Murat Altinay

Where in the brain is depression

Major depressive disorder is a serious medical illness which is responsible for considerable morbidity and disability. Despite decades of research, the neural basis for depression is still incompletely understood. In this review, evidence from neuroimaging, neuropsychiatric and brain stimulations studies are explored to answer the question regarding the localization of depression in the brain. Neuroimaging studies indicate that although many regions of the brain have been repeatedly implicated in the pathophysiology of depression, not many consistent findings have been found until present. In recent times, the focus of neuroimaging has shifted from regional brain abnormalities to circuit level connectivity abnormalities. However, connectivity models are inherently more complicated, and the validity of these models remains to be tested. Neuropsychiatric studies of illnesses such as Parkinson’s disease and stroke provide promising clues regarding areas involved in depression, but again consistent findings are rare. Similarly, stimulation of a variety of brain regions and circuits has been reported as being effective in depression. Therefore, the current knowledge indicates that the pathophysiology of depression may be distributed across many brain regions and circuits. In future studies, this distributed nature of depression needs to be further investigated, primary and secondary areas affected need to be identified, and new paradigms to explain complex mental functions need to be explored.

Differential Resting-State Functional Connectivity of Striatal Subregions in Bipolar Depression and Hypomania.

Bipolar disorder (BP) is characterized by periods of depression (BPD) and (hypo)mania (BPM), but the underlying state-related brain circuit abnormalities are not fully understood. Striatal functional activation and connectivity abnormalities have been noted in BP, but consistent findings have not been reported. To further elucidate striatal abnormalities in different BP states, this study investigated differences in resting-state functional connectivity of six striatal subregions in BPD, BPM, and healthy control (HC) subjects. Ninety medication-free subjects (30 BPD, 30 BPM, and 30 HC), closely matched for age and gender, were scanned using 3T functional magnetic resonance imaging (fMRI) acquired at resting state. Correlations of low-frequency blood oxygen level dependent signal fluctuations for six previously described striatal subregions were used to obtain connectivity maps of each subregion. Using a factorial design, main effects for differences between groups were obtained and post hoc pairwise group comparisons performed. BPD showed increased connectivity of the dorsal caudal putamen with somatosensory areas such as the insula and temporal gyrus. BPM group showed unique increased connectivity between left dorsal caudate and midbrain regions, as well as increased connectivity between ventral striatum inferior and thalamus. In addition, both BPD and BPM exhibited widespread functional connectivity abnormalities between striatal subregions and frontal cortices, limbic regions, and midbrain structures. In summary, BPD exhibited connectivity abnormalities of associative and somatosensory subregions of the putamen, while BPM exhibited connectivity abnormalities of associative and limbic caudate. Most other striatal subregion connectivity abnormalities were common to both groups and may be trait related.

A comprehensive review of the use of deep brain stimulation (DBS) in treatment of psychiatric and headache disorders.

Neurostimulation as a treatment option for refractory neuropsychiatric disorders has been increasingly utilized in recent years. For patients with such refractory disorders who have often failed to respond to various medical interventions, deep brain stimulation (DBS) has emerged as a promising treatment modality. DBS is a reversible and adjustable form of brain stimulation (also known as functional neurosurgery) in which desired brain structures (or circuits) are given focal electric stimulation via electrodes that are implanted in the brain tissue during a surgical procedure. It has been utilized among various psychiatric and neurological illnesses, in particular headache disorders.

Reply to: Subanesthetic dose ketamine does not induce an affective switch in three independent samples of treatment-resistant major depression.

To the Editor: We agree with several excellent points raised by Niciu and colleagues: 1) the case report that we presented was a description of possible induction of mania in a patient receiving ketamine therapy. Because it was a case report, several issues could not be controlled for, including toxic or withdrawal effects of medications that the patient was receiving/using; 2) the data presented from controlled studies of effects of ketamine in depression is likely to be much more reliable; 3) an increase in manic symptoms is likely in bipolar (particularly bipolar I) patients, if antidepressants are not given under the cover of mood stabilizer medication. However, despite there being insufficient evidence from 98 patients studied with ketamine by the National Institutes of Health group, there are several indications that ketamine, like other antidepressants, could potentially induce mania. At least one bipolar II patient in the ketamine study developed mania despite being on lithium, and two patients in the ketamineriluzole study developed transitory mania-like symptoms. If ketamine is classified as an antidepressant, then there is no reason to think that it would be less likely than a traditional

Lithium monotherapy associated clinical improvement effects on amygdala-ventromedial prefrontal cortex resting state connectivity in bipolar disorder

BACKGROUND This study, for the first time, investigated lithium monotherapy associated effects on amygdala- ventromedial prefrontal cortex (vMPFC) resting-state functional connectivity and correlation with clinical improvement in bipolar disorder (BP) METHODS: Thirty-six medication-free subjects - 24 BP (12 hypomanic BPM) and 12 depressed (BPD)) and 12 closely matched healthy controls (HC), were included. BP subjects were treated with lithium and scanned at baseline, after 2 weeks and 8 weeks. HC were scanned at same time points but were not treated. The effect of lithium was studied for the BP group as a whole using two way (group, time) ANOVA while regressing out effects of state. Next, correlation between changes in amygdala-vMPFC resting-state connectivity and clinical global impression (CGI) of severity and improvement scale scores for overall BP illness was calculated. An exploratory analysis was also conducted for the BPD and BPM subgroups separately. RESULTS Group by time interaction revealed that lithium monotherapy in patients was associated with increase in amygdala-medial OFC connectivity after 8 weeks of treatment (p = 0.05 (cluster-wise corrected)) compared to repeat testing in healthy controls. Increased amygdala-vMPFC connectivity correlated with clinical improvement at week 2 and week 8 as measured with the CGI-I scale. LIMITATIONS The results pertain to open-label treatment and do not account for non-treatment related improvement effects. Only functional connectivity was measured which does not give information regarding one regions effect on the other. CONCLUSIONS Lithium monotherapy in BP is associated with modulation of amygdala-vMPFC connectivity which correlates with state-independent global clinical improvement.

Vagus Nerve Stimulation (VNS)

Vagus nerve stimulation (VNS) appears to be a safe and reasonably effective treatment modality and represents a new addition to the toolbox of the clinician in treating patients with severe, recurrent unipolar, and bipolar affective disorders. VNS is a bottom-up approach (brain stem to cortex) in treating depression. It modulates the neural circuitry of depression by stimulating vagal afferent fibers in the neck, which carry impulses to the brain stem and target structures involved in mood regulation, including the noradrenergic locus ceruleus and the serotonergic dorsal raphe nucleus.

Quetiapine Extended Release Open-Label Treatment Associated Changes in Amygdala Activation and Connectivity in Anxious Depression: An fMRI Study.

Background This study investigated extended release quetiapine (quetiapine XR) associated changes in functional MRI (fMRI) measures of task-induced amygdalar activation and resting state connectivity in anxious unipolar major depressive disorder (AMDD). Methods Anxious unipolar major depressive disorder patients (n = 15) (17-item Hamilton Depression Rating Scale (HAM-D) >18 and Hamilton Anxiety Scale (HAM-A) >18) and closely matched healthy control (HC) subjects were compared at baseline for task induced amygdala activation and resting state connectivity on fMRI. Subsequently, AMDD patients were treated for 8 weeks with open-label quetiapine XR. Weekly HAM-D and HAM-A ratings were obtained, and the fMRI scan was repeated at weeks 2 and 8. Changes in fMRI measures were calculated using repeated-measures analysis of variance and correlation with decrease in HAM-D and HAM-A scores was examined. Results At baseline, AMDD compared with HC exhibited increased task-induced left amygdalar activation (P = 0.05 clusterwise corrected) and decreased resting state amygdala-cortical and amygdala-pons connectivity (P < 0.05 clusterwise corrected). Quetiapine XR treatment was associated with significant decrease in HAM-D (df = 1,28; female [F] = 39; P = 0.001) and HAM-A scores (df = 1,28; F = 55; P = 0.001). The AMDD group showed increased amygdala-cortical connectivity (P < 0.05 [clusterwise corrected]) at week 2, which was maintained at week 8. At week 8, additional areas showed increased connectivity including insula and putamen. At 8 weeks, decrease in HAM-D scores correlated with increase in amygdala-mid cingulate and amygdala-cuneus connectivity (P = 0.05 [clusterwise corrected]). Decrease in HAM-A scores correlated with increase in amygdala-cuneus and parietal cortex connectivity (P = 0.05 [clusterwise corrected]). Limitations Small sample-size, open-label single-arm design, HC only tested at baseline, focused only on amygdala. Conclusions Quetiapine XR effects in the treatment of AMDD are associated with modulation of amygdala connectivity.