Evidence: PET scans using markers like TSPO have shown increased microglial activation in major depressive disorder, correlating with disease severity.
  • Animal Models: Chronic stress in animal models promotes the production of pro-inflammatory cytokines in the prefrontal cortex, indicating a direct link between stress, inflammation, and depression.
  • Behavioral Changes: Inflammation in key brain regions is associated with changes in behavior and mood, as evidenced by various studies using animal models and human subjects.

Neuromodulation Interventions to Treat Anxiety & Depression with Anti-Inflammatory Effects

Neuromodulation therapy, encompassing both non-invasive and invasive techniques, is rapidly emerging as a promising approach to modulate inflammation and alleviate psychiatric symptoms.

Transcranial Magnetic Stimulation (TMS)

Application: Used in refractory depression and anxiety disorders.

Impact on Inflammation: Studies have shown TMS can decrease serum levels of inflammatory markers like IL-1β and TNF-α in depressed patients. It also affects hippocampal inflammation in animal models.

Transcranial Electrical Stimulation (TES)

Application: Explored in bipolar depression, major depressive disorder (MDD), and Alzheimer’s disease.

Inflammatory Response: TES has been found to decrease plasma IL-6 and IL-8 levels and reduce microglia activation.

Electroconvulsive Therapy (ECT)

Application: A longstanding treatment for refractory major depression.

Inflammatory and Neuroplasticity Effects: ECT activates peripheral blood mononuclear cells and modulates levels of IL-1β and IL-6. It also influences neuroplasticity and brain connectivity.

Photobiomodulation (PBM)

Application: Utilizes light therapy for treating depression.

Neuroinflammatory and Antioxidative Effects: PBM influences mitochondrial energy metabolism and has anti-inflammatory and antioxidative effects, impacting brain regions like the hippocampus.

Transcranial Ultrasound Stimulation (TUS)

Application: Shows promise in treating neuropsychiatric diseases.

Anti-inflammatory Role: TUS modulates inflammatory signaling pathways, reducing pro-inflammatory cytokines and enhancing neuroprotective mechanisms.

Deep Brain Stimulation (DBS)

Application: Investigated for anxiety and depression.

Inflammation Modulation: DBS can lead to both acute and chronic changes in inflammation, with potential anti-inflammatory effects contributing to its therapeutic efficacy.

Vagus Nerve Stimulation (VNS)

Application: Approved for treatment-resistant depression.

Mechanism: VNS engages the parasympathetic anti-inflammatory pathway, affecting neurotransmitter systems and cytokine production.

Preliminary Research of Neuromodulation & Neuroinflammation (Summary)

TMS: Demonstrated a decrease in pro-inflammatory factors in the brain, correlating with symptom improvement.

TES: Shown to reduce hippocampal inflammation in animal models, suggesting its potential in neuroinflammatory conditions.

ECT: Exhibited both activation and reduction of inflammatory pathways, indicating a complex interaction with the immune system.

PBM: Improved inflammatory responses in aged rats, indicating its potential in age-related neuropsychiatric disorders.

TUS: Found effective in modulating the expression of inflammatory cytokines, providing a non-invasive approach to influence neuroinflammation.

DBS: Showed varying effects on inflammation, with some studies indicating its potential to suppress pro-inflammatory gene expression and microglial activation.

VNS: Demonstrated effectiveness in reducing systemic inflammation, suggesting its role in modulating both central and peripheral inflammatory responses.

Limitations & Future Research of Neuromodulation Therapies

While the prospects of neuromodulation therapies are encouraging, several limitations must be addressed:

  • Heterogeneity in Patient Responses: The effectiveness of neuromodulation varies among individuals, reflecting the complex nature of psychiatric disorders. This variability necessitates personalized treatment strategies.
  • Understanding of Neuroinflammatory Mechanisms: The exact mechanisms by which neuromodulation influences neuroinflammation are not fully understood. Future research should focus on elucidating these pathways to optimize treatment efficacy.
  • Biomarker Reliability and Accessibility: The use of TSPO-PET and other biomarkers in clinical practice is limited by factors like heterogeneity in radioligands and the need for large-scale validation. Developing more reliable and accessible biomarkers is crucial for broader clinical application.
  • Technological Advancements: Continued innovation in material science, miniaturization, energy storage, and delivery systems is essential to enhance the precision and effectiveness of neuromodulation devices.
  • Long-Term Outcomes and Side Effects: More research is needed to understand the long-term effects and potential side effects of neuromodulation therapies, particularly for newer modalities like TUS and DBS.
  • Integration with Other Treatments: Integrating neuromodulation with pharmacological and psychotherapeutic interventions could offer a more comprehensive approach to treating psychiatric disorders.

Takeaway: Neuromodulation for Inflammation & Mental Disorders

Neuromodulation therapies represent a frontier in the treatment of psychiatric disorders, offering a novel approach that intersects with the burgeoning field of neuroinflammation.

These therapies, ranging from transcranial magnetic stimulation to deep brain stimulation, show promise in modulating the inflammatory responses implicated in mental illnesses like depression and anxiety.

The emerging use of biomarkers, particularly TSPO-PET imaging, for tracking neuroinflammatory changes, heralds a new era of precision medicine in psychiatry.

By targeting specific neural circuits and leveraging technological advancements, neuromodulation therapies have the potential to significantly improve outcomes for patients with refractory psychiatric disorders.


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