Response inhibition related neural oscillatory patterns show reliable early identification of bipolar from unipolar depression in a Go/No-Go task.

BACKGROUND: Response inhibition is a key neurocognitive factor contributing to impulsivity in mood disorders. Here, we explored the common and differential alterations of neural circuits associated with response inhibition in bipolar disorder (BD) and unipolar disorder (UD) and whether the oscillatory signatures can be used as early biomarkers in BD. METHODS: 39 patients with BD, 36 patients with UD, 29 patients initially diagnosed with UD who later underwent diagnostic conversion to BD, and 36 healthy controls performed a Go/No-Go task during MEG scanning. We carried out time-frequency and connectivity analysis on MEG data. Further, we performed machine learning using oscillatory features as input to identify bipolar from unipolar depression at the early clinical stage. RESULTS: Compared to healthy controls, patients had reduced rIFG-to-pre-SMA connectivity and delayed activity of rIFG. Among patients, lower beta power and higher peak frequency were observed in BD patients than in UD patients. These changes enabled accurate classification between BD and UD with an accuracy of approximately 80 %. CONCLUSIONS: The inefficiency of the prefrontal control network is a shared mechanism in mood disorders, while the abnormal activity of rIFG is more specific to BD. Neuronal responses during response inhibition could serve as a diagnostic biomarker for BD in early stage.

Attenuated post-movement beta rebound reflects psychomotor alterations in major depressive disorder during a simple visuomotor task: a MEG study.

BACKGROUND: Psychomotor alterations are a common symptom in patients with major depressive disorder (MDD). The primary motor cortex (M1) plays a vital role in the mechanism of psychomotor alterations. Post-movement beta rebound (PMBR) in the sensorimotor cortex is abnormal in patients with motor abnormalities. However, the changes in M1 beta rebound in patients with MDD remain unclear. This study aimed to primarily explore the relationship between psychomotor alterations and PMBR in MDD. METHODS: One hundred thirty-two subjects were enrolled in the study, comprising 65 healthy controls (HCs) and 67 MDD patients. All participants performed a simple right-hand visuomotor task during MEG scanning. PMBR was measured in the left M1 at the source reconstruction level with the time-frequency analysis method. Retardation factor scores and neurocognitive test performance, including the Digit Symbol Substitution Test (DSST), the Making Test Part A (TMT-A), and the Verbal Fluency Test (VFT), were used to measure psychomotor functions. Pearson correlation analyses were used to assess relationships between PMBR and psychomotor alterations in MDD. RESULTS: The MDD group showed worse neurocognitive performance than the HC group in all three neurocognitive tests. The PMBR was diminished in patients with MDD compared to HCs. In a group of MDD patients, the reduced PMBR was negatively correlated with retardation factor scores. Further, there was a positive correlation between the PMBR and DSST scores. PMBR is negatively associated with the TMT-A scores. CONCLUSION: Our findings suggested that the attenuated PMBR in M1 could illustrate the psychomotor disturbance in MDD, possibly contributing to clinical psychomotor symptoms and deficits of cognitive functions.

Spontaneous beta power, motor-related beta power and cortical thickness in major depressive disorder with psychomotor disturbance.

INTRODUCTION: The psychomotor disturbance is a common symptom in patients with major depressive disorder (MDD). The neurological mechanisms of psychomotor disturbance are intricate, involving alterations in the structure and function of motor-related regions. However, the relationship among changes in the spontaneous activity, motor-related activity, local cortical thickness, and psychomotor function remains unclear. METHOD: A total of 140 patients with MDD and 68 healthy controls performed a simple right-hand visuomotor task during magnetoencephalography (MEG) scanning. All patients were divided into two groups according to the presence of psychomotor slowing. Spontaneous beta power, movement-related beta desynchronization (MRBD), absolute beta power during movement and cortical characteristics in the bilateral primary motor cortex were compared using general linear models with the group as a fixed effect and age as a covariate. Finally, the moderated mediation model was tested to examine the relationship between brain metrics with group differences and psychomotor performance. RESULTS: The patients with psychomotor slowing showed higher spontaneous beta power, movement-related beta desynchronization and absolute beta power during movement than patients without psychomotor slowing. Compared with the other two groups, significant decreases were found in cortical thickness of the left primary motor cortex in patients with psychomotor slowing. Our moderated mediation model showed that the increased spontaneous beta power indirectly affected impaired psychomotor performance by abnormal MRBD, and the indirect effects were moderated by cortical thickness. CONCLUSION: These results suggest that patients with MDD have aberrant cortical beta activity at rest and during movement, combined with abnormal cortical thickness, contributing to the psychomotor disturbance observed in this patient population.

Convergent and divergent cognitive impairment of unipolar and bipolar depression: A magnetoencephalography resting-state study.

BACKGROUND: Unipolar depression (UD) and bipolar depression (BD) showed convergent and divergent cognitive impairments. Neural oscillations are linked to the foundational cognitive processes. We aimed to investigate the underpinning spectral neuronal power patterns by magnetoencephalography (MEG), which combinates high spatial and temporal resolution. We hypothesized that patients with UD and BD exhibit common and distinct patterns, which may contribute to their cognitive impairments. METHODS: Group cognitive tests were performed. Eyes closed resting-state MEG data were collected from 61 UD, 55 BD, and 52 healthy controls (HC). Nonparametric cluster-based permutation tests were performed to deal with the multiple comparison problem on channel-frequency MEG data. Correlation analysis of cognitive dysfunction scores and MEG oscillation were conducted by Spearman or partial correlation analysis. RESULTS: Wisconsin Card Sorting Test showed similar cognitive impairment in patients with UD and BD. Moreover, patients with BD exhibited extensive cognitive deficits in verbal executive functions and visuospatial processing. Compare to HC, both patients with UD and BD showed increased frontal-central beta power while high gamma power was decreased in UD groups during the resting-state. The significant correlations between cognitive function and average beta power were observed. CONCLUSIONS: Patients with BD had more cognitive impairments on different dimensions than those with UD, involving disrupted beta power modulations. Our investigation provides a better understanding of the neuroelectrophysiological process underlying cognitive impairments in patients with UD and BD.

The Correlation Between Thyroid Function, Frontal Gray Matter, and Executive Function in Patients With Major Depressive Disorder.

The present study was aimed to investigate the relationships between serum thyroid hormones (THs), frontal gray matter volume, and executive function in selected patients with major depressive disorder (MDD). One hundred and four MDD patients and seventy-five healthy controls (HCs) were subjected to thyroid-stimulating hormone (TSH), free Triiodothyronine (fT3), free Thyroxine (fT4), and executive function tests and underwent structural magnetic resonance imaging (MRI). Voxel-based morphometry (VBM) analysis was performed to compare group differences in the gray matter for the frontal lobe. Furthermore, mediation analysis was used to investigate whether gray matter volumes of the frontal gyrus mediated the relationship between serum THs and executive function in MDD patients. MDD patients exhibited significant gray matter volume reduction in several brain regions, including the left rectus, right middle frontal cortex, and left middle frontal cortex. Serum TSH levels are positively associated with altered regional gray matter volume patterns within MFG and executive function. Importantly, gray matter in the right MFG was a significant mediator between serum TSH levels and executive function. These findings expand our understanding of how thyroid function affects brain structure changes and executive function in MDD patients.

Sex differences in the association between symptom profiles and cognitive functioning in patients with depressive disorder.

OBJECTIVE: Depressive disorder (DD) is a heterogeneous disease with sex differences in symptom profiles and cognitive performance. However, sex differences in cognitive dysfunction associated with different symptom profiles have received little systematic study. This study aimed to explore the association between clinical symptoms and cognitive deficits in patients with DD. METHODS: A cohort of 222 hospitalized patients with DD (males/females = 114/108) and 173 healthy controls (males/females = 80/93) were enrolled. Cognitive function was measured using a comprehensive neuropsychological battery. Depression was assessed using the 17-item Hamilton Rating Scale for Depression (HAMD-17). According to different genders, the relationship between symptom profiles and cognitive deficits was identified using partial correlation analysis and multiple regression analysis. RESULTS: Patients with DD performed significantly worse than healthy controls in all cognitive domains investigated (all p < 0.05). Remarkably, female patients scored better than male patients on information processing speed (p < 0.05). Multivariate regression analyses showed that the retardation factor score was independently associated with attention and cognitive flexibility, and the sleep disturbance factor score was independently associated with information processing speed in male patients. Furthermore, the anxiety/somatization factor score was independently associated with working memory in female patients. CONCLUSION: In the present study, we showed that significant sex differences in the association between symptom profiles and cognitive impairment are present in DD patients. Understanding how DD patients' clinical features and cognitive performance are linked from a sex perspective may have clinical implications for predicting and interfering with the outcome of depression.

Connectivity of the Frontal Cortical Oscillatory Dynamics Underlying Inhibitory Control During a Go/No-Go Task as a Predictive Biomarker in Major Depression.

BACKGROUND: Major depressive disorder (MDD) is characterized by core functional deficits in cognitive inhibition, which is crucial for emotion regulation. To assess the response to ruminative and negative mood states, it was hypothesized that MDD patients have prolonged disparities in the oscillatory dynamics of the frontal cortical regions across the life course of the disease. METHOD: A "go/no-go" response inhibition paradigm was tested in 31 MDD patients and 19 age-matched healthy controls after magnetoencephalography (MEG) scanning. The use of minimum norm estimates (MNE) examined the changes of inhibitory control network which included the right inferior frontal gyrus (rIFG), pre-supplementary motor area (preSMA), and left primary motor cortex (lM1). The power spectrum (PS) within each node and the functional connectivity (FC) between nodes were compared between two groups. Furthermore, Pearson correlation was calculated to estimate the relationship between altered FC and clinical features. RESULT: PS was significantly reduced in left motor and preSMA of MDD patients in both beta (13-30 Hz) and low gamma (30-50 Hz) bands. Compared to the HC group, the MDD group demonstrated higher connectivity between lM1 and preSMA in the beta band (t = 3.214, p = 0.002, FDR corrected) and showed reduced connectivity between preSMA and rIFG in the low gamma band (t = -2.612, p = 0.012, FDR corrected). The FC between lM1 and preSMA in the beta band was positively correlated with illness duration (r = 0.475, p = 0.005, FDR corrected), while the FC between preSMA and rIFG in the low gamma band was negatively correlated with illness duration (r = -0.509, p = 0.002, FDR corrected) and retardation factor scores (r = -0.288, p = 0.022, uncorrected). CONCLUSION: In this study, a clinical neurophysiological signature of cognitive inhibition leading to sustained negative affect as well as functional non-recovery in MDD patients is highlighted. Duration of illness (DI) plays a key role in negative emotional processing, heighten rumination, impulsivity, and disinhibition.

Autonomic Nervous System Is Related to Inhibitory and Control Function Through Functional Inter-Region Connectivities of OFC in Major Depression.

OBJECTIVE: To investigate the mechanism of interactions between autonomic nervous system (ANS) and cognitive function in Major depression (MD) with Magnetoencephalography (MEG) measurements. METHODS: Participants with MD (n = 20), and Health controls (HCs, n = 18) were completed MEG measurements during the performance of a go/no-go task. Heart rate variability (HRV) indices (SDANN, and RMSSD) were derived from the raw MEG data. The correlation analysis of the HRV and functional connectivities in different brain regions was conducted by Pearson's r in two groups. RESULTS: The go/no-go task performances of HCs were better than MD patients; HRV indices were lower in the MD group. Under the no-go task, a brain MEG functional connectivity analysis based on the seed regions of the orbitofrontal cortex (OFC) displayed increased functional inter-region connectivity networks of OFC in MD group. HRV indices were correlated with different functional inter-region connectivity networks of OFC in two groups, respectively. CONCLUSION: ANS is related to inhibitory and control function through functional inter-region connectivity networks of OFC in MD. These findings have important implications for the understanding pathophysiology of MD, and MEG may provide an image-guided tool for interventions.

Decreased Task-Related HRV Is Associated With Inhibitory Dysfunction Through Functional Inter-Region Connectivity of PFC in Major Depressive Disorder.

The regulation of the autonomic nervous system (ANS) can improve cognitive function in major depressive disorders (MDD). Heart rate variability (HRV) derives from the dynamic control of the ANS and reflects the balance between the activities of the sympathetic and parasympathetic nervous systems by measuring tiny changes in adjacent heart beats. Task-related HRV may reflect the association between the flexibility of cognition and ANS function. The study was to investigate the neural mechanism of interactions between ANS and cognitive function in MDD with Magnetoencephalography (MEG) measurements. Participants included 20 MDD patients and 18 healthy controls (HCs). All participants were measured with a go/no-go task MEG. HRV indices, the standard deviation of the average normal-to-normal (NN) interval calculated over short periods (SDANN) and the square root of the mean squared differences of successive NN intervals (RMSSD), were derived from the raw MEG data. Results showed that MDD patients showed decreased SDANN and RMSSD. In MDD patients, both resting-state and task-related RMSSD were related to inhibitory and control dysfunction. In the go/no-go task, many areas in the prefrontal cortex (PFC) are responsible for an individual's inhibitory function. A brain MEG functional connectivity analysis revealed that there were significant differences in four brain regions within the prefrontal cortex (PFC) between MDD patients and HCs. Task-related RMSSD in HCs were related to the functional connectivity between the left middle frontal gyrus and the anterior cingulate cortex (ACC), while in MDD patients, these values were not related to the above functional connectivity but were related to the functional connectivity between the left middle frontal gyrus and insula. However, the resting-state RMSSD value was not related to these significant difference functional connectivity networks in all participants. It concludes that the decreased task-related HRV is associated with inhibitory dysfunction through functional inter-region connectivity in the PFC in MDD, and the task-related HRV can be used as an index of the association between MDD and autonomic dysregulation.

Multichannel matching pursuit of MEG signals for discriminative oscillation pattern detection in depression.

Magnetoencephalography (MEG) power topography may be useful for obtaining discriminative brain activity patterns that can distinguish depressed patients from healthy control subjects at the individual level. However, the application is still limited due to the lack of adequate analysis strategies to remove artifacts from the MEG signals. In this study, the multichannel matching pursuit (MMP) method was designed; in this technique, a linear decomposition method that provides components by iteratively reanalysing a residual signal after removing previously found components,. Forty-four subjects, half depressed patients and half healthy subjects, were recruited for MEG scanning whilst watching a video of sad faces. MMP was implemented to manage multichannel, multi-trial MEG signals. The representative post-MMP analysis signals were utilised to calculate the power topography over the whole brain and designed as inputs for a Support Vector Machine (SVM) classifier. A statistically significant discriminative accuracy of 86% (p=0.002) after a permutation test was achieved. Comparing the system classification performance to that of the ensemble averaging method and the established Independent Component Analysis (ICA), we demonstrated the ability of MMP to represent critical MEG information and, in turn, to mark the abnormality of oscillatory activities under negative stimuli using images of sad faces.

Ni-to-Ni+ 3-ethylene-bridged partially modified retro-inverso tetrapeptide beta-turn mimetic: design, synthesis, and structural characterization.

A 10-membered heterocyclic ring system 1,3,8-trisubstituted 2,5,7-trioxo-1,4,8-triazadecane that represents a Ni-to-Ni+ 3-ethylene-bridged partially modified retro-inverso tetrapeptide beta-turn mimetic (EBRIT-BTM) has been designed, synthesized, and structurally analyzed. These compounds utilize an ethylene bridge to replace the COi...HNi + 3 10-membered hydrogen bond of standard beta-turns. The N,N'-ethylene-bridged dimer was obtained in 90% yield by reductive alkylation of phenylalanylamide with a tert-butyl N-(9-fluorenylmethyloxycarbonyl),N-(2-formylmethyl)-glycinate. An orthogonal protection strategy and HATU-mediated couplings allowed efficient stepwise additions of monomeric building blocks leading to a N(i)-to-N(i+3)-ethylene-bridged linear precursor: Further elaboration of the linear precursor generated the ethylene-bridged model compounds (16) and (18) (g, gem-diaminoalkyl; m, malonyl; and r, direction-reversed amino acid residue) in 44 and 39% yields, respectively. The structural features of the two EBRIT-BTM compounds were determined using 1H NMR and extensive computer simulations. The results indicate that the 10-membered rings are conformationally constrained with well-defined structural features and that the three amide bonds in the ring are in the trans orientation. The topological arrangement of the residues in the ring system closely resembles a type II' beta-turn. Transformation of CONH(2) in the N-terminal amino acid residue of 16 into NHCOCH3 in 18 resulted in the formation of a hydrogen bond between the NH of gPhe-COCH3 and the C-terminal carboxyl of Gly, initiating an antiparallel beta-sheet. The formulation of the concept applying a minimalistic structural elaboration approach and the synthetic exploration, together with the conformational analysis, offer a new molecular scaffolding system and a true tetrapeptide secondary structure mimetic that can be used to generate peptidomimetics of biological interest.

Homologs of 1,2,5-hexahydro-3-one-1H-1,4-diazepine (DAP) as novel dipeptidomimetics and molecular scaffolds: efficient preparation of synthons.

Structurally constraint dipeptidomimetics represent an important class of conformationally rigid dipeptide surrogates and molecular scaffolds, which are frequently employed in peptide-based structure-activity relationships (SAR) and construction of combinatorial libraries. We report on the design of an improved and general synthetic procedure to prepare synthons related to the trisubstituted 1,2,5-hexahydro-3-one-1H-1,4-diazepines [DAP(Xxx)(alpha7)] (DAP: 1,2,5-hexahydro-3-one-1H-1,4-diazepine; DAP(Xxx)(alpha7): the homologous series of DAP in which alpha refers to the location of the chiral carbon in the i(th) amino acid, Xxx represents the three letter notation for the i-1 amino acids, and 7 denotes the number of atoms in the ring) and their higher homologs [DAP(Xxx)(alphaN)] [Xxx = Phe, Asp(beta-OcHex) (cHex: cyclohexyl), and Arg(N(G)-Tos] (Tos: p-toluenesulfonyl); N = 8-10]. These dipetidomimetic structures are generated by reductive alkylation-mediated Calpha(i)-to-N(i-1) bridging between a Calpha (i)-(CH(2))(i-1)(n)-COSEt (n = 1-4) and H(2)N-C(i-1)HR-CO(2)Fm (Fm: 9-fluorenylmethyl) followed by H(2)N(i)-to-C(i-1)-CO(2)H lactam formation. We also describe the preparation of blocked N-Ac-[DAP(Phe)(alphaN)]-CONMe(2) (N = 8-10), which serve as model systems for detailed conformational analysis reported in the accompanying article.

Structural characterization of a cyclic dipeptidomimetic: the effect of ring size on a 1,2,5-trisubstituted-3-oxo-1,4-diazepine system.

A series of dipeptidomimetics derived from C(alpha)(i)-to-N(i-1) side chain-to-backbone amide cyclization of adjacent amino acids are structurally characterized. The resulting ring systems are either 1,2,5-trisubstituted-3-oxo-1,4-diazepine (DAP) structurally related to benzodiazepines, commonly used in drug candidates and therapeutic agents, or higher homologs of it. Here, we examine the structural consequences of enlarging the ring size from seven members to eight-, nine-, and ten-membered rings. The structural features determined by high-resolution NMR methods, relying largely on homo- and heteronuclear coupling constants, indicate that variation of the ring leads to alternative conformations and topological orientations of the attached chemical moieties or functional groups. Controlling the topological display of the ring substituents required for biological action, using a molecular scaffold made up entirely of functional groups found in peptides, should facilitate the rational, stepwise transformation of peptide lead candidate into a nonpeptidic drug candidate.

A Novel, One-Pot Reductive Alkylation of Amines by S-Ethyl Thioesters Mediated by Triethylsilane and Sodium Triacetoxyborohydride in the Presence of Palladium on Carbon.

The reductive alkylation of primary amines with aldehydes or ketones is an important tool in the synthesis of wide variety of amines. We described here a novel, one-pot reductive alkylation method using multifunctional S-ethyl thioesters as a source for in situ generation of aldehydes to alkylate a range of multifunctional primary amines. The corresponding multifunctional secondary amines were obtained in good to excellent yields (mostly >90%). This one-pot reductive alkylation included the treatment of a mixture of protected S-ethyl thioester, primary amine, 10% Pd/C, and sodium triacetoxyborohydride in N,N-dimethylformamide with triethylsilane for 30 min at temperature lower than 20 degrees C. This method has special merit when the aldehyde is not stable enough to allow isolation and therefore does not lend itself to a stepwise strategy of reductive alkylation. This was the case with tert-butyl 1(S)-[(9-fluorenylmethoxycarbonyl)amino]-4-oxobutyrate (10) which could not be obtained from the alpha-tert-butyl gamma-S-ethyl (S)-N-(9-fluorenylmethoxycarbonyl) thioglutamate (9). However, by our one-pot reductive alkylating method, treatment of 9-fluorenemethyl phenylalaninate (6a) with 9 afforded tert-butyl 2(S)-[(9-fluorenylmethoxycarbonyl)amino]-4-[[3-phenyl-1(S)-(9-fluorenylmethoxycarbonyl)propyl]amino]butyrate (11) in 76% yield. Furthermore, the acid labile tert-butyloxycarbonyl, and the hydogenation labile benzyloxycarbonyl and benzyl protecting groups, were stable in the one-pot reductive alkylation reaction. While the conjugated double bond is stable in these reaction conditions, the monosubstituted C-C double bond, as in the allyl protecting group in alpha-allyl beta-cyclohexyl aspartate, was reduced to the corresponding propyl ester.