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Interhemispheric imbalance in mood disorders
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Resumo(s)
Mood disorders are very common and disabling conditions worldwide. Classically, two poles have been
described in mood disorders spectrum, namely depression and mania. While depression is characterized by
negative mood, such as sadness and anhedonia, mania is associated with positive affect, including euphoria
and increased energy. When recurrent periods of depression are the sole manifestation of a mood disorder,
it is known as major depressive disorder (MDD). However, recurrent depressive and manic symptoms may
occur in different episodes, which is known as bipolar disorder (BD). Despite the impact of mood disorders
on patients’ well-being, their diagnosis and treatment are still a clinical challenge. Disentangling mood
disorders’ neurobiology would be an invaluable contribution, since it would help find biomarkers that can
assist the diagnosis of mania and depression but may also help guide new treatment strategies. Different
paths have been explored to clarify neurobiology of mood disorders and have converged on the existence of
compromised cortical excitability and neuroplastic phenomena. Neuronal plasticity is the capacity of an event
to modulate neuronal circuits functions by changing synaptic-level phenomena. Additionally, any outcome
from these circuits can be facilitated by different neurotransmission mechanisms, determining their
excitability. Both mechanisms are potentially impaired in mood disorders, impacting how mood-related brain
regions function together, i.e., their functional connectivity. While still a matter of debate, such impact has
been hypothesized to occur in specific and potentially lateralized brain regions that have been associated to
mood regulation.
Here, I first tested the hypothesis that cortical excitability measures acquired using transcranial magnetic
stimulation (TMS) are lateralized in mood disorders. I found that in MDD there is lower cortical excitability in
the left compared to the right hemisphere and the reverse pattern in bipolar depression and possibly in
mania. Then, I focused on understanding the neuroanatomy of mood disorders, specifically mania. Anecdotal
evidence suggests that lesions causing mania may occur preferentially in right-hemisphere, but this
hypothesis has never been systematically and formally tested. In the third chapter of this thesis, using a
neuroimaging analysis method called lesion topography, I found that there is a preferential association
between mania occurrence and right-hemisphere lesions, particularly in brain areas relevant to mood
regulation, namely inferior temporal gyrus, fusiform gyrus, para-hippocampus and thalamus. Since no unique
region was preferentially insulted in lesional mania, I hypothesized that lesions causing mania were
connected to specific brain networks. In the fourth chapter, I test this hypothesis using a neuroimaging
analysis method called lesion network mapping (LNM) and found that brain lesions associated with mania
are characterized by a right-sided pattern of brain connectivity involving orbitofrontal cortex, inferior
temporal gyrus, and frontal pole. Importantly, these results were independent of the connectivity analysis
methodology, as demonstrated in the fifth chapter. In an exploratory analysis, I used LNM to clarify what is
the connectivity pattern of secondary mania associated to deep brain stimulation. In the sixth chapter, I
found that mania associated with subthalamic nucleus deep brain stimulation for Parkinson’s disease is
associated with left-sided functional connectivity pattern, namely OFC and frontal pole. Finally, to clarify if
lateralized topography and connectivity is a characteristic of lesional mania and not observed in other
neuropsychiatric syndromes, I explored these two questions in the context of lesional obsessive compulsive
disorder (OCD). In the seventh chapter of this thesis, I found no evidence of either topography or connectivity
lateralization in lesional OCD. Lesions causing OCD-like symptoms were more frequently located in bilateral
orbitofrontal cortex and right middle and superior temporal pole. Additionally, they showed a unique pattern
of brain connectivity to bilateral orbitofrontal cortex and bilateral basal ganglia.
Overall, the findings reported in this thesis support the occurrence of a hemispheric asymmetry dysfunction
in mood disorders that is not associated with a specific side impairment, but to a disruption in the interplay
between both hemispheres. They suggest that brain activity may be imbalanced towards right-sided
hypoactivity and/or left-sided hyperactivity in mania, while the opposite may occur in MDD. Future research
specifically studying right-left activity imbalance, will help confirm this hypothesis, exploring its potential as
a neurobiological marker or its clinical impact as a guide for new treatment strategies in mood disorders.