“Plastics”

Many of us of a certain age will never forget the sage, one-word piece of occupational advice given to Benjamin Braddock in the movie, The Graduate:   “Plastics.”  In the early 1960’s, plastics were thought to be the next big area of economic growth.  Benjamin, as we all remember, takes in this recommendation with alienated befuddlement.  However from the vantage point of 21st century psychiatric research, this advice may have been unwittingly prescient.

The plasticity of brain structure, or neuroplasticity, has become a major focus of scientific study over the last 10 to 15 years.  Neuroplasticity refers to the degree to which the organization and function of the brain changes through experience.  This article will briefly review the background of this area, some basic findings, and its relevance for understanding and treating bipolar disorders.

Several factors stimulated research on neuroplasticity.  First, shortcomings of the monoamine theory of depression.  Monoamines, like dopamine, norepinephrine, and serotonin are neurotransmitters involved in mood regulation.  In its most simple form, the monoamine theory postulated that deficiencies in monoamine levels caused depression.  We now know that this model has major limitations.  Foremost among them, the several-week lag period between starting an antidepressant and experiencing symptomatic relief.  Given that antidepressants lift monoamine levels almost immediately, there is obviously another mechanism at work that underlies depressed mood states and their response to medication.  Second, we know that the brains of people with bipolar disorder show structural differences from those without the illness.  Affected individuals exhibit overall reductions in gray matter (the part of the brain composed of nerve cells themselves in contrast to white matter which consists of the nerve axons, the long fibers that snake through the brain connecting one cell to another) , increases in amygdala size, and shrinkage or atrophy of specific areas, such as the hippocampus and the dorsolateral prefrontal cortex.  Notably, it has been found that lithium, valproate (Depakote) and certain antidepressants correct these changes.  The last phenomenon shifting attention towards brain structure has been the increased recognition of cognitive impairment occurring in mood disorders.  Roughly correlating with duration of illness and number of episodes, the occurrence of cognitive impairment – especially when independent of mood states – has suggested a chronic, structural problem with the memory-specific areas of the brain.  Together, these three factors shifted research attention away from purely biochemical, neurotransmitter-based models of mood pathology towards a focus on the underlying wiring and arrangement of neural groups in the brain.  This emphasis on brain structure and its malleability has generated several basic ideas that are guiding investigation in this area.

First, the brain is a dynamic organ that responds to new experiences with microscopic changes in its circuitry and functioning.  Read that last sentence again.  The wiring and connections of neurons actually become modified through experience.  This is the first and most significant finding of this new field.  Based initially on animal studies and more recently through MRI and other neuroimaging techniques in humans, researchers are now able to visualize how neurons respond to new experience.  This includes increases in the size and number of dendrites (the part of the nerve cell specialized to receive input from other nerve cells), weakening or strengthening of synaptic connections, and shrinkage or growth of cell groups.   Using a map analogy, we can think of our genetics as providing the layout of the major thoroughfares and neural pathways of our brain.  It is our individual experiences though, which chart out the streets, alleys, and more personally specific wiring that provide our own distinct psychology and physiology.  Hence, we need to give up the outdated view of the brain as a static given and replace it with something much more like a control center muscle that changes its size and abilities based on experience.  This understanding leads to two new questions:  How quickly and when do these structural changes occur?  Additionally, what types of experience are capable of producing these changes?

The initial perspective on neuroplasticity was that it was a phenomenon confined to childhood.  We know that the brains of all mammals expand and develop throughout infancy.  The earlier view was that this potential for change was limited to a critical period of development and that this window closed as the individual matured into adulthood.  The discovery of new brain growth – neurogenesis – in adult mammals was made only recently.  It has been a game-changer.  With more detailed neuroimaging methods, research has shown that many areas of the brain retain the capacity for growth, regeneration, and modification throughout life.  While diminished from its earlier childhood potential, this lifelong capacity is significant and can be activated by a range of experience and interventions.  What types of experience and interventions act on this neuroplastic foundation?  Short answer:  almost everything.

New experiences, new learning, the acquisition of new skills – all these developments result in, and are mediated by microscopic changes in neural circuitry.  This is the second paradigm shift of this young field.  Not only is the brain a dynamic organ, but it changes on a daily basis in response to everything that happens to us.  The new friend we make, the first job we hold, the unexpected storm that hits, the birth of a child, the loss of a parent, the hilarious joke we hear, the new food we try – the experiences of our lives are constantly being processed by, and changing the cellular architecture of our brains.  This realization sets up the final two ideas of this article:  What does neuroplasticity have to do with bipolar disorder?   And what can be done about it?

Current thought holds that impaired neuroplasticity contributes to the abnormal mood states, impaired cognition, structural changes, and delayed antidepressant response found in bipolar disorders.   In times of health, our brains and minds retain the ability to learn, grow, forget, strengthen, and prioritize certain information.  When depressed though, one might only focus on negative events and memories.  One might forget that his or her depressions are always brief and quickly respond to therapy, and feel instead that their black state will go on forever.  In contrast, in mania it may be difficult to appreciate the risks and difficulties of unrestrained plans and ambitions.  From a neuroplasticity perspective, these moods reflect a condition of cognitive and emotional constraint, and an underlying impairment in learning and brain malleability.  Here too, this theory makes intuitive sense to anyone that has experienced or dealt with the above mood states.   It is often difficult to help a person get perspective (i.e., think differently, remember other times, etc…) on their emotional condition.  Neuroplasticity theory would also suggest that the subtle cognitive impairment and structural changes found in the brains of bipolar individuals reflect the same type of reduced potential for experience-based brain circuit modification.  Through this lens, manic depressive illness is seen as a disorder of structural, cognitive and emotional unresponsiveness, constriction, and shrinkage.  Things get locked in a narrow groove from which one cannot easily escape.  So what’s to be done about this?

Neuroplasticity models suggest a role for therapy, medications, and a host of adjunctive interventions to restore the free-flowing dynamism of a healthy brain.  As a new form of experience, psychotherapy is uniquely suited to challenge, unlock, and expand the cognitive and structural constrictions of extreme mood states.  Psychotherapy is designed to provide new experiences for patients.  Its effectiveness may lie in its ability to do this.  Interestingly, antidepressant medications have also been found to restore the reshaping potential of mammalian brains.  The neuroplasticity model arguesthat it is this mechanism which mediates antidepressant response and accounts for the delay between rising monoamine levels and improvement.  Last, animal research has demonstrated the effects of environmental and behavioral changes on brain structure.  Rats caged in enriched environments show increased brain growth, enhanced neuronal resilience in response to stress and greater dendritic arborization (branching) than their peers housed in standard, barren cages.  This line of research has been extended to exercise, video games, and may also apply to environmental exposure to adequate sunlight, level of socializing, and intellectual stimulation.   This model argues that all effective therapeutic modalities will act by directly or indirectly restoring the mind’s ability to freely process information and the brain’s capacity for experience-guided fine-tuning.

Research on neuroplasticity presents a new way of thinking about the brain and bipolar illness.   It moves us away from a more fixed model of the central nervous system to one that is intrinsically reactive and evolving.  It elaborates on simple ideas about excess or reduced neurotransmitter levels to more complex models that include attention to the scaffolding, layout, and modifiability of the surrounding cellular matrix and nerve pathways.  In so doing, it encourages a wider range of therapeutic interventions for the difficult mood states that characterize this challenging disorder.

Plastics.  Indeed.

In future pieces, we will describe some of important mechanisms and major molecular players involved in mediating neuroplasticity.

References

  1. Carlson, P. J., J. B. Singh, et al. (2006). Neural circuitry and neuroplasticity in mood disorders: insights for novel therapeutic targets. NeuroRx 3(1): 22-41.
  2. Kapczinski F, Frey BN, Kauer-Sant’Anna M, Grassi-Oliveira R. (2008). Brain-derived neurotrophic factor and neuroplasticity in bipolar disorder. Expert Rev Neurother. 2008 Jul;8(7):1101-13.
  3. Krishnan, V. and E. J. Nestler (2010). Linking molecules to mood: new insight into the biology of depression. American Journal of Psychiatry 167(11): 1305-1320
  4. Bavelier, D., D. M. Levi, et al. (2010). Removing brakes on adult brain plasticity: from molecular to behavioral interventions. Journal of Neuroscience 30(45): 14964-14971.
  5. Castren, E. (2013). Neuronal network plasticity and recovery from depression. JAMA Psychiatry 70(9): 983-989.

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