Exploratory genome-wide analyses of cortical inhibition, facilitation, and plasticity in late-life depression.

Late-life depression (LLD) is a heterogenous mood disorder influenced by genetic factors. Cortical physiological processes such as cortical inhibition, facilitation, and plasticity may be markers of illness that are more strongly associated with genetic factors than the clinical phenotype. Thus, exploring the relationship between genetic factors and these physiological processes may help to characterize the biological mechanisms underlying LLD and improve diagnosis and treatment selection. Transcranial magnetic stimulation (TMS) combined with electromyography was used to measure short interval intracortical inhibition (SICI), cortical silent period (CSP), intracortical facilitation (ICF), and paired associative stimulation (PAS) in 79 participants with LLD. We used exploratory genome-wide association and gene-based analyses to assess for genetic correlations of these TMS measures. MARK4 (which encodes microtubule affinity-regulating kinase 4) and PPP1R37 (which encodes protein phosphatase 1 regulatory subunit 37) showed genome-wide significant association with SICI. EGFLAM (which encodes EGF-like fibronectin type III and laminin G domain) showed genome-wide significant association with CSP. No genes met genome-wide significant association with ICF or PAS. We observed genetic influences on cortical inhibition in older adults with LLD. Replication with larger sample sizes, exploration of clinical phenotype subgroups, and functional analysis of relevant genotypes is warranted to better characterize genetic influences on cortical physiology in LLD. This work is needed to determine whether cortical inhibition may serve as a biomarker to improve diagnostic precision and guide treatment selection in LLD.

Identifying Neurophysiological Markers of Intermittent Theta Burst Stimulation in Treatment-Resistant Depression Using Transcranial Magnetic Stimulation-Electroencephalography.

BACKGROUND: Intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex is effective for treatment-resistant depression, but the effects of iTBS on neurophysiological markers remain unclear. Here, we indexed transcranial magnetic stimulation-electroencephalography (TMS-EEG) markers, specifically, the N45 and N100 amplitudes, at baseline and post-iTBS, comparing separated and contiguous iTBS schedules. TMS-EEG markers were also compared between iTBS responders and nonresponders. METHODS: TMS-EEG was analyzed from a triple-blind 1:1 randomized trial for treatment-resistant depression, comparing a separated (54-minute interval) and contiguous (0-minute interval) schedule of 2 × 600-pulse iTBS for 30 treatments. Participants underwent TMS-EEG over the left dorsolateral prefrontal cortex at baseline and posttreatment. One hundred fourteen participants had usable TMS-EEG at baseline, and 98 at posttreatment. TMS-evoked potential components (N45, N100) were examined via global mean field analysis. RESULTS: The N100 amplitude decreased from baseline to posttreatment, regardless of the treatment group (F1,106 = 5.20, p = .02). There were no changes in N45 amplitude in either treatment group. In responders, the N100 amplitude decreased after iTBS (F1,102 = 11.30, p = .001, pcorrected = .0004). Responders showed higher posttreatment N45 amplitude than nonresponders (F1,94 = 4.11, p = .045, pcorrected = .016). Higher baseline N100 amplitude predicted lower post-iTBS depression scores (F4,106 = 6.28, p = .00014). CONCLUSIONS: These results provide further evidence for an association between the neurophysiological effects of iTBS and treatment efficacy in treatment-resistant depression. Future studies are needed to test the predictive potential for clinical applications of TMS-EEG markers.

Low-Dose Augmentation With Buprenorphine for Treatment-Resistant Depression: A Multisite Randomized Controlled Trial With Multimodal Assessment of Target Engagement.

Background: The experimental therapeutics approach that combines a placebo-controlled clinical trial with translational neuroscience methods can provide a better understanding of both the clinical and physiological effects of pharmacotherapy. We aimed to test the efficacy and tolerability of low-dose augmentation with buprenorphine (BPN) for treatment-resistant depression, combined with multimodal assessment of target engagement. Methods: In this multisite randomized clinical trial, 85 participants ≥50 years of age with a major depressive episode that had not responded to venlafaxine extended release were randomized to augmentation with BPN or placebo for 8 weeks. The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale. In addition, three linked experiments were conducted to test target engagement: 1) functional magnetic resonance imaging using the monetary incentive delay task, 2) brain positron emission tomography of healthy participants using a novel kappa opioid receptor antagonist tracer [11C]LY2795050, and 3) transcranial magnetic stimulation measure of cortical transmission after daily BPN administration. Results: The mean ± SD dosage of BPN was 0.59 ± 0.33 mg/day. There were no significant differences between the BPN and placebo groups in Montgomery-Åsberg Depression Rating Scale changes over time or adverse effects. BPN administration had minimal effects on functional magnetic resonance imaging blood oxygen level-dependent responses in regions involved in reward anticipation and response, no significant displacement of kappa opioid receptor radioligand in positron emission tomography imaging, and no significant changes in transcranial magnetic stimulation measures of inhibitory and excitatory cortical transmission. Conclusions: Our findings suggest a lack of clinical effect of low-dose BPN augmentation and lack of target engagement with this dosage and physiological probes.

Transcranial Magnetic Stimulation Indices of Cortical Excitability Enhance the Prediction of Response to Pharmacotherapy in Late-Life Depression.

BACKGROUND: Older adults with late-life depression (LLD) often experience incomplete or lack of response to first-line pharmacotherapy. The treatment of LLD could be improved using objective biological measures to predict response. Transcranial magnetic stimulation (TMS) can be used to measure cortical excitability, inhibition, and plasticity, which have been implicated in LLD pathophysiology and associated with brain stimulation treatment outcomes in younger adults with depression. TMS measures have not yet been investigated as predictors of treatment outcomes in LLD or pharmacotherapy outcomes in adults of any age with depression. METHODS: We assessed whether pretreatment single-pulse and paired-pulse TMS measures, combined with clinical and demographic measures, predict venlafaxine treatment response in 76 outpatients with LLD. We compared the predictive performance of machine learning models including or excluding TMS predictors. RESULTS: Two single-pulse TMS measures predicted venlafaxine response: cortical excitability (neuronal membrane excitability) and the variability of cortical excitability (dynamic fluctuations in excitability levels). In cross-validation, models using a combination of these TMS predictors, clinical markers of treatment resistance, and age classified patients with 73% ± 11% balanced accuracy (average correct classification rate of responders and nonresponders; permutation testing, p < .005); these models significantly outperformed (corrected t test, p = .025) models using clinical and demographic predictors alone (60% ± 10% balanced accuracy). CONCLUSIONS: These preliminary findings suggest that single-pulse TMS measures of cortical excitability may be useful predictors of response to pharmacotherapy in LLD. Future studies are needed to confirm these findings and determine whether combining TMS predictors with other biomarkers further improves the accuracy of predicting LLD treatment outcome.

Cortical inhibition, facilitation and plasticity in late-life depression: effects of venlafaxine pharmacotherapy.

BACKGROUND: Late-life depression is often associated with non-response or relapse following conventional antidepressant treatment. The pathophysiology of late-life depression likely involves a complex interplay between aging and depression, and may include abnormalities in cortical inhibition and plasticity. However, the extent to which these cortical processes are modifiable by antidepressant pharmacotherapy is unknown. METHODS: Sixty-eight patients with late-life depression received 12 weeks of treatment with open-label venlafaxine, a serotonin-norepinephrine reuptake inhibitor (≤ 300 mg/d). We combined transcranial magnetic stimulation of the left motor cortex with electromyography recordings from the right hand to measure cortical inhibition using contralateral cortical silent period and paired-pulse short-interval intracortical inhibition paradigms; cortical facilitation using a paired-pulse intracortical facilitation paradigm; and short-term cortical plasticity using a paired associative stimulation paradigm. All measures were collected at baseline, 1 week into treatment (n = 23) and after approximately 12 weeks of treatment. RESULTS: Venlafaxine did not significantly alter cortical inhibition, facilitation or plasticity after 1 or 12 weeks of treatment. Improvements in depressive symptoms during treatment were not associated with changes in cortical physiology. LIMITATIONS: The results presented here are specific to the motor cortex. Future work should investigate whether these findings extend to cortical areas more closely associated with depression, such as the dorsolateral prefrontal cortex. CONCLUSION: These findings suggest that antidepressant treatment with venlafaxine does not exert meaningful changes in motor cortical inhibition or plasticity in late-life depression. The absence of changes in motor cortical physiology, alongside improvements in depressive symptoms, suggests that age-related changes may play a role in previously identified abnormalities in motor cortical processes in latelife depression, and that venlafaxine treatment does not target these abnormalities.

Dopaminergic Plasticity in the Bilateral Hippocampus Following Threat Reversal in Humans.

When a cue no longer predicts a threat, a diminished ability to extinguish or reverse this association is thought to increase risk for stress-related disorders. Despite the clear clinical relevance, the mediating neurochemical mechanisms of threat reversal have received relatively little study. One neurotransmitter implicated in rodent research of changing associations with threat is dopamine. To study whether dopamine is involved in threat reversal in humans, we used high-resolution positron emission tomography (PET) coupled with 18F-fallypride. Twelve healthy volunteers (6 F/6 M) underwent three PET scans: (i) at baseline, (ii) following threat conditioning (the response to a cue associated with electric wrist shock), and (iii) following threat reversal (the response to the same cue now associated with safety). We observed moderate evidence of reduced dopamine D2/3 receptor availability, consistent with greater dopamine release, in the bilateral anterior hippocampus following threat reversal, in response to a safety cue that was previously associated with threat, as compared to both baseline and during exposure to the same cue prior to threat reversal. These findings offer the first preliminary evidence that the response to a previously threatening cue that has since become associated with safety involves dopaminergic neurotransmission within the hippocampus in healthy humans.

An inverse relationship between cortical plasticity and cognitive inhibition in late-life depression.

Executive dysfunction is a common and disabling component of late-life depression (LLD), yet its neural mechanisms remain unclear. In particular, it is not yet known how executive functioning in LLD relates to measures of cortical physiology that may change with age and illness, namely cortical inhibition/excitation and plasticity. Here, we used transcranial magnetic stimulation (TMS) to measure cortical inhibition/excitation (n = 51), and the potentiation of cortical activity following paired associative stimulation, which is thought to reflect long-term potentiation (LTP)-like cortical plasticity (n = 32). We assessed the correlation between these measures of cortical physiology and two measures of executive functioning: cognitive inhibition, assessed using the Delis-Kaplan Executive Function System Color-Word Interference ["Stroop"] Test, and cognitive flexibility, assessed using the Trail Making Test. Correlations with recall memory and processing speed were also performed to assess the specificity of any associations to executive functioning. A significant correlation was found between greater LTP-like cortical plasticity and poorer cognitive inhibition, a core executive function (rp = -0.56, p < 0.001). We did not observe significant associations between cortical inhibition/excitation and executive functioning, or between any neurophysiological measure and cognitive flexibility, memory, or processing speed. Our finding that elevated cortical plasticity is associated with diminished cognitive inhibition emphasizes the importance of balanced synaptic strengthening to healthy cognition. More specifically, our findings suggest that hyper-excitability of cortical circuits following repeated cortical activation may promote inappropriate prepotent responses in LLD. LTP-like cortical plasticity might therefore represent a neural mechanism underlying an inhibitory control cognitive endophenotype of LLD.

Why Is Aging a Risk Factor for Cognitive Impairment in Parkinson's Disease?-A Resting State fMRI Study.

Using resting-state functional MRI (rsfMRI) data of younger and older healthy volunteers and patients with Parkinson's disease (PD) with and without mild cognitive impairment (MCI) and applying two different analytic approaches, we investigated the effects of age, pathology, and cognition on brain connectivity. When comparing rsfMRI connectivity strength of PD patients and older healthy volunteers, reduction between multiple brain regions in PD patients with MCI (PD-MCI) compared with PD patients without MCI (PD-non-MCI) was observed. This group difference was not affected by the number and location of clusters but was reduced when age was included as a covariate. Next, we applied a graph-theory method with a cost-threshold approach to the rsfMRI data from patients with PD with and without MCI as well as groups of younger and older healthy volunteers. We observed decreased hub function (measured by degree and betweenness centrality) mainly in the medial prefrontal cortex (mPFC) in older healthy volunteers compared with younger healthy volunteers. We also found increased hub function in the posterior medial structure (precuneus and the cingulate cortex) in PD-non-MCI patients compared with older healthy volunteers and PD-MCI patients. Hub function in these posterior medial structures was positively correlated with cognitive function in all PD patients. Together these data suggest that overlapping patterns of hub modifications could mediate the effect of age as a risk factor for cognitive decline in PD, including age-related reduction of hub function in the mPFC, and recruitment availability of the posterior medial structure, possibly to compensate for impaired basal ganglia function.

Assessment of neuroplasticity in late-life depression with transcranial magnetic stimulation.

BACKGROUND: Studies using Transcranial Magnetic Stimulation (TMS), a non-invasive method of brain stimulation, have implicated impaired neuroplasticity in the pathophysiology of depression in younger adults. The role of neuroplasticity in late-life depression (LLD) has not yet been explored using TMS. OBJECTIVE: This study aimed at evaluating motor cortical neuroplasticity using paired associative stimulation (PAS). Single-pulse TMS was used to induce motor-evoked potentials (MEP) in the contralateral hand muscle before and after PAS. The potentiation of MEP amplitudes after PAS was used as an indirect index of associative plasticity and long-term potentiation (LTP) (i.e. PAS-LTP). RESULTS: 48 older adults with depression and 34 age-matched healthy controls (HC) were compared. PAS- LTP was successfully induced in 68.8% of older adults with depression and 47.1% of HC. At the group level, older adults with depression failed to show statistically significant induction of neuroplasticity, which was observed in HC. However, no significant differences were observed between the two groups for PAS-LTP. CONCLUSION: Our results suggest that associative plasticity does not differ substantially between older adults with depression and age-matched HC. Continued research is needed to more comprehensively understand the role of neuroplasticity in the pathophysiology of LLD.

Reduced GABAergic cortical inhibition in aging and depression.

The neurobiology underlying depression in older adults is less extensively evaluated than in younger adults, despite the putative influence of aging on depression neuropathology. Studies using transcranial magnetic stimulation (TMS), a neurophysiological tool capable of probing inhibitory and excitatory cortical neurotransmission, have identified dysfunctional GABAergic inhibitory activity in younger adults with depression. However, GABAergic and glutamatergic cortical neurotransmission have not yet been studied in late-life depression (LLD). Here, we used single- and paired-pulse TMS to measure cortical inhibition and excitation in 92 LLD patients and 41 age-matched healthy controls. To differentiate the influence of age and depression, we also compared these TMS indices to those of 30 younger depressed adults and 30 age- and sex-matched younger healthy adults. LLD patients, older healthy adults, and younger depressed adults demonstrated significantly lower GABAA receptor-mediated cortical inhibition than younger healthy controls. By contrast, no significant differences in cortical inhibition were observed between older adults with and without depression. No significant differences in GABAB receptor-mediated inhibition or cortical excitation were found between the groups. Altogether, these findings suggest that reduced cortical inhibition may be associated with both advancing age and depression, which (i) supports the model of depression as a disease of accelerated aging, and (ii) prompts future investigation into diminished GABAergic neurotransmission in late-life as a biological predisposing factor to the development of depression. Given that cortical neurophysiology was similar in depressed and healthy older adults, future prospective studies need to establish the relative influence of age and depression on cortical inhibition deficits.

Brain serotonin synthesis capacity in obsessive-compulsive disorder: effects of cognitive behavioral therapy and sertraline.

Cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) are both effective treatments for some patients with obsessive-compulsive disorder (OCD), yet little is known about the neurochemical changes related to these treatment modalities. Here, we used positron emission tomography and the α-[11C]methyl-L-tryptophan tracer to examine the changes in brain regional serotonin synthesis capacity in OCD patients following treatment with CBT or SSRI treatment. Sixteen medication-free OCD patients were randomly assigned to 12 weeks of either CBT or sertraline treatment. Pre-to-post treatment changes in the α-[11C]methyl-L-tryptophan brain trapping constant, K* (ml/g/min), were assessed as a function of symptom response, and correlations with symptom improvement were examined. Responders/partial responders to treatment did not show significant changes in relative regional tracer uptake; rather, in responders/partial responders, 12 weeks of treatment led to serotonin synthesis capacity increases that were brain-wide. Irrespective of treatment modality, baseline serotonin synthesis capacity in the raphe nuclei correlated positively with clinical improvement. These observations suggest that, for some patients, successful remediation of OCD symptoms might be associated with greater serotonergic tone.

Posterior dopamine D2/3 receptors and brain network functional connectivity.

Recent studies suggest that dopaminergic tone influences resting state activity in multiple brain networks. Although dopamine receptors and transporters have been identified in the posteromedial and parietal cortices, which are linked to functional networks such as the default mode network (DMN), the relationship between dopamine receptor distribution in these posterior regions and resting-state connectivity has yet to be explored. Here, we used a multi-modal neuroimaging strategy, combining resting-state functional magnetic resonance imaging (rsfMRI) and [18 F]-fallypride high-resolution positron emission tomography (PET), to examine the association between within-network functional connectivity and the dopamine D2/3 receptor distribution in the posterior portion of the brain in 13 healthy adults. Our results indicate that the posterior distribution of D2/3 receptors coincides primarily with the posterior portion of the DMN. Furthermore, in the posterior portion of the brain, the level of [18 F]-fallypride binding in the posteromedial cortex correlated positively with the functional connectivity strength of the DMN and sensorimotor network, and negatively with the functional connectivity strength of the dorsal attention network, the salience network, and a network that included the anterior part of the temporo-parietal junction. On the basis of these findings, we propose that posterior brain dopamine influences the configuration of the posterior DMN and several other functional brain networks. The posterior distribution of D2/3 receptors binding (hot colour spectrum) coincides with the functional connectivity of the posterior portion of the default mode network (green colour spectrum). The mean BPND in a posteromedial cortex and the mean ICA-Z score in the precuneus showed significant positive correlation.

A longitudinal study of stress-induced hippocampal volume changes in mice that are susceptible or resilient to chronic social defeat.

Hippocampal shrinkage is a commonly found neuroanatomical change in stress-related mood disorders such as depression and post-traumatic stress disorders (PTSD). Since the onset and severity of these disorders have been found to be closely related to stressful life events, and as stress alone has been shown to reduce hippocampal volume in animal studies, vulnerability to mood disorders may be related to a susceptibility to stress-induced hippocampal shrinkage. However, a smaller hippocampal volume before stress exposure has also been suggested to confer vulnerability of stressed individuals to PTSD or depression. In this study, we examined the contribution of either innate hippocampal volume differences or hippocampal susceptibility to stress-induced shrinkage to the formation of stress-related psychopathology using longitudinal MRI measurements of hippocampal volume in inbred C57 mice before and after chronic social defeat stress. We found that only half of the stressed C57 mice were susceptible to stress and developed psychopathological behaviors such as social avoidance. The other half was resilient to stress and exhibited no social avoidance. Before exposure to stress, we observed a positive correlation between hippocampal volume and social avoidance. After chronic social defeat stress, we found significant increases in left hippocampal volume in resilient and nonstressed control mice. Intriguingly, this increase in hippocampal volume was not found in susceptible mice, suggesting an arrestment of hippocampal growth in these mice. Our findings suggest that both a susceptibility to stress-induced hippocampal volume changes and a larger hippocampus before stress exposure confer vulnerability to psychopathology after chronic stress.