Mania is characterized by emotional dysregulation, sleep disturbances, and impaired judgment.
Understanding its underlying brain circuitry could lead to improved diagnosis and treatment.
Key Facts:
- Mania involves decreased activity in the right ventral prefrontal cortex (PFC) and increased activity in the left amygdala, left anterior cingulate cortex (ACC), and left basal ganglia.
- This lateralized limbic circuit dysfunction likely leads to disinhibited behavior and mood elevation in mania.
- Non-invasive brain stimulation targeting areas of this circuit can potentially treat or prevent manic episodes.
- Lesion locations causing secondary “lesional” mania overlap with dysfunctional areas found in primary mania.
- The right-left imbalance of brain activity aligns with the mood laterality theory linking negative and positive emotions to the right and left hemispheres.
Source: Transl Psychiatry
The Neurocircuitry Underpinning Mania
Mania is a hallmark feature of bipolar disorder characterized by elevated, expansive mood, increased activity and energy, impulsivity, disinhibited behavior, insomnia, grandiosity, and impaired judgment.
It represents a significant alteration from a person’s normal baseline behavior and functioning.
Understanding the brain abnormalities underlying mania could lead to major advances in its diagnosis and treatment.
Research suggests that mania involves dysregulation in limbic brain circuits important for emotional processing and regulation.
Specifically, studies indicate decreased activity in ventral regions of the right prefrontal cortex (PFC), including the ventromedial PFC (VMPFC) and ventrolateral PFC (VLPFC).
These areas normally keep our emotions and behaviors in check.
Conversely, mania exhibits increased activity in the left amygdala, left anterior cingulate cortex (ACC), and left basal ganglia – regions involved in emotional arousal and reward processing.
This combination of impaired prefrontal brakes and revved up limbic accelerators is proposed to drive the disinhibited emotions and behaviors of mania.
The right-left imbalance aligns with the mood laterality theory, whereby left hemisphere circuits regulate positive emotions and the right negative ones.
Right Ventral PFC: The Inhibitory Brake That Is Off
The ventral PFC regions – including the VMPFC, VLPFC, and orbitofrontal cortex (OFC) – play key roles in emotional regulation and decision-making.
Neuroimaging studies have consistently found that these areas, particularly on the right side, show decreased activity in mania patients relative to healthy controls and euthymic bipolar states.
The VMPFC evaluates emotional information and modulates responses, while the VLPFC exerts cognitive control.
Their impaired function in mania is believed to remove an important inhibitory brake on emotions and behaviors.
People with mania exhibit disinhibition and poor decision-making accordingly.
Stimulating the right VLPFC with brain stimulation techniques can treat mania, confirming its involvement.
Overactive Left Limbic Accelerator Regions
In contrast to the ventral PFC brake dysfunction, limbic regions involved in emotional arousal and reward show increased left-lateralized activity in mania.
The left amygdala, which assigns emotional significance to stimuli, exhibits heightened activation.
This likely drives the mood elevation and emotional intensity in mania.
Activity in the left ACC, which regulates emotional processing, is also amplified.
ACC hyperactivity positively correlates with mania severity.
Finally, left basal ganglia regions like the caudate nucleus and globus pallidus activate excessively.
The basal ganglia contribute to reward processing and goal-directed activities which are increased in mania.
Again, this left-sided hyperactivity agrees with the mood laterality theory.
Stimulation of these regions can also evoke mania.
A Disconnected Limbic Circuit
In addition to isolated regional dysfunction, connectivity analyses reveal decoupling between areas in this limbic circuit in mania.
The hyperactive left amygdala shows reduced functional connections to the right ventral PFC.
Furthermore, white matter connections between the amygdala and ACC are impaired.
This breakdown in communication between emotional control centers likely prevents proper regulation of mood and behavior.
Treatments that restore coordinated circuit function hold promise for treating mania.
Lesional Mania Confirms the Dysfunctional Network
Rare cases of “lesional mania” provide additional confirmation of this model.
Focal brain lesions, like from stroke, that cause secondary mania map onto areas of dysfunction seen in primary mania.
Lesions provoking mania occur more frequently in the right hemisphere and involve ventral PFC and temporal lobe regions.
Looking at lesion connectivity also highlights the right VLPFC and VMPFC as critical nodes.
Lesional cases validate the circuits malfunctioning in primary manic episodes.
Neuromodulation Targets for Treating and Preventing Mania
Understanding these dysfunctional brain networks paves the way for targeted neuromodulation treatments.
Non-invasive brain stimulation like repetitive transcranial magnetic stimulation (rTMS) can modulate activity in these areas.
For example, inhibitory rTMS to the right VLPFC could mimic its impaired function in mania and inadvertently trigger mania.
Conversely, excitatory rTMS to the right VLPFC could treat mania by restoring normal activity levels.
Similarly, damping down left amygdala and ACC hyperactivity could reduce manic symptoms.
Exciting frontal regions that connect to this circuit is also beneficial.
Optimally targeting frontal entry points of the circuit is an active area of investigation.
Finally, avoiding stimulation of left ventral striatum and subthalamic nucleus could prevent therapy-induced secondary mania, a side effect seen in disorders like Parkinson’s disease.
Overall, a circuit-based neuromodulation approach informed by the neurobiology of mania holds significant promise.
What do we know about brain activity in mania?
In summary, mania involves lateralized dysfunction in a limbic emotional regulation circuit encompassing ventral prefrontal, cingulate, and mesolimbic regions.
Right-sided hypoactivity impairs inhibition, while left-sided hyperactivity amplifies emotional drive.
This yin-yang imbalance leads to the unconstrained euphoric mood and behaviors of mania.
Understanding these brain mechanisms opens doors to biomarker-based diagnosis, early intervention, and novel neuromodulation therapies.
Moving forward, leveraging brain circuit dynamics for precision medicine could transform the treatment landscape for this debilitating psychiatric condition.
References
- Study: Functional neuroanatomy of mania
- Authors: Goncalo Cotovio & Albino J. Oliveira-Maia (2022)
