The Tapestry of Neuroplasticity: Rewiring Our Brain

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As Psychiatric Times celebrates its 40th year, psychiatry’s tapestry is just beginning. The threads that currently exist seem to be weaving into a magnificent fabric that we have named neuroplasticity. Our challenge and opportunity is to optimize all of the threads we currently understand and remain open to the many additional threads that are currently unknown or just beginning to appear.

Some of the most important threads that facilitate brain health, which provides a necessary foundation for neuroplasticity to occur, get lost in the Western medical model treatment process, where time is limited and interventions commonly focus on medications and procedures. We know now that the same factors that maximize cardiac health also maximize brain health: healthy blood pressure/cholesterol levels/blood glucose/body mass index, minimal substance use, quality sleep, good nutrition, physical activity, ability to manage stress, and supportive relationships. In addition to these, the brain thrives when it is learning new information, encountering novel experiences, and solving problems. Although certainly not a panacea, neuroplasticity provides hope that we have an inborn ally during our journey toward healing and maximum functioning.

The Birth of Neuroplasticity

In the 1970s, experimental research that involved severing the afferent neuron of a monkey’s limb just before where it enters the spinal cord to ascend to the brain led to the revolutionary field of neuroplasticity. This research extended into the early 1990s when it demonstrated that the monkey’s brain undergoes cortical remapping and connects to any adjacent active neurons when it ceases receiving input from the deafferented limb. Thus, the neuroplasticity property of the human brain was born.¹

Learning Music as a Model

During that early excitement, researchers looked for potential models that could quantify brain changes over time in an activity that required rigorous ongoing training. Researchers hypothesized that musicians provided an ideal model to study brain plasticity by using neuroimaging to monitor brain structure and function before and after a period of intensive training.²

Another research team reported on structural brain changes in early childhood following 15 months of musical training. Structural changes correlated with improvements in relevant motor and auditory musical skills.³ Similarly, a review of studies looking at changes in brain structure and function in musicians after their musical practice, magnetic resonance imaging demonstrated structural plasticity while neurophysiological activation patterns demonstrated functional plasticity. The authors concluded “experience can shape brain anatomy and brain physiology.”⁴

BDNF: A Proxy for Neuroplasticity

An established intermediary in the process of neuroplasticity is brain-derived neurotrophic factor (BDNF), which is present throughout the peripheral and central nervous systems, especially in the hippocampus and prefrontal cortex. BDNF has been shown to facilitate the maturation, differentiation, and longevity of neurons. One well-established pathway involves a presynaptic glutamate surge. Postsynaptically, this agonizes AMPA-glutamate receptors, which induces production of BDNF. BDNF agonizes tropomyosin-related kinase B receptors, which promote a cascade of molecular events, culminating in increased activity of the mammalian target of rapamycin (mTOR). mTOR serves as the orchestrator of the synthesis of scaffolding proteins and dendritic growth/synaptogenesis.⁵

Many psychiatric disorders are associated with decreased levels of BDNF compared with those found in healthy individuals. A growing literature has looked at serum and/or plasma BDNF levels as a proxy for neuroplasticity in patients pre- and post treatment. The strongest data supporting BDNF as a proxy for neuroplasticity comes from research in psychopharmacology, with a growing body of evidence supporting BDNF’s role in psychotherapy.

Psychotherapy and Other Treatments

Jeffrey Schwartz, MD, a pioneer in demonstrating the ability of cognitive behavior therapy to change brain chemistry without medications in patients with obsessive-compulsive disorder,⁶ demonstrated a significant bilateral decrease in caudate nucleus metabolic rates of glucose through positron emission tomography after 10 weeks of intensive exposure-response prevention and cognitive behavior therapy treatment, resulting in symptomatic improvement. Subsequent research has supported the hypothesis that psychotherapy can facilitate a rewiring of the brain through the production of increased BDNF.^7,8

Other investigators have even hypothesized that good quality psychotherapy may facilitate interbrain plasticity between the therapist and patient during their sessions as a result of recurrent exposure to high interbrain synchrony that can lead to enduring neuroplastic changes in the patient that are then activated in relationships outside of therapy.⁹

Beyond psychotherapy, there are other treatments that impact neuroplasticity. Electroconvulsive therapy (ECT), one of psychiatry’s oldest treatments, has demonstrated increased BDNF levels in individuals with medication-resistant depression. For most patients, the significant increase in BDNF appeared 1 month after the completion of the ECT.¹⁰

Psychopharmacology

One intriguing property of certain psychiatric medications is their effect of increasing BDNF, sometimes as soon as several hours after administration. We are early in understanding the effect on BDNF by specific antidepressants and antipsychotics, although it is well-documented that BDNF plays an important role in depression, bipolar disorder, and psychosis, especially in the hippocampus and the prefrontal cortex.¹¹

Lithium is an example of such an agent. It has been shown to upregulate BDNF, and chronic treatment with lithium has demonstrated an associated increase in BDNF when administered in therapeutic as well as low doses in both the hippocampal and cortical regions of the brain.^12,13 Neuroimaging studies have demonstrated an association between long-term lithium treatment and increased gray matter volume in the ventral prefrontal cortex and other brain regions related to cognition and emotional processing.¹⁴ It has also been proposed that chronic lithium treatment in patients with bipolar disorder may delay or decrease the risk of the onset of dementia.¹⁵

Medication-Assisted Psychotherapy

Psychoplastogens are a molecularly diverse class of medications that initiate rapid neuronal plasticity via the rapid production of BDNF.^16,17 These medications include 3,4-methylenedioxymethamphetamine (MDMA), ketamine, esketamine, psilocybin, and lysergic acid diethylamide (LSD). The downstream effect is increased activity of mTOR.^18,19

With medication-assisted psychotherapies (MAPs), the psychoplastogens are administered to patients early in treatment and commonly in a small number of doses—usually between 1 and 3—in the presence of the psychotherapist(s) with whom they will work intensively (for up to as many as 15 sessions). Hypothetically, the psychoplastogen (eg, MDMA) increases patients’ access to difficult psychological material, it facilitates a meaningful experience with a strong emotional response (as with psilocybin/LSD), and/or it creates a window of neuroplasticity that can enhance improved functioning of a dysregulated circuit (as with ketamine/esketamine). With all 3 agents, an extended period of neuroplasticity may allow for significant and enduring changes in neuronal connectivity through the intensive psychotherapeutic process that is an integral part of the treatment.

(Disappointingly, MAP received a setback in August 2024 when the FDA decided against approving MDMA-assisted psychotherapy and requested an additional phase 3 study.)

Conclusion

Thirty years ago, the medical profession and neuroscientists believed that the human brain was fully wired at birth. In retrospect this was naive, as we have the ability to learn new information, languages, musical instruments, and technical skills, and adapt to significant changes throughout our lives. Where but in the brain would the capacity for all of this learning, adaptation, and mastery occur? The catch is that it takes time, motivation, practice, and intention for us to orchestrate this neuroplasticity.

In my opinion, the current structure of clinical psychiatric practice lacks these qualities, with a focus on the 15-minute medication check as the common standard time spent with a patient. If our treatment goal is to facilitate enduring neuroplastic changes in our patients’ brains, we must create a new treatment paradigm that supports that process. Then we can truly continue to weave our tapestry.

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times; Staff Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

References

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18. Sottile RJ, Vida T. A proposed mechanism for the MDMA-mediated extinction of traumatic memories in PTSD patients treated with MDMA-assisted therapy. Front Psychiatry. 2022;13:991753.

19. Calder AE, Hasler G. Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacology. 2023; 48(1):104-112.