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Imbalance between Left and Right Dorsolateral Prefrontal Cortex in Major Depression Is Linked to Negative Emotional Judgment: An fMRI Study in Severe Major Depressive Disorder
Abstract
Although recent neuroimaging and therapeutic transcranial magnetic cortex stimulation (TMS) studies suggest imbalance between left and right dorsolateral prefrontal cortex (DLPFC) in major depressive disorder (MDD) the fundamental neuropsychological characterization of left DLPFC hypoactivity and right DLPFC hyperactivity in MDD remains poorly understood.
We used event-related functional magnetic resonance imaging (fMRI) to investigate neural activity in left and right DLPFC related to unattended (unexpected) and attended (expected) judgment of emotions. Participating in the study were 20 medication-free patients with MDD and 30 healthy subjects.
The MDD patients showed hypoactivity in the left DLPFC during both unattended and attended emotional judgment and hyperactivity in the right DLPFC during attended emotional judgment. In contrast to healthy subjects, left DLPFC activity during emotional judgment was not parametrically modulated by negative emotional valence and was inversely modulated by positive emotional valence in MDD patients. Hyperactivity in the right DLPFC correlated with depression severity.
Results demonstrate that left DLPFC hypoactivity is associated with negative emotional judgment rather than with emotional perception or attention while right DLPFC hyperactivity is linked to attentional modulation. Left-right DLPFC imbalance is characterized in neuropsychological regard, which bridges the gap from resting metabolism and therapeutic repetitive transcranial magnetic stimulation effects to functional neuroanatomy of altered emotional-cognitive interaction in MDD.
... This theory proposes that individuals with MDD have an imbalance in activity in the dorsolateral prefrontal cortex (DLPFC), leading to the dysregulation of activity downstream in the limbic system. Functional Magnetic Resonance Imaging (fMRI) studies have found that patients with MDD tend to have a hypoactive left DLPFC and/or hyperactive right DLPFC [5][6][7], which subsequently leads to the dysregulation of connectivity and control of the limbic system. Similarly, one study using single-pulse Transcranial Magnetic Stimulation (TMS) has demonstrated this frontal imbalance in excitation and inhibition through concurrent measurement of electroencephalography (EEG) [8]. ...
... While these results must be interpreted with extreme caution due to the limited statistical significance of the model and the lack of post-treatment EEG measures that could illustrate within-subject changes in asymmetry, the observed pattern can be interpreted as one of two possibilities. First, that activity in the left hemisphere might be characterized by a relatively greater inhibitory drive, a potential indicator of hypoactivity, or second, the right hemisphere might be characterized by greater excitatory drive, a potential indicator of hyperactivity [6]. Seeing that LFR, which aims to quiet a hyperactive right hemisphere, was more effective for these patients, we can speculate that targeting patients with right hemisphere hyperactivity using LFR stimulation is a potentially optimal treatment strategy, as opposed to HFL. ...
Major depressive disorder (MDD) is a highly prevalent, debilitating disorder with a high rate of treatment resistance. One strategy to improve treatment outcomes is to identify patient-specific, pre-intervention factors that can predict treatment success. Neurophysiological measures such as electroencephalography (EEG), which measures the brain’s electrical activity from sensors on the scalp, offer one promising approach for predicting treatment response for psychiatric illnesses, including MDD. In this study, a secondary data analysis was conducted on the publicly available Two Decades Brainclinics Research Archive for Insights in Neurophysiology (TDBRAIN) database. Logistic regression modeling was used to predict treatment response, defined as at least a 50% improvement on the Beck’s Depression Inventory, in 119 MDD patients receiving repetitive transcranial magnetic stimulation (rTMS). The results show that both age and baseline symptom severity were significant predictors of rTMS treatment response, with older individuals and more severe depression scores associated with decreased odds of a positive treatment response. EEG measures contributed predictive power to these models; however, these improvements in outcome predictability only trended towards statistical significance. These findings provide confirmation of previous demographic and clinical predictors, while pointing to EEG metrics that may provide predictive information in future studies.
... This theory proposes that individuals with MDD have an imbalance in activity in the dorsolateral prefrontal cortex (DLPFC), leading to dysregulation of activity downstream in the limbic system. Functional Magnetic Resonance Imaging (fMRI) studies have found that patients with MDD tend to have a hypoactive left DLPFC and/or hyperactive right DLPFC [24][25][26], which subsequently leads to dysregulation of connectivity and control of the limbic system. Similarly, one study using single-pulse Transcranial Magnetic Stimulation (TMS) has demonstrated this frontal imbalance in excitation and inhibition through concurrent measurement of EEG [27]. ...
... Past studies of MDD have demonstrated that depressed patients tend to have a hypoactive left DLPFC and/or hyperactive right DLPFC [24][25][26]. Based on this pathophysiology, rTMS protocols have been developed to reduce hyperactivity of the right hemisphere through 1 Hz, inhibitory stimulation and to reverse hypoactivity of the left hemisphere through 10 Hz excitatory stimulation. Prior research has demonstrated that the aperiodic EEG exponent reflects the balance between excitation and inhibition in the brain [62]. ...
Major depressive disorder (MDD) is a highly prevalent, debilitating disorder with a high rate of treatment resistance. One strategy to improve treatment outcomes is to identify patient-specific, pre-intervention factors that can predict treatment success. Neurophysiological measures such as electroencephalography (EEG), which measures the brain’s electrical activity from sensors on the scalp, offer one promising approach for predicting treatment response for psychiatric illnesses, including MDD. In this study, a secondary data analysis was conducted on the publicly available Two Decades-Brainclinics Research Archive for Insights in Neurophysiology (TDBRAIN) database. Specifically, hierarchical regression modeling was used to predict treatment response from baseline demographics, symptom severity, and resting-state EEG features in 119 MDD patients receiving repetitive transcranial magnetic stimulation (rTMS). Across models, both age and baseline symptom severity, assessed by the Beck’s Depression Inventory, were significant predictors of rTMS treatment response, with older individuals and more severe depression scores associated with decreased odds of a positive treatment response. EEG measures contributed predictive power to these models; however, these improvements in outcome predictability only trended towards statistical significance (p~0.07 in multiple models). These findings provide confirmation of previous demographic and clinical predictors, while pointing to EEG metrics that may provide predictive information in future studies.
... While it has been established that an imbalance of activities between the bilateral DLPFC is characteristic of patients with MDD [40], anxiety symptoms have also been related to an imbalance in activity between the bilateral DLPFC, specifically manifested as decreased activity in the left and increased activity in the right [41,42]. The reduced activity in the right DLPFC is associated with negative emotional judgment, whereas the increased activity is linked to attentional modulation [41]. ...
... While it has been established that an imbalance of activities between the bilateral DLPFC is characteristic of patients with MDD [40], anxiety symptoms have also been related to an imbalance in activity between the bilateral DLPFC, specifically manifested as decreased activity in the left and increased activity in the right [41,42]. The reduced activity in the right DLPFC is associated with negative emotional judgment, whereas the increased activity is linked to attentional modulation [41]. Considering this mechanism, the main tDCS montage of patients with anxiety symptoms is usually bicephalic DLPFC. ...
... This study refers to an OT program that incorporates mindfulness as mindfulness occupational therapy (MOT). Regarding brain function, an imbalance between the left and right dorsolateral prefrontal cortex (dlPFC) in MDD [35], brain changes in activity with recovery from depression in response to medication or psychotherapy [36], a relationship between rumination and decreased activation of the left dlPFC [37], and functional changes in the dlPFC after mindfulness meditation [38] have been reported in previous functional imaging studies. However, there have been no reports on the relationship between the effects of MOT and these brain functions. ...
... Neuropsychobiology DOI: 10.1159/000531487 9 the present study due to the lack of information of the brain region, the present results suggest that elevated beta activity in the dlPFC does not seem to be associated with anxiety and depression. Previous fMRI studies analyzing brain function in patients with MDD have shown hypoactivity in the left dlPFC [35], which is associated with cognitive decline and ruminative symptoms of depression [68]. Other studies reported a significant association between wellbeing and the left dlPFC [69], and that a positive reappraisal technique improved the sense of wellbeing and showed an increase in metabolic activity in the left dlPFC [70]. ...
Introduction:
This study examined the efficacy of an 8-week occupational therapy program incorporating mindfulness (MOT) as a form of psychiatric rehabilitation to ameliorate residual social and occupational impairment in patients with anxiety disorders and depression. The objective was to evaluate the effects of MOT on their personal well-being and to assess the impact of MOT on brain function using quantitative electroencephalography (qEEG).
Methods:
This study was a randomized, wait-list control trial with assessments performed at baseline, post-intervention (9 weeks), and follow-up (18 weeks) in outpatients with anxiety disorders and depression. The MOT was conducted in small groups, comprising eight weekly 1.5-h sessions. The primary outcome was the mean score change between the pre- and post-interventions with Questionnaire about the Process of Recovery (QPR) scale. Other clinical assessments and qEEG served as secondary and biological outcomes, respectively.
Results:
A total of 25 patients (mean age: 44.1) were included in the analysis. The MOT group demonstrated a significantly improved QPR compared to the control group after adjusting for baseline covariates (p < 0.01). This improvement was sustained for 9 weeks after the 8-week intervention. In the qEEG analysis, a significant increase in current source density in the β2 band of the left dorsolateral prefrontal cortex was observed in the MOT group compared to the control group (p < 0.02).
Conclusion:
This study demonstrates that MOT improves subjective well-being and potentially, global function. This suggests that MOT may serve as a viable option for those whose symptoms have abated but who still struggle with social and occupational functioning.
... Transcranial direct current stimulation (tDCS) is under investigation as an antidepressant treatment. Depression is associated with hypoactivity in the left, and hyperactivity in the right dorsolateral prefrontal cortex (DLPFC) (1)(2)(3). In depression trials, a bifrontal tDCS montage is commonly used which applies anodal (excitatory) tDCS to left, and cathodal (inhibitory) tDCS to right DLPFC, with the aim to re-balance activity between these regions (4,5). ...
... Reduction in negative bias has been shown to be one mechanism of action of antidepressant drugs (10)(11)(12). Negative biases are associated with hypoactivity in the left, and hyperactivity in the right DLPFC (1,3). Bilateral tDCS is applied with the physiological aim to rebalance activity between these areas. ...
Background: Transcranial direct current stimulation (tDCS) applied to dorsolateral prefrontal cortex has mild to moderate antidepressant effects. Little is known about the mechanisms of action. Other antidepressant treatments have been shown to act in part by reducing negative biases, which are thought to play a causal role in the maintenance of depression. Negative biases are hypothesized to stem from aberrant reinforcement learning processes, more precisely from overestimation of the informativeness of negative outcomes. The aim of this study was to test whether bifrontal tDCS might normalise such aberrant reinforcement learning processes in depressed mood.
Methods: 85 community volunteers with low mood received tDCS during (or before) the performance of a reinforcement learning task that manipulated the informativeness (volatility) of positive and negative outcomes. In two sessions participants received real or sham tDCS in counter-balanced order. Baseline performance (sham tDCS) was compared to a sample of healthy individuals (n = 40) to identify the effect of low mood on task performance. The impact of tDCS on task performance was assessed by contrasting real and sham tDCS.
Results: Low mood was characterised by decreased adjustment of loss relative to win learning rates in response to changes in informativeness. Bifrontal tDCS applied during task performance normalised this deficit by increasing the adjustment of loss learning rates to informativeness. Bifrontal tDCS applied before task performance had no effect indicating that the stimulation effect is cognitive state dependent.
Conclusions: Our study provides preliminary evidence that bifrontal tDCS can normalise aberrant reinforcement learning processes in low mood. Crucially, this was only the case if stimulation was applied during task performance, suggesting that combining tDCS with a concurrent cognitive manipulation might increase the functional impact on cognitive functions and potentially on emotional symptoms. Future studies are needed to test if the effect on learning processes might have a beneficial effect on mood itself.
... In this trial, we targeted the stimulation to the left dorsal lateral prefrontal cortex (DLPFC), guided by a real-time MRI brain imaging. The basis for the choice of the selected brain region was based on previous research [36] into depression. Specifically, it was due to the fact that there is an imbalance between left and right DLPFC in patients with major depressive disorder (MDD). ...
... Th In this trial, we targeted the stimulation to the left dorsal lateral prefrontal corte (DLPFC), guided by a real-time MRI brain imaging. The basis for the choice of the selecte brain region was based on previous research [36] into depression. Specifically, it was du to the fact that there is an imbalance between left and right DLPFC in patients with majo depressive disorder (MDD). ...
Transcranial pulse stimulation (TPS) is a recent development in non-invasive brain stimulations (NIBS) that has been proven to be effective in terms of significantly improving Alzheimer patients’ cognition, memory, and execution functions. Nonetheless, there is, currently, no trial evaluating the efficacy of TPS on adults with major depression disorder (MDD) nationwide. In this single-blinded, randomized controlled trial, a 2-week TPS treatment comprising six 30 min TPS sessions were administered to participants. Participants were randomized into either the TPS group or the Waitlist Control (WC) group, stratified by gender and age according to a 1:1 ratio. Our primary outcome was evaluated by the Hamilton depression rating scale-17 (HDRS-17). We recruited 30 participants that were aged between 18 and 54 years, predominantly female (73%), and ethnic Chinese from 1 August to 31 October 2021. Moreover, there was a significant group x time interaction (F(1, 28) = 18.8, p < 0.001). Further, when compared with the WC group, there was a significant reduction in the depressive symptom severity in the TPS group (mean difference = −6.60, p = 0.02, and Cohen’s d = −0.93). The results showed a significant intervention effect; in addition, the effect was large and sustainable at the 3-month follow-up. In this trial, it was found that TPS is effective in reducing depressive symptoms among adults with MDD.
... With this analysis, we wanted to test whether a negative-mood related functional asymmetry effect, which might be a promising neurofeedback candidate process, can be identified in fMRI. While FA effects have been extensively studied especially with EEG, the fMRI literature on this topic is rather limited 37,40,[60][61][62][63][64] . ...
Frontal functional asymmetry (FA) has been proposed as a potential target for neurofeedback (NFB) training for mental disorders but most FA NFB studies used electroencephalography while the investigations of FA NFB in functional magnetic resonance imaging (fMRI) are rather limited. In this study, we aimed at identifying functional asymmetry effects in fMRI and exploring its potential as a target for fMRI NFB studies by re-analyzing an existing data set containing a resting state measurement and a sad mood induction task of n = 30 participants with remitted major depressive disorder and n = 30 matched healthy controls. We applied low-frequency fluctuations (ALFF), fractional ALFF, and regional homogeneity and estimated functional asymmetry in both a voxel-wise and regional manner. We assessed functional asymmetry during rest and negative mood induction as well as functional asymmetry changes between the phases, and associated the induced mood change with the change in functional asymmetry. Analyses were conducted within as well as between groups. Despite extensive analyses, we identified only very limited effects. While some tests showed nominal significance, our results did not contain any clear identifiable patterns of effects that would be expected if a true underlying effect would be present. In conclusion, we do not find evidence for FA effects related to negative mood in fMRI, which questions the usefulness of FA measures for real-time fMRI neurofeedback as a treatment approach for affective disorders.
... A neural mechanism for top-down visual stimulus recognition proposes that visual stimuli are first projected to the prefrontal cortex for initial recognition and then to the temporal cortex in combination with bottom-up processes, allowing for more rapid recognition 46 . The dorsolateral prefrontal cortex in the left hemisphere has also been associated with attention regulation 47 . Therefore, the results might indicate that the neural mechanisms of top-down emotion regulation in response to emotional stimuli differ among depressive state groups, and there may be a significant relationship between how they respond to negative stimuli and their cognitive schema. ...
Subthreshold depressive (sD) states and major depression are considered to occur on a continuum, and there are only quantitative and not qualitative differences between depressive states in healthy individuals and patients with depression. sD is showing a progressively increasing prevalence and has a lifelong impact, and the social and clinical impacts of sD are no less than those of major depressive disorder (MDD). Because depression leads to biased cognition, patients with depression and healthy individuals show different visual processing properties. However, it remains unclear whether there are significant differences in visual information recognition among healthy individuals with various depressive states. In this study, we investigated the event-related potentials (ERPs) and event-related spectrum perturbation (ERSP) of healthy individuals with various depressive states during the perception of emotional visual stimulation. We show that different neural activities can be detected even among healthy individuals. We divided healthy participants into high, middle, and low depressive state groups and found that participants in a high depressive state had a lower P300 amplitude and significant differences in fast and slow neural responses in the frontal and parietal lobes. We anticipate our study to provide useful parameters for assessing the evaluation of depressive states in healthy individuals.
... Decreased emotional regulation is observed in patients with mild cognitive impairment [5]. Patients with mild cognitive impairment and depression have abnormally high activity in the right prefrontal cortex, and low-frequency transcranial magnetic stimulation of the right DLPFC for depression may correct the imbalance between the right and left prefrontal activity, leading to normalization [6,7]. Most previous studies have used high-frequency left DLPFC, whereas low-frequency right stimulation is better tolerated and may reduce the risk of seizures compared with high-frequency left stimulation. ...
Currently, there are no cases of targeted, individualized repeated transcranial magnetic stimulation (rTMS) treatment based on event-related potential (ERPs) results showing the activation of functional brain regions. The identification and treatment of mild cognitive impairment after traumatic brain injury are challenging. rTMS has shown unique advantages in previous studies, with positive effects on noninvasive modulation and neuroplasticity after brain injury. The selection of the rTMS parameters and targets remains controversial. ERPs indicate the cortical activity involved in cognitive processing in patients. Therefore, this study proposes that ERPs can be used as biomarkers of cognitive recovery. The results of this study will guide the development of rTMS protocols for patient treatment. To help clinicians better apply rTMS and ERPs in combination, we conducted a relevant literature review and discussion, detailing the therapeutic mechanisms of the combination of ERPs and rTMS. This will facilitate the precise assessment and personalized treatment of such patients, improve the abnormal processing patterns of patients, and promote their return to life and society.
... It has been suggested that the dorsolateral prefrontal cortex (DLPFC), especially the left DLPFC, has a role in the pathophysiology and the treatment of major depressive disorder (MDD). Positron emission tomography and functional magnetic resonance imaging studies have shown that the left DLPFC is hypoactive in patients suffering from MDD. 1,2 The best evidence for that major role of the left DLPFC in MDD is that applying transcranial magnetic stimulation (TMS) to the left DLPFC is a well-established treatment of MDD. 3 The importance of γ-aminobutyric acid (GABA) in the pathophysiology of MDD has gained increased recognition. 4,5 Recent data show that medications that directly modulate the GABA receptors display rapid antidepressant activity. ...
Background:
It has been suggested that the dorsolateral prefrontal cortex (DLPFC), especially the left DLPFC, has an important role in the pathophysiology and the treatment of major depressive disorder (MDD); furthermore, the contributory and antidepressant role of γ-aminobutyric acid (GABA) is increasingly recognized. Given that most female patients with MDD are of reproductive age, we sought to assess in vivo baseline GABA levels in the left DLPFC among unmedicated females of reproductive age with depression.
Methods:
We compared healthy females and females with MDD. Both groups were of reproductive age. We confirmed absence of current or past psychiatric diagnosis among healthy controls or a current diagnosis of MDD via a structured interview. We measured GABA+ (including homocarnosine and macromolecules), referenced to creatine and phosphocreatine, via magnetic resonance spectroscopy using a 3 Tesla magnet.
Results:
We included 20 healthy controls and 13 participants with MDD. All participants were unmedicated at the time of the study. All females were scanned during the early follicular phase of the menstrual cycle. Levels of GABA+ in the left DLPFC were significantly lower among participants with MDD (median 0.08) than healthy controls (median 0.10; U = 66.0, p = 0.02, r = 0.41).
Limitations:
When we adjusted for fit error as a covariate, we lost statistical significance for left DLPFC GABA+. However, when we adjusted for signal-to-noise ratio, statistical significance was maintained.
Conclusion:
Our results suggest that GABA+ levels in the left DLPFC may vary by depression status and should be examined as a possible treatment target.
... The DLPFC is the standard targeting site used in rTMS studies for both adults and adolescents. The conventional rationale to target the DLPFC is based on its hemispheric asymmetry and imbalance of activities in depression, in which the left DLPFC is hypoactive and the right DLPFC is hyperactive [38,39]. To balance both hemispheres of the DLPFC, high-frequency rTMS (10-20 Hz) is used to increase neuronal excitability of the L-DLPFC, while low-frequency rTMS (1 Hz) is used to induce neuronal inhibition of the R-DLPFC [40]. ...
High-frequency repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (L-DLPFC) shows promise as a treatment for treatment-resistant depression in adolescents. Conventional rTMS coil placement strategies include the 5 cm, the Beam F3, and the magnetic resonance imaging (MRI) neuronavigation methods. The purpose of this study was to use electric field (E-field) models to compare the three targeting approaches to a computational E-field optimization coil placement method in depressed adolescents. Ten depressed adolescents (4 females, age: 15.9±1.1) participated in an open-label rTMS treatment study and were offered MRI-guided rTMS five times per week over 6–8 weeks. Head models were generated based on individual MRI images, and E-fields were simulated for the four targeting approaches. Results showed a significant difference in the induced E-fields at the L-DLPFC between the four targeting methods (χ2=24.7, p<0.001). Post hoc pairwise comparisons showed that there was a significant difference between any two of the targeting methods (Holm adjusted p<0.05), with the 5 cm rule producing the weakest E-field (46.0±17.4V/m), followed by the F3 method (87.4±35.4V/m), followed by MRI-guided (112.1±14.6V/m), and followed by the computational approach (130.1±18.1V/m). Variance analysis showed that there was a significant difference in sample variance between the groups (K2=8.0, p<0.05), with F3 having the largest variance. Participants who completed the full course of treatment had median E-fields correlated with depression symptom improvement (r=−0.77, p<0.05). E-field models revealed limitations of scalp-based methods compared to MRI guidance, suggesting computational optimization could enhance dose delivery to the target.
... Our findings can be explained within the framework of frontal asymmetry theories, suggesting that dispositional negative affect and poor regulation of negative emotions are associated to higher right than left prefrontal activity (Jackson et al., 2003;Thibodeau et al., 2006). Of note, functional hemispheric imbalance of the PFC has been found in patients with mood disorders, which are characterized by a pattern of relatively less left than right resting frontal activity (Disner et al., 2011;Grimm et al., 2008). Consistent with this view, enhancing the activity of the left PFC by means of neuromodulation techniques was shown to decrease the attentional bias to negative emotions in clinically anxious and depressed individuals (Heeren et al., 2017;Ironside et al., 2016). ...
Negative emotional stimuli can strongly bias attention, particularly in individuals with high levels of dispositional negative affect (NA). The current study investigated whether the prefrontal cortex (PFC), a brain region involved in the top-down regulation of emotional processing, plays a different role in controlling attention to emotions, depending on the individual NA. Sham and anodal transcranial direct current stimulation (tDCS) was delivered over the right or left PFC while assessing attentional bias (AB) to emotions (happy, angry, sad faces) in individuals with higher and lower trait NA. When tDCS was inactive (sham), individuals with higher trait NA showed AB toward angry and away from sad faces, while individuals with lower trait NA presented with no AB. Right anodal-tDCS abolished the AB toward angry faces and induced an AB toward sad faces in individuals with higher trait NA, while no effect was found in individuals with lower trait NA. Left anodal-tDCS abolished any AB in individuals with higher trait NA and induced an AB away from happy faces in individuals with lower trait NA. These findings confirm a critical role of trait NA in AB to emotions and demonstrate a different involvement of PFC in emotional processing based on dispositional affect.
... Two major modalities of rTMS used are high frequency rTMS (≥1 Hz) and low frequency rTMS (≤1 Hz), which have stimulating and inhibitory effects on the cerebral cortex, respectively [69]. It is postulated that patients with depression have asymmetrical functioning of the frontal lobe [70] and thus inhibitory (low frequency) stimulation has been applied to the right dorsolateral prefrontal cortex (DLPFC) [71]. Treatment regimen is usually delivered daily for 6 weeks or 30 treatments. ...
The prevalence of major depressive disorder (MDD) is estimated to be 13.3%, while depressive symptoms are estimated to occur in 28.4% of older adults. A range of medical, functional, and psychosocial risk factors contribute to depression in this population. Depression in older adults may present differently than in younger adults with more physical complaints. Diagnosis becomes even more challenging in the presence of delirium and dementia, which often overlap in an older adult with MDD. It is important to assess suicide risks in older adults with depressive symptoms. Psychotherapy is recommended for mild to moderate depression, while antidepressants should be considered for severe depression or when psychotherapy is not available. Careful monitoring of side effects is important in older adults due to reduced physiological reserves.
... The dysfunction of prefrontal cortical regions account for the psychiatric disorders related to mood dysregulation [68,69]. Moreover, it is known that DLPFC performs lateralized functioning during depression in the form of hyperactivity of right DLPFC and hypoactivity of left DLPFC [62,70]. In our study, the inhibition of excitatory connection from rAMG to rDLPFC after rTMS highlights the importance of the inhibitory influence on rDLPFC which may affect emotional balance. ...
Emotional dysregulation such as that seen in depression, are a long-term consequence of mild traumatic brain injury (TBI), that can be improved by using neuromodulation treatments such as repetitive transcranial magnetic stimulation (rTMS). Previous studies provide insights into the changes in functional connectivity related to general emotional health after the application of rTMS procedures in patients with TBI. However, these studies provide little understanding of the underlying neuronal mechanisms that drive the improvement of the emotional health in these patients. The current study focuses on inferring the effective (causal) connectivity changes and their association with emotional health, after rTMS treatment of cognitive problems in TBI patients (N = 32). Specifically, we used resting state functional magnetic resonance imaging (fMRI) together with spectral dynamic causal model (spDCM) to investigate changes in brain effective connectivity, before and after the application of high frequency (10 Hz) rTMS over left dorsolateral prefrontal cortex. We investigated the effective connectivity of the cortico-limbic network comprised of 11 regions of interest (ROIs) which are part of the default mode, salience, and executive control networks, known to be implicated in emotional processing. The results indicate that overall, among extrinsic connections, the strength of excitatory connections decreased while that of inhibitory connections increased after the neuromodulation. The cardinal region in the analysis was dorsal anterior cingulate cortex (dACC) which is considered to be the most influenced during emotional health disorders. Our findings implicate the altered connectivity of dACC with left anterior insula and medial prefrontal cortex, after the application of rTMS, as a potential neural mechanism underlying improvement of emotional health. Our investigation highlights the importance of these brain regions as treatment targets in emotional processing in TBI.
... In patients with MDD, tDCS is mainly applied over the dorsolateral prefrontal cortex (DLPFC), which is a brain region that presents an unbalanced activity between the left and right hemispheres in MDD (7,8). The rationale behind tDCS antidepressant effects is that the current can restore the balance between left and right DLPFC activity (9). Moreover, by stimulating the DLPFC, deeper brain areas implicated in depression, such as the subgenual anterior cingulate cortex (sgACC) can be indirectly modulated via its structural and functional connections with the DLPFC (10,11,12). ...
Transcranial direct current stimulation (tDCS) presents mixed effects for major depressive disorder (MDD) symptoms, partially owing to a large inter-experimental variability in tDCS protocols and their correlated induced electric fields (E-fields). We investigated whether tDCS-induced E-field strength of distinct tDCS parameters was associated with antidepressant effect. A meta-analysis was performed with tDCS placebo-controlled clinical trials enrolling MDD patients. PubMed, EMBASE and Web of Science were searched from inception to March 10, 2023. Effect sizes of tDCS protocols were correlated with E-field simulations (SimNIBS) of brain regions of interest (bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral subgenual anterior cingulate cortex (sgACC)). Moderators of tDCS responses were also investigated. A total of twenty studies were included (21 datasets, 1008 patients) using eleven distinct tDCS protocols. Results revealed a moderate effect for MDD (g=0.41, 95% CI [0.18,0.64]), while cathode position and treatment strategy were found to be moderators of response. A negative association between the effect size and tDCS-induced E-field magnitude was seen, showing that stronger E-fields in the right frontal and medial parts of the DLPFC (targeted by the cathode) led to smaller effects. No association was found for the left DLPFC and the bilateral sgACC. An optimized tDCS protocol was presented.
... Furthermore, studies have also shown the functional asymmetry between the hemispheres. There is hyperactivation of the right DLPFC and hypofunction of the left DLPFC (Grimm et al., 2008). Neuromodulation strategies have targeted these dysfunctions to treat depression. ...
Background:
Patients with major depressive disorder who have a poor or inconsistent response to antidepressants have been treated using transcranial direct current stimulation (tDCS). Early tDCS augmentation may help with the early amelioration of symptoms. In this study, the efficacy and safety of tDCS as early augmentation therapy in major depressive disorder were evaluated.
Methods:
Fifty adults were randomized into two groups and were administered either active tDCS or sham tDCS, along with escitalopram 10 mg/day. A total of 10 tDCS sessions with anodal stimulation at the left dorsolateral prefrontal cortex (DLPFC) and cathode at the right DLPFC were given over two weeks. Assessments were done using Hamilton Depression Rating Scale (HAM-D), Beck's Depression Inventory (BDI), and Hamilton Anxiety Rating Scale (HAM-A) at baseline, two weeks, and four weeks. A tDCS side effect checklist was administered during therapy.
Results:
A significant reduction in HAM-D, BDI, and HAM-A scores were observed in both groups from baseline to week-4. At week-2, the active group had a significantly greater reduction in HAM-D and BDI scores than the sham group. However, at the end of therapy, both groups were comparable. The active group was 1.12 times more likely to experience any side effect than the sham group, but the intensity ranged from mild to moderate.
Conclusion:
tDCS is an effective and safe strategy for managing depression as an early augmentation strategy, and it produces an early reduction of depressive symptoms and is well tolerated in moderate to severe depressive episodes.
... Another potential cortical region involved is the dorsolateral prefrontal cortex (dlPFC). This region is primarily responsible for social and executive functioning [48,49] and appears to be critical for on-going mood regulation with negative emotional judgment and major depressive disorders [50][51][52]. A recent study by Sesa-Ashton and colleagues showed that stimulation of dlPFC, either left or right, in awake humans resulted in cyclic modulation of MSNA, BP and heart rate, and a significant increase in BP [53]. ...
Purpose of Review
The response to natural stressors involves both cardiac stimulation and vascular changes, primarily triggered by increases in sympathetic activity. These effects lead to immediate flow redistribution that provides metabolic support to priority target organs combined with other key physiological responses and cognitive strategies, against stressor challenges. This extremely well-orchestrated response that was developed over millions of years of evolution is presently being challenged, over a short period of time. In this short review, we discuss the neurogenic background for the origin of emotional stress-induced hypertension, focusing on sympathetic pathways from related findings in humans and animals.
Recent Findings
The urban environment offers a variety of psychological stressors. Real or anticipatory, emotional stressors may increase baseline sympathetic activity. From routine day-to-day traffic stress to job-related anxiety, chronic or abnormal increases in sympathetic activity caused by emotional stressors can lead to cardiovascular events, including cardiac arrhythmias, increases in blood pressure and even sudden death. Among the various alterations proposed, chronic stress could modify neuroglial circuits or compromise antioxidant systems that may alter the responsiveness of neurons to stressful stimuli. These phenomena lead to increases in sympathetic activity, hypertension and consequent cardiovascular diseases.
Summary
The link between anxiety, emotional stress, and hypertension may result from an altered neuronal firing rate in central pathways controlling sympathetic activity. The participation of neuroglial and oxidative mechanisms in altered neuronal function is primarily involved in enhanced sympathetic outflow. The significance of the insular cortex-dorsomedial hypothalamic pathway in the evolution of enhanced overall sympathetic outflow is discussed.
... 30 Relevant neuroimaging studies revealed that the right hemisphere metabolism of patients with unipolar depressed was enhanced 31 and the severity of depression is related to increased right hemisphere metabolism. 32 Considering that the frontal region is crucial for controlling emotions and the occipital region is related to visual emotional stimuli. We measure the occipital-frontal Granger causal index in both depressed and healthy MEGs. ...
In this study, we employ the Granger causality of a polynomial kernel to identify the coupling causality of depressed magnetoencephalography (MEG). We collect MEG under positive, neutral, and negative emotional stimuli and focus on the β-band activities. According to test results, depressed people display stronger left–right symmetrical interconnection in their prefrontal and occipital lobes under nonpositive stimuli(namely neutral and negative stimuli), indicating that they are more sensitive to nonpositive stimuli. The intensity of the right occipital information flow is higher in depressed people. We also see the Granger causality index increased in the occipital–frontal areas of depressed patients under negative stimuli. In general, detecting the polynomial kernel Granger causality of the MEG can effectively characterize the strength of the interconnected brain regions in depressed patients, which can be used as a clinical diagnosis aid.
... There is hypofunction of left DLPFC and hyperfunctioning of right DLPFC. 18 Amongst varying protocols, up to 10 sessions of anodal stimulation over left DLPFC and cathodal inhibition over right DLPFC with a current intensity of 2mA for 20 minutes is the most commonly used protocol. [19][20][21] Evidence has shown the efficacy of active tDCS over sham tDCS in the management of refractory depressive symptoms. ...
Background: Transcranial direct current stimulation (tDCS) used for augmentation improves depressive symptoms in patients who have a partial or poor response to antidepressant medications. However, its role and effectiveness as an early intervention have not been studied much. This study aims to determine the efficacy and safety of add-on tDCS as an early augmentation strategy in drug-naive patients with major depressive disorder.Methods: A total of 40 patients will be enrolled in the study, randomized into two groups (active and sham), and receive uniform medication Escitalopram 10 mg per day. A total of 10 sessions of tDCS will be given within 2 weeks. Assessments will be done using scales Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D) and Beck’s Depression Inventory (BDI) at baseline, week 2, and week 4 of the study. After each session of tDCS, a side effects checklist will be applied to monitor side effects. The trial has been registered in the Clinical Trials Registry, India(CTRI/2022/01/039123).Result: After data collection, statistical analysis will be done using a computerized statistical program, Statistical Package for Social Sciences. Mean changes in the rating scale scores will be compared after each assessment and between the groups. Conclusion: The findings will help to assess the efficacy of tDCS in the early augmentation of depressive disorder
... These findings support the Nahas and Williams trials which resulted in up to 80% sustained remission Williams et al., 2016Williams et al., , 2018 while, in a separate study, unilateral (left-sided) conventional DLPFC stimulation produced an average of 30% remission (Kopell et al., 2011). This also highlights the potential to utilize EpCS as an alternative approach in TRD patients non-responsive to TMS, perhaps drawing on similar key mechanisms (Fitzgerald et al., Grimm et al., 2008). ...
Non-invasive brain stimulation is designed to target accessible brain regions that underlie many psychiatric disorders. One such method, transcranial magnetic stimulation (TMS), is commonly used in patients with treatment-resistant depression (TRD). However, for non-responders, the choice of an alternative therapy is unclear and often decided empirically without detailed knowledge of precise circuit dysfunction. This is also true of invasive therapies, such as deep brain stimulation (DBS), in which responses in TRD patients are linked to circuit activity that varies in each individual. If the functional networks affected by these approaches were better understood, a theoretical basis for selection of interventions could be developed to guide psychiatric treatment pathways. The mechanistic understanding of TMS is that it promotes long-term potentiation of cortical targets, such as dorsolateral prefrontal cortex (DLPFC), which are attenuated in depression. DLPFC is highly interconnected with other networks related to mood and cognition, thus TMS likely alters activity remote from DLPFC, such as in the central executive, salience and default mode networks. When deeper structures such as subcallosal cingulate cortex (SCC) are targeted using DBS for TRD, response efficacy has depended on proximity to white matter pathways that similarly engage emotion regulation and reward. Many have begun to question whether these networks, targeted by different modalities, overlap or are, in fact, the same. A major goal of current functional and structural imaging in patients with TRD is to elucidate neuromodulatory effects on the aforementioned networks so that treatment of intractable psychiatric conditions may become more predictable and targeted using the optimal technique with fewer iterations. Here, we describe several therapeutic approaches to TRD and review clinical studies of functional imaging and tractography that identify the diverse loci of modulation. We discuss differentiating factors associated with responders and non-responders to these stimulation modalities, with a focus on mechanisms of action for non-invasive and intracranial stimulation modalities. We advance the hypothesis that non-invasive and invasive neuromodulation approaches for TRD are likely impacting shared networks and critical nodes important for alleviating symptoms associated with this disorder. We close by describing a therapeutic framework that leverages personalized connectome-guided target identification for a stepwise neuromodulation paradigm.
... Previous fMRI studies have shown asymmetrical cerebral hemisphere activation, with positive emotional valence associated with left hemisphere hyperactivity (decreases in prefrontal inhibitory alpha oscillations) and negative valence with right hemisphere hyperactivity in healthy controls (39,41,42). Additionally, lesion studies have shown right-hemispheric hypoactivity in mania and left-hemispheric hypoactivity in depression (39,(43)(44)(45). It follows that an approach to treating a patient with dominant manic symptoms would be exciting the hypofunctional area (right DLPFC) or inhibiting the hyperfunctional area (the left DLPFC). ...
Introduction
Bipolar major depressive episodes with mixed features are diagnosed in patients who meet the full criteria for a major depressive episode exhibiting three additional concurrent symptoms of hypomania or mania. Up to half of patients with bipolar disorder experience mixed episodes, which are more likely to be treatment-refractory than pure depression or mania/hypomania alone.
Case
We present a 68-year-old female with Bipolar Type II Disorder with a four-month medication-refractory major depressive episode with mixed features referred for neuromodulation consultation. Previous failed medication trials over several years included lithium, valproate, lamotrigine, topiramate, and quetiapine. She had no history of treatment with neuromodulation. At the initial consultation, her baseline Montgomery-Asberg Depression Rating Scale (MADRS) was moderate in severity at 32. Her Young Mania Rating Scale (YMRS) was 22, with dysphoric hypomanic symptoms consisting of heightened irritability, verbosity and increased rate of speech, and decreased sleep. She declined electroconvulsive therapy but elected to receive repetitive transcranial magnetic stimulation (rTMS).
Interventions
The patient underwent repetitive transcranial magnetic stimulation (rTMS) with a Neuronetics NeuroStar system, receiving nine daily sessions over the left dorsolateral prefrontal cortex (DLPFC). Standard settings of 120% MT, 10 Hz (4 sec on, 26 sec off), and 3,000 pulses/session were used. Her acute symptoms showed a brisk response, and at the final treatment, her repeat MADRS was 2, and YMRS was 0. The patient reported feeling “great,” which she defined as feeling stable with minimal depression and hypomania for the first time in years.
Conclusion
Mixed episodes present a treatment challenge given their limited treatment options and diminished responses. Previous research has shown decreased efficacy of lithium and antipsychotics in mixed episodes with dysphoric mood such as the episode our patient experienced. One open-label study of low-frequency right-sided rTMS showed promising results in patients with treatment-refractory depression with mixed features, but the role of rTMS in the management of these episodes is largely unexplored. Given the concern for potential manic mood switches, further investigation into the laterality, frequency, anatomical target, and efficacy of rTMS for bipolar major depressive episodes with mixed features is warranted.
... The DLPFC is the standard targeting site used in rTMS studies for both adults and adolescents. The conventional rationale to target the DLPFC is based on its hemispheric asymmetry and imbalance of activities in depression, in which the left DLPFC is hypoactive and the right DLPFC is hyperactive [30,31]. ...
Background
A promising treatment option for adolescents with treatment-resistant depression is high-frequency repetitive transcranial magnetic stimulation (rTMS) delivered to the left dorsolateral prefrontal cortex (L-DLPFC). Conventional coil placement strategies for rTMS in adults include the 5-cm rule, the Beam F3 method, and the magnetic resonance imaging (MRI) neuronavigation method. The purpose of this study was to compare the three targeting approaches to a computational E-field optimization coil placement method in depressed adolescents.
Methods
Ten consenting and assenting depressed adolescents (4 females, age: 15.9 ± 1.1) participated in an open-label rTMS treatment study. Participants were offered MRI-guided rTMS 5 times per week over 6–8 weeks. To compute the induced E-field, a head model was generated based on MRI images, and a figure-8 TMS coil (Neuronetics) was placed over the L-DLPFC using the four targeting approaches.
Results
Results show that there was a significant difference in the induced E-field at the L-DLPFC between the four targeting methods ( χ ² = 24.7, p < 0.001). Post hoc pairwise comparisons show that there was a significant difference between any two of the targeting methods (Holm adjusted p < 0.05), with the 5-cm rule producing the weakest E-field (46.0 ± 17.4 V/m), followed by the F3 method (87.4 ± 35.4 V/m), followed by the MRI-guided (112.1 ± 14.6 V/m), and followed by the computationally optimized method (130.1 ± 18.1 V/m). The Bartlett test of homogeneity of variances show that there was a significant difference in sample variance between the groups ( K ² = 8.0, p < 0.05), with F3 having the largest variance. In participants who completed the full course of treatment, the median E-field strength in the L-DLPFC was correlated with the change in depression severity ( r = – 0.77, p < 0.05).
Conclusions
The E-field models revealed inadequacies of scalp-based targeting methods compared to MRI-guidance. Computational optimization may further enhance E-field dose delivery to the treatment target.
... More importantly, at a time when researchers are struggling to find a much better treatment for resistant depression, rTMS has earned itself a place in the management of depressive disorders globally, and more research is being conducted to evaluate the same. Study findings indicate asymmetry in the functioning of patients diagnosed with MDD [27]. Therefore, researchers have to apply an inhibitory rTMS stimulation (low frequency) to the right dorsolateral prefrontal cortex (DLPFC) and excitatory stimulation (high frequency) to the left DLPFC in TRD patients [28]. ...
Background: Treatment-resistant depression (TRD) is considered one of the major clinical challenges in the field of psychiatry. An estimated 44% of patients with major depressive disorder (MDD) do not respond to two consecutive antidepressant therapies, and 33% do not respond to up to four antidepressants. Over 15% of all patients with MDD remain refractory to any treatment intervention. rTMS is considered a treatment option for patients with TRD. Likewise, iCBT is evidence-based, symptom-focused psychotherapy recommended for the treatment of TRD. Objective: This study aimed to evaluate the initial comparative clinical effectiveness of rTMS treatment with and without iCBT as an innovative intervention for the treatment of participants diagnosed with TRD. Methods: This study is a prospective two-arm randomized controlled trial. Overall, 78 participants diagnosed with TRD were randomized to one of two treatment interventions: rTMS sessions alone and rTMS sessions plus iCBT. Participants in each group were made to complete evaluation measures at baseline, and 6 weeks (discharge) from treatment. The primary outcome measure was baseline to six weeks change in mean score for the 17-item Hamilton depression rating scale (HAMD-17). Secondary outcomes included mean baseline to six-week changes in the Columbia suicide severity rating scale (CSSRS) for the rate of suicidal ideations, the QIDS-SR16 for subjective depression, and the EQ-5D-5L to assess the quality of health in participants. Results: A majority of the participants were females 50 (64.1%), aged ≥ 40 39 (50.0%), and had college/university education 54 (73.0%). After adjusting for the baseline scores, the study failed to find a significant difference in the changes in mean scores for participants from baseline to six weeks between the two interventions under study on the HAMD-17 scale: F (1, 53) = 0.15, p = 0.70, partial eta squared = 0.003, CSSRS; F (1, 56) = 0.04 p = 0.85, partial eta squared = 0.001, QIDS-SR16 scale; F (1, 53) = 0.04 p = 0.61, partial eta squared = 0.005, and EQ-5D-VAS; F (1, 51) = 0.46 p = 0.50, and partial eta squared = 0.009. However, there was a significant reduction in means scores at week six compared to baseline scores for the combined study population on the HAMD-17 scale (42%), CSSRS (41%), QIDS-SR16 scale (35%), and EQ-VAS scale (62%). Conclusion: This study did not find that combined treatment of TRD with rTMS + iCBT (unguided) was superior to treatment with rTMS alone. Our findings do not support the use of combined treatment of rTMS + iCBT for the management of TRD disorders.
... Second, the imbalance hypothesis of MDD postulates prefrontal asymmetry with relative hypoactivity in the left DLPFC. Correspondingly, fMRI studies during emotional stimulation have also reported hypoactivity of the left DLPFC that is correlated with the severity of depressive symptoms [86,87]. Increased left DLPFC reactivity to positive stimuli might indicate an enhancement of cognitive processing by emotional content. ...
Introduction:
Cognition and emotion are fundamentally integrated in the brain and mutually contribute to behavior. The relation between working memory (WM) and emotion is particularly suited to investigate cognition-emotion interaction since WM is an essential component of many higher cognitive functions. Ketamine affects not only WM but also has a profound impact on emotional processing. Effects of acute ketamine challenge are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release. Accordingly, a combination of these approaches should be particularly suited to investigate cognition-emotion interaction.
Methods:
Seventy five healthy subjects were investigated in a double-blind, placebo-controlled, randomized, single-dose, parallel-group study with three treatment conditions. All subjects underwent two scanning sessions (acute/post 24 h).
Results:
Compared to placebo, acute ketamine administration induced significant dissociative, psychotomimetic, and cognitive effects, as well as an increase in neural activity during WM for positive stimuli. Inhibition of glutamate release by pretreatment with lamotrigine did not influence ketamine's subjective effects, but significantly attenuated its impact on emotional WM and associated neural activity. There was no effect on these measures 24 h after ketamine administration.
Conclusion:
Our results demonstrate differential acute effects of modulated glutamate release and a swift restoration of disturbed neurobehavioral homeostasis in healthy subjects.
... Left frontal peak brain activity in the 100-200 ms post-stimulus period was most heightened in the directly exposed group, and this group also showed a significantly greater neural response relative to the indirectly exposed group. Frontal neural activity is a signature of cognitive effort [72], and left frontal dysfunction and dysconnectivity in particular has been observed in relevant neuropsychiatric conditions such as depression [73,74] and PTSD [75,76]. Indeed in partial correlations that accounted for fireexposure group, we found that left frontal activity correlated with interference processing efficiency, i.e. greater cognitive effort represented by this neural signature was associated with better performance. ...
As climate change accelerates extreme weather disasters, the mental health of the impacted communities is a rising concern. In a recent study of 725 Californians we showed that individuals that were directly exposed to California’s deadliest wildfire, the Camp Fire of 2018, had significantly greater chronic symptoms of post-traumatic stress disorder, anxiety and depression than control individuals not exposed to the fires. Here, we study a subsample of these individuals: directly exposed (n = 27), indirectly exposed (who witnessed the fire but were not directly impacted, n = 21), versus age and gender-matched non-exposed controls (n = 27). All participants underwent cognitive testing with synchronized electroencephalography (EEG) brain recordings. In our sample, 67% of the individuals directly exposed to the fire reported having experienced recent trauma, while 14% of the indirectly exposed individuals and 0% of the non-exposed controls reported recent trauma exposure. Fire-exposed individuals showed significant cognitive deficits, particularly on the interference processing task and greater stimulus-evoked fronto-parietal activity as measured on this task. Across all subjects, we found that stimulus-evoked activity in left frontal cortex was associated with overall improved interference processing efficiency, suggesting the increased activity observed in fire exposed individuals may reflect a compensatory increase in cortical processes associated with cognitive control. To the best of our knowledge this is the first study to examine the cognitive and underlying neural impacts of recent climate trauma.
... On a neurological level, evidence shows that deficits in executive function, memory, and attention are associated with MDD (94). More specifically, task-related hypoactivity in the left dorsolateral prefrontal cortex, as observed in people with MDD (95), is associated with negative emotional judgment (96) and reduced planning and action control (14,97). These malfunctions seem to be caused by structural changes, hence may be reversible with improvement in illness trajectory (97,98). ...
Introduction: A physical activity counseling intervention based on a motivation-volition model was developed and delivered to in-patients with Major Depressive Disorders with the aim of increasing lifestyle physical activity. The aim of this study is to evaluate the short-term outcomes of this intervention.
Methods: A multi-center randomized controlled trial was conducted in four Swiss psychiatric clinics. Adults who were initially insufficiently physically active and were diagnosed with Major Depressive Disorder according to ICD-10 were recruited. The sample consisted of 113 participants in the intervention group (Mage = 42 years, 56% women) and 107 in the control group (Mage = 40 years, 49% women). Motivation and volition determinants of physical activity were assessed with questionnaires. Implicit attitudes were assessed with an Implicit Association Test. Physical activity was self-reported and measured with hip-worn accelerometers over 7 consecutive days starting on the day following the data collection.
Results: According to accelerometer measures, step count decreased on average 1,323 steps less per day (95% CI = −2,215 to −431, p < 0.01) over time in the intervention group compared to the control group. A trend was recognized indicating that moderate-to-vigorous physical activity decreased on average 8.37 min less per day (95% CI = −16.98 to 0.23, p < 0.06) over time in the intervention group compared to the control group. The initial phase of the intervention does not seem to have affected motivational and volitional determinants of and implicit attitudes toward physical activity.
Conclusion: Physical activity counseling may be considered an important factor in the transition from in-patient treatment. Methods to optimize the intervention during this period could be further explored to fulfill the potential of this opportunity.
... Some studies suggest that functional imbalances between the left and right DLPFC (Maeda et al. 2000;Hasey 2001;Funk & George 2008;Hale et al. 2009) are responsible for symptoms of major depressive disorder. Patients might thus benefit from excitatory TMS to the left DLPFC and inhibitory TMS over the right DLPFC (Grimm et al. 2008). ...
The unipolar depression and bipolar disorder depressive episode have different pathogenesis, which are difficult to distinguish in the early clinical stage. Patients with bipolar disorder begin with depressive episode more often than with manic episodes, during which hypomania lasts for a short time with mild symptoms, making them difficult to distinguish from normal emotion changes. Patients with depressive episode at a young age and a family history of bipolar disorder, who once had a history of transient mania and are currently manifested by mixed depression, retardative depression, agitated depression, and psychotic depression, are mostly considered as having bipolar depression. At present, the main complaints are somatic symptoms, with initial insomnia, anorexia, and unipolar depression. Despite the accumulation of numerous data on brain imaging, neuroendocrine, neurotransmitter, neurophysiological, and other biological markers of unipolar and bipolar affective disorders, the differences in the physiopathologic mechanism between the two disorders remain unclear in essence so far. In terms of treatment, both are primarily treated through medication, psychological approach, behavioral approach, and neurostimulation techniques. Drug treatments include selective norepinephrine reuptake inhibitors (SNRIs), selective serotonin uptake inhibitors (SSRIs), and tricyclic antidepressants. Neurostimulation techniques include electroconvulsive (ECT), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS).
Electroconvulsive therapy (ECT) remains the most potent antidepressant treatment available for patients with major depressive disorder (MDD). ECT is highly effective, achieving a response rate of 70–80% and a remission rate of 50–60% even in treatment-resistant patients. The underlying mechanisms of ECT are not fully understood, although several hypotheses have been proposed, including the monoamine hypothesis, anticonvulsive hypothesis, neuroplastic effects, and immunomodulatory properties. In this paper, we provide an overview of magnetic resonance imaging evidence that addresses the neuroplastic changes that occur after ECT at the human systems level and elaborate further on ECTs potent immunomodulatory properties. Despite a growing body of evidence that suggests ECT may normalize many of the structural and functional changes in the brain associated with severe depression, there is a lack of convergence between neurobiological changes and the robust clinical effects observed in depression. This may be due to sample sizes used in ECT studies being generally small and differences in data processing and analysis pipelines. Collaborations that acquire large datasets, such as the GEMRIC consortium, can help translate ECT’s clinical efficacy into a better understanding of its mechanisms of action.
Transcranial magnetic stimulation (TMS) is a safe, tolerable, and evidence‐based intervention for major depressive disorder (MDD). However, even after decades of research, nearly half of the patients with MDD fail to respond to conventional TMS, with responding slowly and requiring daily attendance at the treatment site for 4–6 weeks. To intensify antidepressant efficacy and shorten treatment duration, accelerated TMS protocols, which involve multiple sessions per day over a few days, have been proposed and evaluated for safety and viability. We reviewed and summarized the current knowledge in accelerated TMS, including stimulation parameters, antidepressant efficacy, anti‐suicidal efficacy, safety, and adverse effects. Limitations and suggestions for future directions are also addressed, along with a brief discussion on the application of accelerated TMS during the COVID‐19 pandemic.
This article is categorized under: Neuroscience > Clinical Neuroscience
There is growing interest in the application of neuromodulatory therapies to the treatment of psychiatric conditions, such as mood and anxiety disorders. Vagus nerve stimulation (VNS) was approved by the United States Food and Drug Administration in 2005 as an adjunctive, long-term therapeutic option for adults with treatment-resistant depression. Clinical studies have demonstrated that augmenting standard antidepressant treatments with VNS is associated with greater reductions in depressive symptoms and improvements in remission rates compared to using standard treatments alone in this population. Moreover, the clinical benefits of VNS appear to increase over time with long-term treatment. Potential mechanisms underlying the antidepressant effects of VNS include effects on neurotransmitter systems, inflammation, and neurogenesis. Despite these demonstrated benefits, the invasive nature of surgically-implanted VNS has limited its clinical application. Noninvasive forms of VNS have recently been developed, including transcutaneous vagus nerve stimulation (tVNS). Although research on clinical applications of tVNS is in its early stages, there is some evidence to suggest that tVNS may improve symptoms of depression, anxiety, and related conditions, such as posttraumatic stress disorder and insomnia. This chapter provides a review of the clinical and preclinical literature exploring the effects of VNS and tVNS on mood and anxiety symptoms. In addition, it discusses potential mechanisms underlying these effects and highlights limitations of available research and important avenues for continued investigation.
Non-pharmacological treatment is essential for patients with major depressive disorder (MDD) that is medication resistant or who are unable to take medications. Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation method that manipulates neural oscillations. In recent years, tACS has attracted substantial attention for its potential as an MDD treatment. This review summarizes the latest advances in tACS treatment for MDD and outlines future directions for promoting its clinical application. We first introduce the neurophysiological mechanism of tACS and its novel developments. In particular, two well-validated tACS techniques have high application potential: high-definition tACS targeting local brain oscillations and bifocal tACS modulating interarea functional connectivity. Accordingly, we summarize the underlying mechanisms of tACS modulation for MDD. We sort out the local oscillation abnormalities within the reward network and the interarea oscillatory synchronizations among multiple MDD-related networks in MDD patients, which provide potential modulation targets of tACS interventions. Furthermore, we review the latest clinical studies on tACS treatment for MDD, which were based on different modulation mechanisms and reported alleviations in MDD symptoms. Finally, we discuss the main challenges of current tACS treatments for MDD and outline future directions to improve intervention target selection, tACS implementation, and clinical validations.
Purpose of Review
Sexual choking/strangulation—usually done as part of consensual sex—has increased in prevalence among U.S. adolescents and young adults. Thus, it is critical for sexual health professionals to become aware of this emerging sexual behavior, how people engage in it, as well as short-term and potential long-term health consequences. The present review addresses these issues.
Recent Findings
Sexual choking refers to a sexual practice in which people apply external pressure to the neck in order to reduce blood flow and/or air flow. Although hands are most often used, people sometimes use a limb (e.g., forearm) or ligature. Young adults report learning about sexual choking from peers, partners, pornography, and social media, among other sources. Sexual choking/strangulation disproportionately affects women as well as sexual and gender minorities, and is more common between relationship partners. Emerging research indicates that a number of short-term health sequelae may occur from being choked (e.g., headaches, bruising, neck pain, neck swelling, loss of consciousness) and that there may be long-term health sequelae, including to neurological health.
Summary
Sexual choking/strangulation has become prevalent among young people in the USA, disproportionately impacts women as well as sexual and gender minorities, and is consequential to health. Future research that focuses on adolescents as well as sexual and gender minorities is warranted; also, prospective research is needed in order to examine potential health sequelae of having been choked/strangled during sex.
Depression is a common mental disorder that seriously affects patients’ social function and daily life. Its accurate diagnosis remains a big challenge in depression treatment. In this study, we used electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) and measured the whole brain EEG signals and forehead hemodynamic signals from 25 depression patients and 30 healthy subjects during the resting state. On one hand, we explored the EEG brain functional network properties, and found that the clustering coefficient and local efficiency of the delta and theta bands in patients were significantly higher than those in normal subjects. On the other hand, we extracted brain network properties, asymmetry, and brain oxygen entropy as alternative features, used a data-driven automated method to select features, and established a support vector machine model for automatic depression classification. The results showed the classification accuracy was 81.8% when using EEG features alone and increased to 92.7% when using hybrid EEG and fNIRS features. The brain network local efficiency in the delta band, hemispheric asymmetry in the theta band and brain oxygen sample entropy features differed significantly between the two groups ( p < 0.05) and showed high depression distinguishing ability indicating that they may be effective biological markers for identifying depression. EEG, fNIRS and machine learning constitute an effective method for classifying depression at the individual level.
Objectives:
When administered in repeated daily doses, transcranial direct current stimulation (tDCS) directed to the prefrontal cortex has cumulative efficacy for the treatment of depression. Depression can be marked by altered processing of emotionally salient information. An acute marker of response to tDCS may be measured as an immediate change in emotional information processing. Using an easily administered web-based task, we tested immediate changes in emotional information processing in acute response to tDCS in participants with and without depression.
Materials and methods:
We enrolled n = 21 women with mild-to-moderate depression and n = 20 controls without depression to complete a web-based visual search task before and after 30 minutes of tDCS directed to the prefrontal cortex. The timed task required participants to identify a target face among arrays showing sad, neutral, or mixed (distractor) expressions.
Results:
At baseline, as predicted, the participants with depression differed from those without in emotional processing speed (mean z score difference -0.66 ± 0.27, p = 0.022) and accuracy in identifying sad stimuli (error rate: 4.4% vs 1.8%, p = 0.039). In response to tDCS, the participants with depression became significantly faster on the distractor condition (pre- vs post-tDCS z scores: -0.45 ± 0.65 vs -0.85 ± 0.65, p = 0.009), suggesting a specific reduction in bias toward negative emotional information. In response to tDCS, the depressed group also had significant improvements in self-reported mood (increased happy, decreased sad and anxious mood).
Conclusions:
Participants with depression vs those without were differentiated by their performance of the visual search task at baseline and in response to tDCS. Given that measurable effects on depression scales may require weeks of tDCS treatments, acute change in emotional information processing can serve as an easily obtainable marker of depression and its response to tDCS.
Clinical trial registration:
The Clinicaltrials.gov registration number for the study is NCT05188248.
The dorsolateral prefrontal cortex (dlPFC) is crucial for regulation of emotion that is known to aid prevention of depression. The broader fronto-cingulo-striatal (FCS) network, including cognitive dlPFC and limbic cingulo-striatal regions, has been associated with a negative evaluation bias often seen in depression. The mechanism by which dlPFC regulates the limbic system remains largely unclear. Here we have successfully induced a negative bias in decision-making in primates performing a conflict decision-making task, by directly microstimulating the subgenual cingulate cortex while simultaneously recording FCS local field potentials (LFPs). The artificially induced negative bias in decision-making was associated with a significant decrease in functional connectivity from cognitive to limbic FCS regions, represented by a reduction in Granger causality in beta-range LFPs from the dlPFC to the other regions. The loss of top-down directional influence from cognitive to limbic regions, we suggest, could underlie negative biases in decision-making as observed in depressive states.
Introduction:
Major Depression Disorder (MDD) and pain appear to be reciprocal risk factors and sharing common neuroanatomical pathways and biological substrates. However, the role of MDD on pain processing remains still unclear. Therefore, this review aims to focus on the effect of depression on pain anticipation, and perception, before and after treatment, through functional magnetic resonance imaging (fMRI).
Methods:
A bibliographic search was conducted on PubMed, Scopus and Web of Science, looking for fMRI studies exploring pain processing in MDD patients.
Results:
Amongst the 602 studies retrieved, 12 met the inclusion criteria. In terms of pain perception, studies evidenced that MDD patients generally presented increased activation in brain regions within the prefrontal cortex, insula and in the limbic system (such as amygdala, hippocampus) and occipital cortex. The studies investigating the effect of antidepressant treatment evidenced a reduced activation in areas such as insula, anterior cingulate, and prefrontal cortices. In terms of pain anticipation, contrasting results were evidenced in MDD patients, which presented both increased and decreased activity in the prefrontal cortex, the insula and the temporal lobe, alongside with increased activity in the anterior cingulate cortex, the frontal gyrus and occipital lobes.
Limitations:
The small number of included studies, the heterogeneous approaches of the studies might limit the conclusions of this review.
Conclusions:
Acute pain processing in MDD patients seems to involve numerous and different brain areas. However, more specific fMRI studies with a more homogeneous population and rigorous approach should be conducted to better highlight the effect of depression on pain processing.
Background:
The neurobiological pathogenesis of major depression disorder (MDD) remains largely controversial. Previous literatures with limited sample size utilizing group-level structural covariance networks (SCN) commonly generated mixed findings regarding the topology of brain networks.
Methods:
We analyzed T1 images from a high-powered multisite sample including 1173 patients with MDD and 1019 healthy controls (HCs). We used regional gray matter volume to construct individual SCN by utilizing a novel approach based on the interregional effect size difference. We further investigated MDD-related structural connectivity alterations using topological metrics.
Results:
Compared to HCs, the MDD patients showed a shift toward randomization characterized by increased integration. Further subgroup analysis of patients in different stages revealed this randomization pattern was also observed in patients with recurrent MDD, while the first-episode drug naïve patients exhibited decreased segregation. Altered nodal properties in several brain regions which have a key role in both emotion regulation and executive control were also found in MDD patients compared with HCs. The abnormalities in inferior temporal gyrus were not influenced by any specific site. Moreover, antidepressants increased nodal efficiency in the anterior ventromedial prefrontal cortex.
Conclusions:
The MDD patients at different stages exhibit distinct patterns of randomization in their brain networks, with increased integration during illness progression. These findings provide valuable insights into the disruption in structural brain networks that occurs in patients with MDD and might be useful to guide future therapeutic interventions.
Background: Several studies on patients with Alzheimer's disease (AD) have used transcranial direct current stimulation (tDCS) to enhance neural excitability in the left dorsolateral prefrontal cortex (lDLPFC). Interindividual differences in brain anatomy in AD patients pose a challenge to efficiently target the lDLPFC using scalp-based coordinates, calling for new and more precise tDCS protocols. Objective: The purpose of this study was to explore how AD-related neuropathology affects the tDCS-induced electric field (EF) across different DLPFC montages using computational modeling. Method: Forty-eight realistic head models were created from structural magnetic resonance scans of AD patients and healthy controls collected from a publicly available database. We compared the tDCS-induced EF in different montages applied in the literature, in addition to a high definition (HD)-tDCS montage centered at electrode F3. Results: There was an overall global reduction in EF strength in the patient group, probably due to structural alterations that were also identified in the patient group. A widespread distribution of the EF was found across the frontal lobe for bipolar montages, while HD-tDCS yielded more focal stimulation, mainly restricted to the lDLPFC. Minor differences in the EF distribution were found when comparing the HD-tDCS montages. Conclusion: Neurodegenerative alterations present in patients with AD affect the magnitude, distribution and variability of the EF. HD-tDCS montages provide more focal stimulation of the target area, compared to bipolar montages with to pronounced group differences between AD patients and healthy matched controls. This finding poses substantial limitations to the comparison of cognitive effects of tDCS both between patients and controls and within patients at different stages of disease progression.
Functional neuroimaging offers a unique view of the link between brain activity and behavior—a relationship at the root of modern psychiatry. As a result, the application of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) to neuropsychiatric disorders began in earnest almost immediately after the technique was first described. As the complexity of the functional architecture of the brain has become more evident, attention has shifted from identifying centers of abnormal activation to characterizing abnormal networks, with increasing use being made of functional connectivity techniques [1]. The analysis of resting state networks has also flourished, partly because it may sidestep a persistent challenge in the use of BOLD-fMRI of neuropsychiatric disease: selection of a paradigm that is appropriate for the clinical features of each type of mental illness. In this chapter, recent trends in the application of functional neuroimaging to selected neuropsychiatric disorders will be illustrated.KeywordsFunctional neuroimagingBOLD fMRINeuropsychiatric disordersAutismSchizophreniaObsessive compulsive disorderMajor depressive disorderBipolar disorderPost-traumatic stress disorder
Work in computational psychiatry suggests that mood disorders may stem from aberrant reinforcement learning processes. Specifically, it has been proposed that depressed individuals believe that negative events are more informative than positive events, resulting in higher learning rates from negative outcomes (Pulcu & Browning, 2019). In this proof-of-concept study, we investigated whether transcranial direct current stimulation (tDCS) applied to dorsolateral prefrontal cortex, as commonly used in depression treatment trials, might change learning rates for affective outcomes. Healthy adults completed an established reinforcement learning task (Pulcu & Browning, 2017) in which the information content of reward and loss outcomes was manipulated by varying the volatility of stimulus-outcome associations. Learning rates on the tasks were quantified using computational models. Stimulation over dorsolateral prefrontal cortex (DLPFC) but not motor cortex (M1) increased learning rates specifically for reward outcomes. The effects of prefrontal tDCS were cognitive state-dependent: tDCS applied during task performance increased learning rates for wins; tDCS applied before task performance decreased both win and loss learning rates. A replication study confirmed the key finding that tDCS to DLPFC during task performance increased learning rates specifically for rewards. Taken together, these findings demonstrate the potential of tDCS for modulating computational parameters of reinforcement learning that are relevant to mood disorders.
Transcranial magnetic stimulation is a safe, effective, and well-tolerated intervention for depression; it is currently approved for treatment-resistant depression. This article summarizes the mechanism of action, evidence of clinical efficacy, and the clinical aspects of this intervention, including patient evaluation, stimulation parameters selection, and safety considerations. Transcranial direct current stimulation is another neuromodulation treatment for depression; although promising, the technique is not currently approved for clinical use in the United States. The final section outlines the open challenges and future directions of the field.
Objective:
The safety and efficacy of transcranial magnetic stimulation (TMS) in the acute treatment of major depressive disorder (MDD) is well established. However, it is not well understood which patient-related factors are associated with a more robust antidepressant response. Identifying predictive factors for therapeutic response to TMS treatment in depression will guide clinicians in patient selection.
Methods:
By systematic review of clinical trial data, the current study aims to identify and analyze reported patient-specific predictors of response to an acute course of TMS treatment for MDD. PubMed was searched for randomized controlled trials of TMS for patients with depression. Studies were appraised for risk of bias using components recommended by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Results:
TMS data were available from 375 studies, 18 of which were included in this review. Treatment response is inversely associated with treatment refractoriness and age.
Conclusion:
Inadequate sample size and large heterogeneity in study parameters among clinical trials limit any strong conclusions from being drawn; nonetheless, despite these limitations, there is mounting evidence, which points to age and treatment refractoriness as candidate variables for predicting clinical outcome. Implications of these findings for treatment of MDD are discussed.
Background:
Electroconvulsive therapy is effectively used for treatment-resistant depression; however, its neural mechanism is largely unknown. Resting-state functional magnetic resonance imaging is promising for monitoring outcomes of electroconvulsive therapy for depression. This study aimed to explore the imaging correlates of the electroconvulsive therapy effects on depression using Granger causality analysis and dynamic functional connectivity analyses.
Methods:
We performed advanced analyses of resting-state functional magnetic resonance imaging data at the beginning and intermediate stages and end of the therapeutic course to identify neural markers that reflect or predict the therapeutic effects of electroconvulsive therapy on depression.
Results:
We demonstrated that information flow between the functional networks analyzed by Granger causality changes during electroconvulsive therapy, and this change was correlated with the therapeutic outcome. Information flow and the dwell time (an index reflecting the temporal stability of functional connectivity) before electroconvulsive therapy are correlated with depressive symptoms during and after treatment.
Limitations:
First, the sample size was small. A larger group is needed to confirm our findings. Second, the influence of concomitant pharmacotherapy on our results was not fully addressed, although we expected it to be minimal because only minor changes in pharmacotherapy occurred during electroconvulsive therapy. Third, different scanners were used the groups, although the acquisition parameters were the same; a direct comparison between patient and healthy participant data was not possible. Thus, we presented the data of the healthy participants separately from that of the patients as a reference.
Conclusions:
These results show the specific properties of functional brain connectivity.
Three retrospective studies were conducted to examine functional brain asymmetry in the regulation of emotion. In the first study, reports of 119 cases were collected of pathological laughing and crying associated with destructive lesions. Pathological laughing was associated with predominantly right-sided damage, whereas pathological crying was associated with predominantly left-sided lesions. In the second study, 19 reports detailing mood following hemispherectomy were collected; right hemispherectomy was associated with euphoric mood change. In the third study, lateralization of epileptic foci was assessed in reports of 91 patients with ictal outbursts of laughing (gelastic epilepsy). Foci were most likely to be predominantly left-sided. The findings are congruent with studies of the effects of unilateral brain insult on mood, and a general model of hemispheric asymmetry in the regulation of emotion is presented.
We contrasted regional cerebral blood flow in matched groups of 30 patients with major depression, 30 patients with Alzheimer's disease and 30 normal controls using the 133Xe inhalation technique. Whereas both the depressed and Alzheimer's disease groups had markedly reduced global cortical blood flow, the Scaled Subprofile Model, developed to identify abnormalities in regional networks, indicated that they had distinct topographic profiles. Previous findings of an abnormal regional network in major depression were unaltered by the inclusion of Alzheimer's disease patients in the analysis. Alzheimer's disease was associated with a distinct parietotemporal deficit and the degree of this abnormality strongly covaried with cognitive impairment. Alzheimer's disease patients also had abnormal manifestation of three other regional networks. We illustrate a method for distinguishing when a disease imposes a new pattern of interactions among brain regions and when a disease alters the expression of regional patterns characteristic of normal functioning.
Transcranial magnetic stimulation (TMS) is a technology that allows for non-invasive modulation of the excitability and function of discrete brain cortical areas. TMS uses alternating magnetic fields to induce electric currents in cortical tissue. In psychiatry, TMS has been studied primarily as a potential treatment for major depression. Most studies indicate that slow-frequency repetitive TMS (rTMS) and higher frequency rTMS have antidepressant properties. A meta-analysis of controlled studies indicates that this effect is fairly robust from a statistical viewpoint. However, effect sizes are heterogeneous, and few studies have shown that rTMS results in substantial rates of clinical response or remission, and the durability of antidepressant effects is largely unknown. We review in detail rTMS studies in the treatment of depression, as well as summarize treatment studies of mania, obsessive-compulsive disorder, post-traumatic stress disorder, and schizophrenia. We also review the application of TMS in the study of the pathophysiology of psychiatric disorders and summarize studies of the safety of TMS in human subjects.
Remitted major depressive disorder is a vulnerable clinical state, suggesting persistence of an underlying disease diathesis between episodes. To investigate neural correlates of such risk and to identify potential depression trait markers, euthymic unipolar patients in remission, acutely depressed patients, and never-depressed volunteers were studied before and after transient sad mood challenge.
Common and differential changes in regional blood flow among the groups relative to the baseline state were examined with [(15)O]H(2)O positron emission tomography after provocation of sadness with autobiographical memory scripts.
Mood provocation in both depressed groups resulted in regional cerebral blood flow (rCBF) decreases in medial orbitofrontal cortex Brodmann's area 10/11, which were absent in the healthy group. In the remitted group, mood provocation produced a unique rCBF decrease in pregenual anterior cingulate 24a. The main effects in healthy subjects, an rCBF increase in subgenual cingulate Brodmann's area 25 and a decrease in right prefrontal cortex Brodmann's area 9, were not present in the depressed groups.
Mood challenge in unipolar euthymic patients in full remission unmasks an apparent depression trait marker. The pattern of acute CBF changes is distinct from that seen in euthymic healthy volunteers and mirrors the untreated depressed state seen during a major depressive episode and the pattern of change seen in depressed patients. These findings suggest that disease-specific modifications of pathways mediating transient mood changes are present in unipolar depression independent of clinical illness status. These findings have implications for understanding the vulnerability of remitted patients for illness relapse.
The ability to cognitively regulate emotional responses to aversive events is important for mental and physical health. Little is known, however, about neural bases of the cognitive control of emotion. The present study employed functional magnetic resonance imaging to examine the neural systems used to reappraise highly negative scenes in unemotional terms. Reappraisal of highly negative scenes reduced subjective experience of negative affect. Neural correlates of reappraisal were increased activation of the lateral and medial prefrontal regions and decreased activation of the amygdala and medial orbito-frontal cortex. These findings support the hypothesis that prefrontal cortex is involved in constructing reappraisal strategies that can modulate activity in multiple emotion-processing systems.
The purpose of this study was to use functional magnetic resonance imaging (fMRI) to probe the neural circuitry associated with reactivity to negative and positive affective stimuli in patients with major depressive disorder before treatment and after 2 and 8 weeks of treatment with venlafaxine. Relations between baseline neural activation and response to treatment were also evaluated.
Patients with major depressive disorder (N=12) and healthy comparison subjects (N=5) were scanned on three occasions, during which trials of alternating blocks of affective and neutral pictorial visual stimuli were presented. Symptoms were evaluated at each testing occasion, and both groups completed self-report measures of mood. Statistical parametric mapping was used to examine the fMRI data with a focus on the group-by-time interactions.
Patients showed a significant reduction in depressive symptoms with treatment. Group-by-time interactions in response to the negative versus neutral stimuli were found in the left insular cortex and the left anterior cingulate. At baseline, both groups showed bilateral activation in the visual cortices, lateral prefrontal cortex, and amygdala in response to the negative versus neutral stimuli, with patients showing greater activation in the visual cortex and less activation in the left lateral prefrontal cortex. Patients with greater relative anterior cingulate activation at baseline in response to the negative versus neutral stimuli showed the most robust treatment response.
The findings underscore the importance of the neural circuitry activated by negative affect in depression and indicate that components of this circuitry can be changed within 2 weeks of treatment with antidepressant medication.
We studied the neural activation associated with the expectancy of emotional stimuli using whole brain fMRI. Fifteen healthy subjects underwent fMRI scanning during which they performed a warned reaction task using emotional pictures carrying pleasant, unpleasant, or neutral content. The task involved an expected or unexpected condition. Data were analyzed by comparing the images acquired under the different conditions. In the expected condition, compared with the unexpected condition, significant activation was observed in the medial, inferior and dorsolateral prefrontal cortex. Whereas the expectancy of pleasant stimuli produced activation in the left dorsolateral and left medial prefrontal cortex as well as in the right cerebellum, the expectancy of unpleasant stimuli produced activation in the right inferior and right medial prefrontal cortex, the right amygdala, the left anterior cingulate cortex, and bilaterally in the visual cortex. These results suggest that the expectancy of emotional stimuli is mediated by the prefrontal area including the medial, inferior, and dorsolateral prefrontal cortex. Furthermore, our data suggest that left frontal activation is associated with the expectancy of pleasant stimuli and that right frontal activation is associated with the expectancy of unpleasant stimuli. Finally, our findings suggest that the amygdala and anterior cingulate cortex may play an important role in the expectancy of unpleasant stimuli and that the input of this negative information is modulated by these specific brain areas.
Transcranial magnetic stimulation (TMS) is a noninvasive and easily tolerated method of altering cortical physiology. The authors evaluate evidence from the last decade supporting a possible role for TMS in the treatment of depression and explore clinical and technical considerations that might bear on treatment success.
The authors review English-language controlled studies of nonconvulsive TMS therapy for depression that appeared in the MEDLINE database through early 2002, as well as one study that was in press in 2002 and was published in 2003. In addition, the authors discuss studies that have examined technical, methodological, and clinical treatment parameters of TMS.
Most data support an antidepressant effect of high-frequency repetitive TMS administered to the left prefrontal cortex. The absence of psychosis, younger age, and certain brain physiologic markers might predict treatment success. Technical parameters possibly affecting treatment success include intensity and duration of treatment, but these suggestions require systematic testing.
TMS shows promise as a novel antidepressant treatment. Systematic and large-scale studies are needed to identify patient populations most likely to benefit and treatment parameters most likely to produce success. In addition to its potential clinical role, TMS promises to provide insights into the pathophysiology of depression through research designs in which the ability of TMS to alter brain activity is coupled with functional neuroimaging.
We performed quantitative meta-analyses on 65 neuroimaging studies of emotion. In an earlier report (NeuroImage 16 (2002), 331). we examined the effects of induction method, specific emotions, and cognitive demand in emotional tasks. This paper focuses on the effects of emotional valence (positive vs negative and approach vs withdrawal) and gender on regional brain activations, with particular emphasis on hypotheses concerning lateralization of brain function in emotion. Overall, we found no support for the hypothesis of overall right-lateralization of emotional function, and limited support for valence-specific lateralization of emotional activity in frontal cortex. In addition, we found that males showed more lateralization of emotional activity, and females showed more brainstem activation in affective paradigms. The study provides evidence that lateralization of emotional activity is more complex and region-specific than predicted by previous theories of emotion and the brain.
The application of functional neuroimaging to the study of human emotion has yielded valuable data; however, the conclusions that may be drawn from any one study are limited. We applied novel statistical techniques to the meta-analysis of 106 PET and fMRI studies of human emotion and tested predictions made by key neuroscientific models. The results demonstrated partial support for asymmetry accounts. Greater left-sided activity was observed for approach emotions, whereas neural activity associated with negative/withdrawal emotions was symmetrical. Support was also found for affect program emotion accounts. The activation distributions associated with fear, disgust, and anger differed significantly. These emotions were most consistently associated in activity in regions associated with selective processing deficits when damaged: the amygdala, the insula and globus pallidus, and the lateral orbitofrontal cortex, respectively. In contrast, the distributions for happiness and sadness did not differ. These findings are considered in the context of conceptualizations of the neural correlates of human emotion.
Recently, there has been a convergence in lesion and neuroimaging data in the identification of circuits underlying positive and negative emotion in the human brain. Emphasis is placed on the prefrontal cortex (PFC) and the amygdala as two key components of this circuitry. Emotion guides action and organizes behavior towards salient goals. To accomplish this, it is essential that the organism have a means of representing affect in the absence of immediate elicitors. It is proposed that the PFC plays a crucial role in affective working memory. The ventromedial sector of the PFC is most directly involved in the representation of elementary positive and negative emotional states while the dorsolateral PFC may be involved in the representation of the goal states towards which these elementary positive and negative states are directed. The amygdala has been consistently identified as playing a crucial role in both the perception of emotional cues and the production of emotional responses, with some evidence suggesting that it is particularly involved with fear-related negative affect. Individual differences in amygdala activation are implicated in dispositional affective styles and increased reactivity to negative incentives. The ventral striatum, anterior cingulate and insular cortex also provide unique contributions to emotional processing.
New theoretical and practical concepts are presented for considerably enhancing the performance of magnetic resonance imaging (MRI) by means of arrays of multiple receiver coils. Sensitivity encoding (SENSE) is based on the fact that receiver sensitivity generally has an encoding effect complementary to Fourier preparation by linear field gradients. Thus, by using multiple receiver coils in parallel scan time in Fourier imaging can be considerably reduced. The problem of image reconstruction from sensitivity encoded data is formulated in a general fashion and solved for arbitrary coil configurations and k-space sampling patterns. Special attention is given to the currently most practical case, namely, sampling a common Cartesian grid with reduced density. For this case the feasibility of the proposed methods was verified both in vitro and in vivo. Scan time was reduced to one-half using a two-coil array in brain imaging. With an array of five coils double-oblique heart images were obtained in one-third of conventional scan time. Magn Reson Med 42:952-962, 1999.
• Three retrospective studies were conducted to examine functional brain asymmetry in the regulation of emotion. In the first study, reports of 119 cases were collected of pathological laughing and crying associated with destructive lesions. Pathological laughing was associated with predominantly right-sided damage, whereas pathological crying was associated with predominantly left-sided lesions. In the second study, 19 reports detailing mood following hemispherectomy were collected; right hemispherectomy was associated with euphoric mood change. In the third study, lateralization of epileptic foci was assessed in reports of 91 patients with ictal outbursts of laughing (gelastic epilepsy). Foci were most likely to be predominantly left-sided. The findings are congruent with studies of the effects of unilateral brain insult on mood, and a general model of hemispheric asynmetry in the regulation of emotion is presented.
Background: Anhedonia is a relative lack of pleasure in response to formerly rewarding stimuli. It is an important diagnostic feature of major depressive disorder (MDD), and predicts antidepressant efficacy. Understanding its neurobiological basis may help to target new treatments and predict treatmentoutcomes. Using a novel paradigm, we aimed to explore the correlations between anhedonia severity and magnitude of neural responses to happy and sad stimuli in regions previously implicated in studies of human reward processing and depressive anhedonia. Methods: Neural responses to happy and sad emotional stimuli (autobiographical prompts and mood congruent facial expressions) were measured using blood oxygen level dependent (BOLD) functional magnetic resonances imaging in twelve MDD individuals with varying degrees of anhedonia. Results: In response to happy stimuli, anhedonia, but not depression severity per se, was positively and negatively correlated with vantromedial prefrontal cortex (VMPFC) and amygdala/ventral striatal activity, respectively. State anxiety independently contributed to a VMPFC-subcorticol dissociation of response to happy (but not sad) stimuli, which was similar, but different, to anhedonia. Conclusions: These findings suggest that anhedonia and state anxiety are associated with dysfunction within neural systems underlying the response ti, and assessment of, the rewarding potential of emotive stimuli in MDD, and highlight the importance of employing a symptom-dimension-based approach in the examination of the neurobiology of depression.
This paper presents a general approach to the analysis of functional MRI time-series from one or more subjects. The approach is predicated on an extension of the general linear model that allows for correlations between error terms due to physiological noise or correlations that ensue after temporal smoothing. This extension uses the effective degrees of freedom associated with the error term. The effective degrees of freedom are a simple function of the number of scans and the temporal autocorrelation function. A specific form for the latter can be assumed if the data are smoothed, in time, to accentuate hemodynamic responses with a neural basis. This assumption leads to an expedient implementation of a flexible statistical framework. The importance of this small extension is that, in contradistinction to our previous approach, any parametric statistical analysis can be implemented. We demonstrate this point using a multiple regression analysis that tests for effects of interest (activations due to word generation), while taking explicit account of some obvious confounds.
By using blocked and rapid event-related functional MRI studies of memory, we explored the implications of using rest periods as a baseline condition in functional MRI studies. Activity in the medial temporal lobe (as well as in other brain regions) was substantially higher during rest than during several alternative baseline conditions. The effect of this elevated activity during rest was to reduce, eliminate, or even reverse the sign of the activity during task conditions relevant to memory functions. The results demonstrate that periods of rest are associated with significant cognitive activity and, therefore, provide a nonoptimal baseline for memory tasks. These results were observed not only when relatively long blocks of rest were used (experiment 1), but also when rest consisted of the short null trials typically used in rapid event-related designs (experiment 2). The findings have important implications for the design and interpretation of a wide range of fMRI studies of cognition.
We studied 10 patients with melancholia before and after sleep deprivation and 8 controls with Tc-99m-hexamethylpropylenamineoxime (HMPAO) single photon emission computed tomography (SPECT). All depressed subjects showed relative hypoperfusion in the left anterolateral prefrontal cortex under both conditions. Only responders showed relative hyperperfusion in parts of the limbic system and a reduction of blood flow in these regions after sleep deprivation.
The need for a simply applied quantitative assessment of handedness is discussed and some previous forms reviewed. An inventory of 20 items with a set of instructions and response- and computational-conventions is proposed and the results obtained from a young adult population numbering some 1100 individuals are reported. The separate items are examined from the point of view of sex, cultural and socio-economic factors which might appertain to them and also of their inter-relationship to each other and to the measure computed from them all. Criteria derived from these considerations are then applied to eliminate 10 of the original 20 items and the results recomputed to provide frequency-distribution and cumulative frequency functions and a revised item-analysis. The difference of incidence of handedness between the sexes is discussed.
We describe an implementation of the general linear model that facilitates the characterization of evoked hemodynamic responses to sensorimotor or cognitive processing, when the exact form of these responses is not known. The importance of this approach is that one can test for differential responses among tasks that may elude more conventional analyses. In particular, we suppose that an evoked response has early and late components and that a differential response may involve (i) both components to the same degree, as in a conventional "activation" or (ii) differential expression of the early and late components in two tasks, as might be seen in differential adaptation, or differences associated with the tasks (e.g., requiring and not requiring sustained attention). Using this approach we were able to demonstrate that the anterior cingulate differentiates, in terms of its response, between two motor tasks that did and did not require sustained attention. This differential response was observed even though there was no classical "activation" (i.e., there was no difference in the mean activity associated with the two conditions). It is suggested that these demonstration results point to the possibility of making greater use of the temporal resolution afforded by fast fMRI techniques.
Depression is one of the most common psychiatric illnesses. Its influence on brain perfusion has been demonstrated, but conflicting data exist on follow-up after drug treatment. The aim of our study was to evaluate the effects of antidepressant drugs on regional cerebral blood flow (rCBF) in patients with depression after 3 weeks and 6 months of drug therapy. Clinical criteria for depression without psychosis were met according to psychiatric evaluation. Severity of depression was evaluated with the Hamilton Depression Rating Scale (HAMD) before every scintigraphic study. rCBF was assessed using technetium-99m bicisate (Neurolite) brain single-photon emission tomography in nine patients with severe depression before the beginning of antidepressant drug therapy and 3 weeks and six months after initiation of therapy. Only patients with no change in antidepressant medication during the study were included. No antipsychotic drugs were used. Cerebellum was used as the reference region. rCBF was evaluated for eight regions in each study in three consecutive transversal slices. Follow-up studies were compared with the baseline study. The mean HAMD score was 25.5 points initially, 16 at the second examination and 8.8 after 6 months. Global CBF was decreased compared with the reference region in drug-free patients. Perfusion of left frontal and temporal regions was significantly lower (P < 0.005) in comparison with the contralateral side. After therapy, a moderate decrease in perfusion was seen in the right frontal region (P < 0.05). Perfusion decreased further after 6 months in the right frontal (P < 0.005) and temporal regions (P < 0.01). The highly significant asymmetry in perfusion between the left and right frontal and temporal lobes almost disappeared during treatment. Our findings implicate dysfunction of the frontal and temporal cortex in clinically depressed patients before specific drug treatment. Clinical improvement and decreases in HAMD score after 3 weeks and after 6 months reflect the treatment effect on mood-related rCBF changes.
Previous studies have shown that hemodynamic response overlap severely limits the maximum presentation rate with event-related functional MRI (fMRI) using fixed intertrial experimental designs. Here we demonstrate that the use of randomized experimental designs can largely overcome this limitation, thereby allowing for event-related fMRI experiments with extremely rapid presentation rates. In the first experiment, fMRI time courses were simulated using a fixed intertrial interval design with intervals of 16, 3, and 1 s, and using a randomized design having the same mean intertrial intervals. We found that using fixed intertrial interval designs the transient information decreased with decreasing intertrial intervals, whereas using randomized designs the transient information increased with decreasing mean intertrial intervals. In a second experiment, fMRI data were collected from two subjects using a randomized paradigm with visual hemifield stimuli presented randomly every 500 ms. Robust event-related activation maps and hemodynamic response estimates were obtained. These results demonstrate the feasibility of performing event-related fMRI experiments with rapid, randomized paradigms identical to those used in electrophysiological and behavioral studies, thereby expanding the applicability of event-related fMRI to a whole new range of cognitive neurosciences questions and paradigms.
When subjects direct attention to a particular location in a visual scene, responses in the visual cortex to stimuli presented at that location are enhanced, and the suppressive influences of nearby distractors are reduced. What is the top-down signal that modulates the response to an attended versus an unattended stimulus? Here, we demonstrate increased activity related to attention in the absence of visual stimulation in extrastriate cortex when subjects covertly directed attention to a peripheral location expecting the onset of visual stimuli. Frontal and parietal areas showed a stronger signal increase during this expectation than did visual areas. The increased activity in visual cortex in the absence of visual stimulation may reflect a top-down bias of neural signals in favor of the attended location, which derives from a fronto-parietal network.
Recently, there has been a convergence in lesion and neuroimaging data in the identification of circuits underlying positive and negative emotion in the human brain. Emphasis is placed on the prefrontal cortex (PFC) and the amygdala as two key components of this circuitry. Emotion guides action and organizes behavior towards salient goals. To accomplish this, it is essential that the organism have a means of representing affect in the absence of immediate elicitors. It is proposed that the PFC plays a crucial role in affective working memory. The ventromedial sector of the PFC is most directly involved in the representation of elementary positive and negative emotional states while the dorsolateral PFC may be involved in the representation of the goal states towards which these elementary positive and negative states are directed. The amygdala has been consistently identified as playing a crucial role in both the perception of emotional cues and the production of emotional responses, with some evidence suggesting that it is particularly involved with fear-related negative affect. Individual differences in amygdala activation are implicated in dispositional affective styles and increased reactivity to negative incentives. The ventral striatum, anterior cingulate and insular cortex also provide unique contributions to emotional processing.
We measured regional cerebral blood flow (rCBF) using positron emission tomography (PET) to determine which brain regions are involved in the assessment of facial emotion. We asked right-handed normal subjects to assess the signalers' emotional state based on facial gestures and to assess the facial attractiveness, as well as to discriminate the background color of the facial stimuli, and compared the activity produced by each condition. The right inferior frontal cortex showed significant activation during the assessment of facial emotion in comparison with the other two tests. The activated area was located within a triangular area of the inferior frontal cortex in the right cerebral hemisphere. These results, together with those of previous imaging and clinical studies, suggest that the right inferior frontal cortex processes emotional communicative signals that could be visual or auditory and that there is a hemispheric asymmetry in the inferior frontal cortex in relation to the processing of emotional communicative signals.
New theoretical and practical concepts are presented for considerably enhancing the performance of magnetic resonance imaging (MRI) by means of arrays of multiple receiver coils. Sensitivity encoding (SENSE) is based on the fact that receiver sensitivity generally has an encoding effect complementary to Fourier preparation by linear field gradients. Thus, by using multiple receiver coils in parallel scan time in Fourier imaging can be considerably reduced. The problem of image reconstruction from sensitivity encoded data is formulated in a general fashion and solved for arbitrary coil configurations and k-space sampling patterns. Special attention is given to the currently most practical case, namely, sampling a common Cartesian grid with reduced density. For this case the feasibility of the proposed methods was verified both in vitro and in vivo. Scan time was reduced to one-half using a two-coil array in brain imaging. With an array of five coils double-oblique heart images were obtained in one-third of conventional scan time. Magn Reson Med 42:952-962, 1999.
Neuroimaging studies of major depressive disorder (MDD) indicate interhemispheric differences in prefrontal cortical activity (right greater than left).
To investigate whether there are any interhemispheric differences of motor cortical excitability in MDD.
Eight patients with treatment-refractory MDD off medication were assessed for the severity of their depression, and transcranial magnetic stimulation studies (bilateral motor threshold and paired-pulse studies) were conducted. Eight normal controls were also studied.
MDD patients showed significant interhemispheric differences in motor threshold and paired-pulse curves, both of which showed lower excitability on the left hemisphere. Such differences were absent in controls.
Our findings may aid the further understanding of the neurophysiology underlying MDD.
Psychophysical and physiological studies have shown that attending to a
stimulus can enhance its sensory processing. Functional imaging studies now
reveal that attention can also modulate activity in sensory brain areas before
stimulus onset, when the observer prepares to attend to an anticipated stimulus.
These preparatory `baseline shifts' in brain activity pose many new questions,
and potentially offer new insights into the neural basis of perceptual awareness.
The aims of this study were to: (1) assess the effects of repetitive transcranial magnetic stimulation (rTMS) on brain activity in depressed patients as measured by single photon emission tomography (SPECT); (2) evaluate the predictive value of brain SPECT on the antidepressant efficacy of rTMS. Patients (n=17) received 1600 rTMS stimuli at a rate of 10 Hz, 5 days per week for 2 weeks to the left dorsolateral prefrontal cortex. Whole brain SPECT data were acquired using Tc99m-Bicisate. Regional cerebral blood flow (rCBF) was correlated with the % change in the 28-item Hamilton Depression Rating Scale Score (Delta-HDRS) and a semiquantitative region of interest (ROI) analysis was conducted. Prior to rTMS there was a significant left-right asymmetry favoring the right, whereas 2 weeks after the rTMS treatment this asymmetry was reversed. The rCBF in limbic structures was negatively correlated with the outcome and rCBF in several neocortical areas was positively correlated. Brain SPECT can provide information about mechanisms of action of rTMS and may have predictive value for the antidepressant efficacy of rTMS.