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Balogh, L.;  Tanaka, M.;  Török, N.;  Vécsei, L.;  Taguchi, S. Neurological Sciences’ Approach to Mood and Anxiety Disorders. Encyclopedia. Available online: (accessed on 05 December 2023).
Balogh L,  Tanaka M,  Török N,  Vécsei L,  Taguchi S. Neurological Sciences’ Approach to Mood and Anxiety Disorders. Encyclopedia. Available at: Accessed December 05, 2023.
Balogh, Lehel, Masaru Tanaka, Nóra Török, László Vécsei, Shigeru Taguchi. "Neurological Sciences’ Approach to Mood and Anxiety Disorders" Encyclopedia, (accessed December 05, 2023).
Balogh, L.,  Tanaka, M.,  Török, N.,  Vécsei, L., & Taguchi, S.(2022, October 24). Neurological Sciences’ Approach to Mood and Anxiety Disorders. In Encyclopedia.
Balogh, Lehel, et al. "Neurological Sciences’ Approach to Mood and Anxiety Disorders." Encyclopedia. Web. 24 October, 2022.
Neurological Sciences’ Approach to Mood and Anxiety Disorders

Psychotherapy is a comprehensive biological treatment modifying complex underlying cognitive, emotional, behavioral, and regulatory responses in the brain, leading patients with mental illness to a new interpretation of the sense of self and others. Psychotherapy is an art of science integrated with psychology and/or philosophy. Neurological sciences study the neurological basis of cognition, memory, and behavior as well as the impact of neurological damage and disease on these functions, and their treatment. Both psychotherapy and neurological sciences deal with the brain; nevertheless, they continue to stay polarized. Existential phenomenological psychotherapy (EPP) has been in the forefront of meaning-centered counseling for almost a century. The phenomenological approach in psychotherapy originated in the works of Martin Heidegger, Ludwig Binswanger, Medard Boss, and Viktor Frankl, and it has been committed to accounting for the existential possibilities and limitations of one’s life. EPP provides philosophically rich interpretations and empowers counseling techniques to assist mentally suffering individuals by finding meaning and purpose to life. The approach has proven to be effective in treating mood and anxiety disorders. 

depression anxiety disorders stroke dementia functional Magnetic existential psychotherapy logotherapy meaning-centered psychotherapy Functional magnetic resonance imaging (fMRI) Biomarker kynurenine

1. Neuroimaging

Recent advances in neuroimaging technology have facilitated the investigation of brain structure and function. Among magnetic resonance imaging, computed tomography, and positron emission tomography, functional MRI (fMRI) provides information on the properties of functional connectivity (FC). Resting-state fMRI investigates behavioral characteristics such as psychological states, sustained attention, personality, temperament traits, creative ability, and cognitive ability including working memory and motor performance [1][2][3][4]. Furthermore, the patterns of resting-state fMRI are correlated with specific symptoms and respond to treatment [5][6]. Analytical methods of resting-state network connectivity include seed-based analysis, the amplitude of low-frequency fluctuation (ALFF) and fractional ALFF techniques, regional homogeneity (ReHo), independent component analysis (ICA), and graph theory.

1.1. Functional Magnetic Resonance Imaging

The Default Mode Network

The default mode network (DMN) is a network of interacting brain regions which shows synchronized activation and deactivation during tasks [7]. DMN includes the medial prefrontal cortices (mPFC), the posterior cingulate cortex (PCC), precuneus, inferior parietal lobule, lateral temporal cortex, and hippocampal formation [8][9]. DMN activity is associated with internal processes including self-referential thinking, autobiographical memory, or thinking about the future [10][11][12]. The DMN is divided into an anterior subdivision centered in the mPFC and a posterior subdivision centered in the PCC. The anterior DMN is more related to self-referential processing, and emotion regulation through its strong connections with limbic areas. The posterior DMN is associated with consciousness and memory processing through its connection with hippocampal formation [13][14] (Figure 1).
Figure 1. Large-scale brain network including the default mode network, the executive control network, and the salience network. DMN: default mode network; ECN: executive control network; SN: salience network; ACC: anterior cingulate cortex; dlPFC: dorsolateral prefrontal cortex; INS: insular cortex; LPC: lateral parietal cortex; mPFC: medial prefrontal cortex; PPC: posterior parietal cortex.
A relative increase in DMN connectivity and significant ReHo reduction were observed in the posterior DMN of patients with late-life depression (LLD) [15][16][17][18]. ICA studies revealed an increased connectivity within the anterior DMN of patients with depression compared to healthy controls [19]. The dissociation between the anterior and posterior DMN subdivisions was observed in patients with major depressive disorder [20]. Antidepressant treatment restored FC abnormality in the posterior DMN but did not correct the FC abnormality in the anterior DMN. Network homogeneity was increased in the anterior DMN but decreased in the posterior DMN [21]. Seed-based analysis using mPFC showed the dissociation between the anterior and posterior DMN and increased connectivity between the anterior DMN and the salience network (SN) in depression [22][23]. Decreased PCC connectivity and increased connectivity in the anterior DMN were observed in depressive patients without medication and 12-weeks treatment of paroxetine partially restored the decreased connectivity [24]. In general, FC between PCC and left medial frontal gyrus decreased in patients with depression and 12-weeks of antidepressant treatment increased FC between PCC to the bilateral medial frontal gyrus [25]. Psychedelics are known to disrupt the activity of the DMN. Serotonergic psychedelic psilocybin-assisted therapy significantly reduced the depression scores of patients with severe depression [26].

The Executive Control Network

The executive control network (ECN) plays an important role in the integration of sensory and memory information, the regulation of cognition and behavior, and the process of working memory [27]. The ECN consists of the dorsolateral prefrontal cortex (dlPFC), medial frontal cortex, lateral parietal cortex, cerebellum, and supplementary motor area [28]. Changes in the ECN were reported in ageing and in patients with LLD, mild cognitive impairment, Alzheimer’s disease, and Parkinson’s disease [29][30][31][32][33] (Figure 1).
Disruptions of the ECN were reported in non-demented elders with LLD [34][35][36]. Seed-based analyses using the dlPFC showed decreased FC in the frontoparietal areas in patients with LLD and current depression [37]. Seed-based analyses of the cerebellum presented decreased FC in ECN nodes in dlPFC and the parietal cortex and DMN nodes [38][39]. ICA analyses reported decreased FC in the dlPFC and superior frontal areas, which is consistent with other resting-state fMRI studies with ReHo and ALFF [17][40][41][42]. Decreased FC in the frontal-parietal cortex was also reported in LLD remitters 3 months after remission [43]. Alteration of the ECN was associated with susceptibility to distraction, and difficulty in sustaining attention, multi-tasking, organizational skills, and concrete thinking [44]. The FC between the dlPFC and other bilateral regions was negatively associated with executive function in patients with LLD [45]. Furthermore, the levels of functional disability were positively correlated with executive dysfunction in LLD [46][47]. Low and slow response to antidepressants and relapse were correlated with deficits in word-list generation and response inhibition which are governed by the executive function network [48][49]. In addition, dissociation between the posterior DMN and ECN was also reported in patients with LLD and current depression [50][51].

The Salience Network

The SN detects and filters salient stimuli and recruits relevant functional networks [52]. The SN is responsible for detecting and incorporating sensory and emotional stimuli, allocating attention, and switching inward and outward cognition. The SN is located in the ventral anterior insula and includes nodes in the amygdala, hypothalamus, ventral striatum, and thalamus [53]. The ventral components play a role in emotional control, while the dorsal components play a role in cognitive control [54]. Cognitive tasks activate the dorsal components including the dorsal anterior cingulate cortex and the right anterior insula. During cognitive tasks, the SN engages ECN and disengages DMN, but vice versa in rest [54][55][56]. Dissociation between the ECN and SN is correlated with cognitive task performance [57] (Figure 1).
Decreased FC from the amygdala to the hippocampus was observed in patients with depression and individuals at high risk of depression [58][59]. A disrupted pattern of SN connectivity was reported in depression, especially in the insula and amygdala [60]. Elevated connectivity was found between the insula and DMN in patients with LLD [61]. Seed-based analysis using the amygdala as a seed region was positively associated with increased amygdala FC with DMN nodes and long-term negative emotions [62]. Increased FC between the SN and DMN is considered to predispose individuals to depression but decreased FC between the amygdala and precuneus was reported in patients with depression [35][63][64]. Decreased negative FC between the ECN and the SN was associated with cognitive impairment and severity of depression in patients with LLD. Disrupted standard SN pattern was associated with a worse treatment response [65].

1.2. Task-Related Functional Magnetic Resonance Imaging

Mood disorders, anxiety disorders, and posttraumatic stress disorder (PTSD) share neurobiologically common characteristics in task-related fMRI. A meta-analysis was conducted using articles studying stereotactic coordinates of whole-brain-based activation in task-related fMRI as between adult patients and controls [66]. Patients with mood disorders, anxiety disorders, or PTSD shared abnormalities in convergence of task-related brain activity in regions associated with inhibitory control and salience processing [66]. Patients who suffered from mood and anxiety disorders presented abnormally lower activity in the inferior prefrontal and parietal cortex, the insula, and the putamen [66]. These regions are responsible for cognitive and motional control, and inhibition of and switching to new mental activities. The patients also showed higher activity in the anterior cingulate cortex, the left amygdala, and the thalamus which process emotional thoughts and feelings [66].

2. Other Relevant Biomarkers and Therapeutic Targets

Besides the large-scale brain network, natural products, endogenous metabolites, neuropeptides, receptor agonists, their synthetic analogues, plasma proteins, and lipids are under extensive study in search of biomarkers and novel drugs for mental disorders [67][68][69][70][71][72][73][74]. In addition, the disruption of neural circuitry-neurogenesis coupling was observed in depression [74]. Several neurotransmitters including serotonin, dopamine, adrenaline, histamine, gamma-aminobutyric acid, and peptides play an important role in the pathogenesis of mood and anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) are major classes of antidepressants currently prescribed for the treatment of depression and anxiety. SSRIs, SNRIs, and MAORs all act on components of neurotransmission. Serotonergic psychedelics are a subclass of hallucinogens that act on the serotonin 5-HT2A receptors. The naturally occurring psychedelic prodrug psylocibin was reported to alleviate depression and anxiety in patients with life-threating diseases [71]. Glutamatergic neural transmission is drawing increasing attention because normal human brain functions are maintained in balance of 80% of excitatory neuronal and 20% of inhibitory neuronal activities [75]. Excitatory neurotransmission is governed by glutamatergic neurons with the N-methyl-D-aspartate (NMDA) receptor [76]. NMDA receptor antagonists are under extensive study for the treatment of TRD [77]. The subanesthetic dose of NMDA receptor antagonist ketamine rapidly improves depressive symptoms and leads to the resolution of suicidal ideation in patients with serious depression [78]. However, the NMDA receptor appears not to be a single pharmacological target of ketamine in the alleviation of depression [79].
Kynurenines (KYNs) are intermediate metabolites of the tryptophan (TRP)-KYN metabolic pathway, which exhibit a wide range of bioactivity such as neurotoxic, neuroprotective, oxidative, antioxidative, and/or immunological actions [80]. The KYN metabolites include a NMDA receptor agonist as well as a NMDA antagonist [81]. Furthermore, the KYN pathway supplies neuroactive metabolites which trigger biological functions not only in synaptic spaces, but also in the non-synaptic microenvironment around the neurons [82]. Moreover, increasing attention has been paid to the KYN pathway since over 95 percent of TRP is metabolized through the KYN pathway, leaving about one percent to the synthesis of serotonin that plays an important role in mood disorders. Kynurenic acid (KYNA) is found to be a diagnostic as well as predicative biomarker for depression, while KYN and KYNA are potential predictive biomarkers for escitalopram treatment in depression [83]. KYNs are agonists or antagonists at the NMDA receptor of the glutamatergic nervous system. Thus, the glutamatergic nervous system has been proposed to be a target for mood disorders [75]. A meta-analysis concluded that an increased risk of depression was correlated with inflammation in chronic illness through the TRP-KYN metabolic pathway [84]. A systematic review reported KYN metabolism abnormalities in TRD and suicidal behavior, proposing the KYN enzymes as novel targets in TRD and suicidality [85].
Gastrointestinal microbiota were observed to participate in development of visceral pain, anxiety, depression, cognitive disturbance, and social behavior and microbiota composition was proposed to be a potential biomarker and target [86][87]. Serum plasma profiles may serve as a potential predictive biomarker for the choice of antidepressants [88]. Foods, or fortified food products beneficial to physiological body functions, were proposed for the treatment of metabolic dysfunction in ageing neurodegenerative diseases [89]. In addition to biomolecules, any measurable indicators are important for risk, diagnosis, prognostic, and predictive biomarkers and interventional targets. Depression was found to be a risk factor for Alzheimer’s disease and dementia. Dyslipidemia treatment reduced the risk of development of dementia in diabetics [90]. The presence of depressive symptoms following acute stroke or transient ischemic attack increased mortality and disability within the following 12-month period, suggesting that depression is a prognostic biomarker in cerebral ischemia [91]. Therefore, the treatment of depression is a crucial measure to avoid the development of comorbid conditions and psychotherapy is certainly able to contribute to the prevention of disease progression and complications for a better quality of life. In addition, depression is a measurable psychobehavioral component of dementia, which can be ameliorated by animal-assisted and pet-robot interventions in patients with dementia [92] (Figure 2).
Figure 2. Meaning-centered psychotherapy, its effective targets, and endpoints. Meaning in life is a predictor of psychological stress. Psychological stress causes depression, anxiety, and cognitive impairment. Depression is a measurable indicator which predicts diagnosis and/or treatment of depression with kynurenines (KYNs), chronic diseases with inflammation, disability and mortality of stroke and transient ischemic attack, and Alzheimer’s disease and dementia. Depression of Alzheimer’s diseases and dementia can be ameliorated by AAI (animal-assisted intervention) and pet-robot intervention (PRI).


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