Tese de Doutoramento Biomedicina 2023 Faculdade de Ciências Médicas, Universidade NOVA de Lisboa

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