Proceedings of the 11th Annual Deep Brain Stimulation Think Tank: pushing the forefront of neuromodulation with functional network mapping, biomarkers for adaptive DBS, bioethical dilemmas, AI-guided neuromodulation, and translational advancements.

The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9-11, 2023 in Gainesville, Florida with the theme of "Pushing the Forefront of Neuromodulation". The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers, and researchers (from industry and academia) can freely discuss current and emerging DBS technologies, as well as logistical and ethical issues facing the field. The group estimated that globally more than 263,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: cutting-edge translational neuromodulation, cutting-edge physiology, advances in neuromodulation from Europe and Asia, neuroethical dilemmas, artificial intelligence and computational modeling, time scales in DBS for mood disorders, and advances in future neuromodulation devices.

Cortical paired associative stimulation shows impaired plasticity of inhibition networks as a function of chronic alcohol use.

BACKGROUND: Response inhibition - or the ability to withhold a suboptimal response - relies on the efficacy of fronto-striatal networks, and is impaired in neuropsychiatric disorders including addiction. Cortical paired associative stimulation (cPAS) is a form of transcranial magnetic stimulation (TMS) which can strengthen neuronal connections via spike-timing-dependent plasticity mechanisms. Here, we used cPAS targeting the fronto-striatal inhibitory network to modulate performance on a response inhibition measure in chronic alcohol use. METHODS: Fifty-five participants (20 patients with a formal alcohol use disorder (AUD) diagnosis (26-74 years, 6[30%] females) and 20 matched healthy controls (HCs) (27-73 years, 6[30%] females) within a larger sample of 35 HCs (23-84 years, 11[31.4%] females) underwent two randomized sessions of cPAS 1-week apart: right inferior frontal cortex stimulation preceding right presupplementary motor area stimulation by either 4 ms (excitation condition) or 100 ms (control condition), and were subsequently administered the Stop Signal Task (SST) in both sessions. RESULTS: HCs showed decreased stop signal reaction time in the excitation condition (t(19) = -3.01, p = 0.007, [CIs]:-35.6 to -6.42); this facilitatory effect was not observed for AUD (F(1,31) = 9.57, p = 0.004, CIs: -68.64 to -14.11). Individually, rates of SST improvement were substantially higher for healthy (72%) relative to AUD (13.6%) groups (OR: 2.33, p = 0.006, CIs:-3.34 to -0.55). CONCLUSION: In line with previous findings, cPAS improved response inhibition in healthy adults by strengthening the fronto-striatal network through putative long-term potentiation-like plasticity mechanisms. Furthermore, we identified a possible marker of impaired cortical excitability, and, thus, diminished capacity for cPAS-induced neuroplasticity in AUD with direct implications to a disorder-relevant cognitive process.

Developing digital interventions for a post-Covid world: A smartphone-based approach-avoidance training to reduce alcohol craving.

Harmful alcohol use is a major public health issue. In-person treatment has been hindered by the restrictions necessary during the Covid-19 pandemic. This study examined the effects of an at-home smartphone-based cognitive bias modification training in heavy drinkers. Experiment 1 tested the effect of a short 20-30-min smartphone-based approach-avoidance training (AAT) on image-induced craving at a 1-day follow-up. Sixty-two participants consuming 14+ units of alcohol/week were allocated to either the training or waitlist group. Experiment 2 used an updated version of the same short AAT intervention with a sample of n = 107 participants who consumed 20+ units of alcohol/week. Training effects at 1-week follow-up were compared to an active control group. Experiment 1 showed a significant reduction in image-induced craving for the training group at 1-day follow-up. Experiment 2 found that AUDIT weekly scores were significantly reduced at 1-week follow-up for the training group, all the while craving for soft drinks remained unchanged. Experiment 1 served as a first proof of concept for the efficacy of the new smartphone-based AAT training, and experiment 2 suggested that training effects on problem alcohol use hold at 1-week follow-up.

Methadone maintenance treatment and impulsivity: premature responding.

INTRODUCTION: Previous research showed that methadone maintenance treatment (MMT) is linked to impulsivity, with higher impulsivity levels being associated with for example, increased drug use. One aspect of impulsivity, most commonly studied in rodent research, is premature responding, the failure to wait for a starting signal. Premature responding is of high translational significance since it predicts the development of addiction-like behaviors in rodents. METHODS: We assessed 45 MMT patients and 46 demographically matched (age, sex, education, and handedness) healthy volunteers (HVs) on premature responding alongside action and inhibition of instructed and intentional trials using the Intentional Hand Task (IHT). RESULTS: The results showed markedly enhanced premature responses in the MMT vs. the HV group, which correlated positively with methadone dosage in the MMT patients. Throughout the task, MMT patients were faster across all trial parts and less accurate in response to instructed trials compared to HVs. CONCLUSIONS: The increase in premature motor reactions during variable waiting periods alongside increased motion speed and lower accuracy might reflect a specific motor inhibition deficit in MMT, a subcomponent of impulsivity not previously assessed in MMT. Incorporating an experimentally defined measure of impulsivity, such as premature responding, into existing test batteries used by clinicians might enable more tailored treatments addressing the increased impulsivity levels and associated dysfunctional behaviors in MMT.

Subacute alpha frequency (10Hz) subthalamic stimulation for emotional processing in Parkinson's disease.

BACKGROUND: Psychiatric comorbidities are common in Parkinson's disease (PD) and may change with high-frequency stimulation targeting the subthalamic nucleus. Numerous accounts indicate subthalamic alpha-frequency oscillation is implicated in emotional processing. While intermittent alpha-frequency (10Hz) stimulation induces positive emotional effects, with more ventromedial contacts inducing larger effects, little is known about the subacute effect of ventral 10Hz subthalamic stimulation on emotional processing. OBJECTIVE/HYPOTHESIS: To evaluate the subacute effect of 10Hz stimulation at bilateral ventral subthalamic nucleus on emotional processing in PD patients using an affective task, compared to that of clinical-frequency stimulation and off-stimulation. METHODS: Twenty PD patients with bilateral subthalamic deep brain stimulation for more than six months were tested with the affective task under three stimulation conditions (10Hz, 130Hz, and off-stimulation) in a double-blinded randomized design. RESULTS: While 130Hz stimulation reduced arousal ratings in all patients, 10Hz stimulation increased arousal selectively in patients with higher depression scores. Furthermore, 10Hz stimulation induced a positive shift in valence rating to negative emotional stimuli in patients with lower apathy scores, and 130Hz stimulation led to more positive valence to emotional stimuli in the patients with higher apathy scores. Notably, we found correlational relationships between stimulation site and affective rating: arousal ratings increase with stimulation from anterior to posterior site, and positive valence ratings increase with stimulation from dorsal to ventral site of the ventral subthalamic nucleus. CONCLUSIONS: Our findings highlight the distinctive role of 10Hz stimulation on subjective emotional experience and unveil the spatial organization of the stimulation effect.

Time-locked acute alpha-frequency stimulation of subthalamic nuclei during the evaluation of emotional stimuli and its effect on power modulation.

Introduction: Deep brain stimulation (DBS) studies in Parkinson's Disease (PD) targeting the subthalamic nucleus (STN) have characterized its spectral properties across cognitive processes. In emotional evaluation tasks, specific alpha frequency (8-12 Hz) event-related de-synchronization (ERD) (reduced power) has been demonstrated. The time-locked stimulation of STN relative to stimuli onset has shown subjective positive valence shifts with 10 Hz but not with 130 Hz. However, neurophysiological effects of stimulation on power modulation have not been investigated. We aim to investigate effects of acute stimulation of the right STN on concurrent power modulation in the contralateral STN and frontal scalp EEG. From our previous study, we had a strong a priori hypothesis that negative imagery without stimulation would be associated with alpha ERD; negative imagery with 130 Hz stimulation would be also associated with alpha ERD given the lack of its effect on subjective valence ratings; negative imagery with 10 Hz stimulation was to be associated with enhanced alpha power given the shift in behavioral valence ratings. Methods: Twenty-four subjects with STN DBS underwent emotional picture-viewing tasks comprising neutral and negative pictures. In a subset of these subjects, the negative images were associated with time-locked acute stimulation at either 10 or 130 Hz. Power of signals was estimated relative to the baseline and subjected to non-parametric statistical testing. Results: As hypothesized, in 130 Hz stimulation condition, we show a decrease in alpha power to negative vs. neutral images irrespective of stimulation. In contrast, this alpha power decrease was no longer evident in the negative 10 Hz stimulation condition consistent with a predicted increase in alpha power. Greater beta power in the 10 Hz stimulation condition along with correlations between beta power across the 10 Hz stimulation and unstimulated conditions suggest physiological and cognitive generalization effects. Conclusion: Acute alpha-specific frequency stimulation presumably was associated with a loss of this expected decrease or desynchronization in alpha power to negative images suggesting the capacity to facilitate the synchronization of alpha and enhance power. Acute time-locked stimulation has the potential to provide causal insights into the spectral frequencies and temporal dynamics of emotional processing.

Evidence Accumulation and Neural Correlates of Uncertainty in Obsessive-Compulsive Disorder.

BACKGROUND: Decision making is frequently associated with risk taking under uncertainty. Elevated intolerance of uncertainty is suggested to be a critical feature of obsessive-compulsive disorder (OCD). However, impairments of latent constructs of uncertainty processing and its neural correlates remain unclear in OCD. METHODS: In 83 participants (24 OCD patients treated with capsulotomy, 28 OCD control participants, and 31 healthy control participants), we performed magnetic resonance imaging using a card gambling task in which participants made decisions whether to bet or not that the next card would be larger than the current one. A hierarchical drift diffusion model was used to dissociate speed and amount of evidence accumulated before a decisional threshold (i.e., betting or no betting) was reached. RESULTS: High uncertainty was characterized by a smaller amount of evidence accumulation (lower thresholds), thus dissociating uncertainty from conflict tasks and highlighting the specificity of this task to test value-based uncertainty. OCD patients exhibited greater caution with poor performance and greater evidence accumulation overall along with slower speed of accumulation, particularly under low uncertainty. Bilateral dorsal anterior cingulate and anterior insula distinguished high- and low-uncertainty decision processes in healthy control participants but not in the OCD groups, indicating impairments in anticipation of differences in outcome variance and salience network activity. There were no behavioral or imaging differences relating to capsulotomy despite improvements in OCD symptoms. CONCLUSIONS: Our findings highlight greater impairments particularly in more certain trials in the OCD groups along with impaired neural differentiation of high and low uncertainty and suggest uncertainty processing as a trait cognitive endophenotype rather than a state-specific factor.

Neural fingerprints of gambling disorder using diffusion tensor imaging.

Gambling disorder (GD) is a behavioral addiction associated with personal, social and occupational consequences. Thus, examining GD's clinical relationship with its neural substrates is critical. We compared neural fingerprints using diffusion tensor imaging (DTI) in GD subjects undergoing treatment relative to healthy volunteers (HV). Fifty-three (25 GD, 28 age-matched HV) males were scanned with structural magnetic resonance imaging (MRI) and DTI. We applied probabilistic tractography based on DTI scanning data, preprocessed and analyzed using permutation testing of individual connectivity weights between regions for group comparison. Permutation-based comparisons between group-averaged connectomes highlighted significant structural differences. The GD group demonstrated increased connectivity, and striatal network reorganisation, contrasted by reduced connectivity within and to frontal lobe nodes. Modularity analysis revealed that the GD group had fewer hubs integrating information across the brain. We highlight GD neural changes involved in controlling risk-seeking behaviors. The observed striatal restructuring converges with previous research, and the increased connectivity affects subnetworks highly active in gambling situations, although these findings are not significant when correcting for multiple comparisons. Modularity analysis underlines that, despite connectivity increases, the GD connectome loses hubs, impeding its neuronal network coherence. Together, these results demonstrate the feasibility of using whole-brain computational modeling in assessing GD.

Mechanisms underlying capsulotomy for refractory obsessive-compulsive disorder: neural correlates of negative affect processing overlap with deep brain stimulation targets.

Ablative procedures such as anterior capsulotomy are potentially effective in refractory obsessive-compulsive disorder (OCD). Converging evidence suggests the ventral internal capsule white matter tracts traversing the rostral cingulate and ventrolateral prefrontal cortex and thalamus is the optimal target for clinical efficacy across multiple deep brain stimulation targets for OCD. Here we ask which prefrontal regions and underlying cognitive processes might be implicated in the effects of capsulotomy by using both task fMRI and neuropsychological tests assessing OCD-relevant cognitive mechanisms known to map across prefrontal regions connected to the tracts targeted in capsulotomy. We tested OCD patients at least 6 months post-capsulotomy (n = 27), OCD controls (n = 33) and healthy controls (n = 34). We used a modified aversive monetary incentive delay paradigm with negative imagery and a within session extinction trial. Post-capsulotomy OCD subjects showed improved OCD symptoms, disability and quality of life with no differences in mood or anxiety or cognitive task performance on executive, inhibition, memory and learning tasks. Task fMRI revealed post-capsulotomy decreases in the nucleus accumbens during negative anticipation, and in the left rostral cingulate and left inferior frontal cortex during negative feedback. Post-capsulotomy patients showed attenuated accumbens-rostral cingulate functional connectivity. Rostral cingulate activity mediated capsulotomy improvement on obsessions. These regions overlap with optimal white matter tracts observed across multiple stimulation targets for OCD and might provide insights into further optimizing neuromodulation approaches. Our findings also suggest that aversive processing theoretical mechanisms may link ablative, stimulation and psychological interventions.

Functional neurological disorder is a feminist issue.

Functional neurological disorder (FND) is a common and disabling disorder, often misunderstood by clinicians. Although viewed sceptically by some, FND is a diagnosis that can be made accurately, based on positive clinical signs, with clinical features that have remained stable for over 100 years. Despite some progress in the last decade, people with FND continue to suffer subtle and overt forms of discrimination by clinicians, researchers and the public. There is abundant evidence that disorders perceived as primarily affecting women are neglected in healthcare and medical research, and the course of FND mirrors this neglect. We outline the reasons why FND is a feminist issue, incorporating historical and contemporary clinical, research and social perspectives. We call for parity for FND in medical education, research and clinical service development so that people affected by FND can receive the care they need.

Serotonergic and dopaminergic control of impulsivity in gambling disorder.

Gambling disorder (GD) is major public health issue. The disorder is often characterized by elevated impulsivity with evidence from analogous substance use disorders underlining prominent roles of brain monoamines in addiction susceptibility and outcome. Critically, GD allows the study of addiction mechanisms without the confounder of the effects of chronic substances. Here, we assessed the roles of striatal dopamine transporter binding and extrastriatal serotonin transporter binding in GD as a function of impulsivity using [123 I]FP-CIT SPECT imaging in 20 older adults with GD (DSM-5 criteria; mean age 64 years) and 40 non-GD age- and sex-matched controls. We focused on GD in older individuals because there are prominent age-related changes in neurotransmitter function and because there are no reported neuroimaging studies of GD in older adults. Volume-of-interest-based and voxelwise analyses were performed. GD patients scored clearly higher on impulsivity and had higher tracer binding in the ventromedial prefrontal cortex than controls (p < 0.001), likely reflecting serotonin transporter activity. The binding in the medial prefrontal cortex positively correlated with impulsivity over the whole sample (r = 0.62, p < 0.001) as well as separately in GD patients (r = 0.46, p = 0.04) and controls (r = 0.52, p < 0.001). Striatal tracer binding, reflecting dopamine transporter activity was also positively correlated with impulsivity but showed no group differences. These findings highlight the role of prefrontal serotonergic function in GD and impulsivity. They identify cerebral coordinates of a potential target for neuromodulation for both GD and high impulsivity, a core phenotypic dimensional cognitive marker in addictions.

Risk and aversion coding in human habenula high gamma activity.

Neurons in the primate lateral habenula fire in response to punishments and are inhibited by rewards. Through its modulation of midbrain monoaminergic activity, the habenula is believed to play an important role in adaptive behavioural responses to punishment and underlie depressive symptoms and their alleviation with ketamine. However, its role in value-based decision-making in humans is poorly understood due to limitations with non-invasive imaging methods which measure metabolic, not neural, activity with poor temporal resolution. Here, we overcome these limitations to more closely bridge the gap between species by recording local field potentials directly from the habenula in 12 human patients receiving deep brain stimulation treatment for bipolar disorder (n = 4), chronic pain (n = 3), depression (n = 3) and schizophrenia (n = 2). This allowed us to record neural activity during value-based decision-making tasks involving monetary rewards and losses. High-frequency gamma (60-240 Hz) activity, a proxy for population-level spiking involved in cognitive computations, increased during the receipt of loss and decreased during receipt of reward. Furthermore, habenula high gamma also encoded risk during decision-making, being larger in amplitude for high compared to low risk. For both risk and aversion, differences between conditions peaked approximately between 400 and 750 ms after stimulus onset. The findings not only demonstrate homologies with the primate habenula but also extend its role to human decision-making, showing its temporal dynamics and suggesting revisions to current models. The findings suggest that habenula high gamma could be used to optimize real-time closed-loop deep brain stimulation treatment for mood disturbances and impulsivity in psychiatric disorders.

Structural and functional correlates of the response to deep brain stimulation at ventral capsule/ventral striatum region for treatment-resistant depression.

BACKGROUND: Though deep brain stimulation (DBS) shows increasing potential in treatment-resistant depression (TRD), the underlying neural mechanisms remain unclear. Here, we investigated functional and structural connectivities related to and predictive of clinical effectiveness of DBS at ventral capsule/ventral striatum region for TRD. METHODS: Stimulation effects of 71 stimulation settings in 10 TRD patients were assessed. The electric fields were estimated and combined with normative functional and structural connectomes to identify connections as well as fibre tracts beneficial for outcome. We calculated stimulation-dependent optimal connectivity and constructed models to predict outcome. Leave-one-out cross-validation was used to validate the prediction value. RESULTS: Successful prediction of antidepressant effectiveness in out-of-sample patients was achieved by the optimal connectivity profiles constructed with both the functional connectivity (R=0.49 at p<10-4; deviated by 14.4±10.9% from actual, p<0.001) and structural connectivity (R=0.51 at p<10-5; deviated by 15.2±11.5% from actual, p<10-5). Frontothalamic pathways and cortical projections were delineated for optimal clinical outcome. Similarity estimates between optimal connectivity profile from one modality (functional/structural) and individual brain connectivity in the other modality (structural/functional) significantly cross-predicted the outcome of DBS. The optimal structural and functional connectivity mainly converged at the ventral and dorsal lateral prefrontal cortex and orbitofrontal cortex. CONCLUSIONS: Connectivity profiles and fibre tracts following frontothalamic streamlines appear to predict outcome of DBS for TRD. The findings shed light on the neural pathways in depression and may be used to guide both presurgical planning and postsurgical programming after further validation.

Frequency dependent emotion differentiation and directional coupling in amygdala, orbitofrontal and medial prefrontal cortex network with intracranial recordings.

The amygdala, orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) form a crucial part of the emotion circuit, yet their emotion induced responses and interactions have been poorly investigated with direct intracranial recordings. Such high-fidelity signals can uncover precise spectral dynamics and frequency differences in valence processing allowing novel insights on neuromodulation. Here, leveraging the unique spatio-temporal advantages of intracranial electroencephalography (iEEG) from a cohort of 35 patients with intractable epilepsy (with 71 contacts in amygdala, 31 in OFC and 43 in mPFC), we assessed the spectral dynamics and interactions between the amygdala, OFC and mPFC during an emotional picture viewing task. Task induced activity showed greater broadband gamma activity in the negative condition compared to positive condition in all the three regions. Similarly, beta activity was increased in the negative condition in the amygdala and OFC while decreased in mPFC. Furthermore, beta activity of amygdala showed significant negative association with valence ratings. Critically, model-based computational analyses revealed unidirectional connectivity from mPFC to the amygdala and bidirectional communication between OFC-amygdala and OFC-mPFC. Our findings provide direct neurophysiological evidence for a much-posited model of top-down influence of mPFC over amygdala and a bidirectional influence between OFC and the amygdala. Altogether, in a relatively large sample size with human intracranial neuronal recordings, we highlight valence-dependent spectral dynamics and dyadic coupling within the amygdala-mPFC-OFC network with implications for potential targeted neuromodulation in emotion processing.

High frequency of Depressive Disorders and Suicidal Phenomena in Late-Stage Parkinson´s Disease - A Cross-Sectional Study.

BACKGROUND: Depressive disorders (DD) are widely recognized as one of the most frequent neuropsychiatric disorders in Parkinson´s disease. Patients with late-stage Parkinson´s disease (LSPD) continue to be a neglected population, and little is known about DD frequency in LSPD. OBJECTIVES: To determine the frequency of DD in LSPD patients through a clinical diagnostic interview (CDI) and according to diagnostic DSM- 5 criteria. Secondary objectives were to determine the predictive ability of depressive scales to detect DD, to identify potential predictors of DD in LSPD and, to evaluate suicidal phenomena in LSPD. METHODS: A cross-sectional study including LSPD patients (≥7 years from symptom onset and Hoehn and Yahr scale score >3 or a Schwab and England scale score <50% in the ON condition) was conducted. Patients were subjected to psychiatric, neurological, and neuropsychological evaluations. Six depression scales were applied. RESULTS: 92 LSPD patients were included. 59.78% of LSPD patients had a current diagnosis of DD according to CDI, 38.04% patients had a diagnosis of major depressive disorder, and 21.72% non-major depressive disorder. Suicidal ideation was present in 36.96% of patients. All applied scales were able to detect depressive disorders. CONCLUSIONS: More than half of LSPD patients met DD diagnostic criteria and over one-third were diagnosed with major depressive disorder. Overall, the LSPD population seem to have a unique clinical phenotype regarding the frequency and features of DD, whose early identification and treatment could improve the quality of life of patients and caregivers.

Subthalamic Oscillatory Activity of Reward and Loss Processing Using the Monetary Incentive Delay Task in Parkinson Disease.

BACKGROUND: The subthalamic nucleus (STN) is an effective deep brain stimulation target for Parkinson disease (PD) and obsessive-compulsive disorder and has been implicated in reward and motivational processing. In this study, we assessed the STN and prefrontal oscillatory dynamics in the anticipation and receipt of reward and loss using a task commonly used in imaging. MATERIALS AND METHODS: We recorded intracranial left subthalamic local field potentials from deep brain stimulation electrodes and prefrontal scalp electroencephalography in 17 patients with PD while they performed a monetary incentive delay task. RESULTS: During the expectation phase, enhanced left STN delta-theta activity was observed in both reward and loss vs neutral anticipation, with greater STN delta-theta activity associated with greater motivation specifically to reward. In the consummatory outcome phase, greater left STN delta activity was associated with a rewarding vs neutral outcome, particularly with more ventral contacts along with greater delta-theta coherence with the prefrontal cortex. We highlight a differential activity in the left STN to loss vs reward anticipation, demonstrating a distinct STN high gamma activity. Patients with addiction-like behaviors show lower left STN delta-theta activity to loss vs neutral outcomes, emphasizing impaired sensitivity to negative outcomes. CONCLUSIONS: Together, our findings highlight a role for the left STN in reward and loss processing and a potential role in addictive behaviors. These findings emphasize the cognitive-limbic function of the STN and its role as a physiologic target for neuropsychiatric disorders.

Effects of Bilateral Subthalamic Nucleus Stimulation on Depressive Symptoms and Cerebral Glucose Metabolism in Parkinson's Disease: A 18F-Fluorodeoxyglucose Positron Emission Tomography/Computerized Tomography Study.

Subthalamic nucleus (STN) deep brain stimulation (DBS) can improve motor symptoms in Parkinson's disease (PD), as well as potentially improving otherwise intractable comorbid depressive symptoms. To address the latter issue, we evaluated the severity of depressive symptoms along with the severity of motor symptoms in 18 PD patients (mean age, 58.4 ± 5.4 years; 9 males, 9 females; mean PD duration, 9.4 ± 4.4 years) with treatment-resistant depression (TRD) before and after approximately 1 year of STN-DBS treatment. Moreover, to gain more insight into the brain mechanism mediating the therapeutic action of STN-DBS, we utilized 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) to assess cerebral regional glucose metabolism in the patients at baseline and 1-year follow-up. Additionally, the baseline PET data from patients were compared with PET data from an age- and sex-matched control group of 16 healthy volunteers. Among them, 12 PD patients underwent post-operative follow-up PET scans. Results showed that the severity of both motor and depressive symptoms in patients with PD-TRD was reduced significantly at 1-year follow-up. Also, patients used significantly less antiparkinsonian medications and antidepressants at 1-year follow-up, as well as experiencing improved daily functioning and a better quality of life. Moreover, relative to the PET data from healthy controls, PD-TRD patients displayed widespread abnormalities in cerebral regional glucose metabolism before STN-DBS treatment, which were partially recovered at 1-year follow-up. Additionally, significant correlations were observed between the patients' improvements in depressive symptoms following STN-DBS and post-operative changes in glucose metabolism in brain regions implicated in emotion regulation. These results support the view that STN-DBS provides a promising treatment option for managing both motor and depressive symptoms in patients who suffer from PD with TRD. However, the results should be interpreted with caution due to the observational nature of the study, small sample size, and relatively short follow-up.

Frequency of Depressive Disorders in Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Depressive disorders are recognized as a common neuropsychiatric disorder of Parkinson's disease (PD). Reported frequencies vary widely among studies and depend on the diagnostic criteria, the methods of ascertainment used, and the population sampled. OBJECTIVE: We aimed to evaluate the frequency of depressive disorders in PD and to investigate the relationship with PD clinical variables. METHODS: A systematic review and meta-analysis of observational studies (community-based, prospective and retrospective cohort, case-control, and cross-sectional studies) reporting the frequency of depressive disorders in PD patients. RESULTS: Electronic database search wielded 3,536 articles; an additional 91 were identified through citation chaining. 163 full-text articles were assessed for eligibility. Of these, 49 met the inclusion criteria for our analysis. The pooled frequency of depressive disorders was 30.7% (95% confidence interval [CI] 25.6 to 36.2; I2 = 95%; 49 studies; combined n = 10,039). The pooled frequency of major depressive disorder was 14.0% (95% CI 10.5 to 18.5; I2 = 88%; 23 studies; combined n = 5,218). Subgroup/meta-regression analyses were conducted to investigate the relationship between frequency and study inclusion criteria, methodology used for diagnosis, and study design. We found a statistically significant correlation between study design and depressive disorders frequency (ranging from 8% in the community-based study to 44% in the retrospective studies) and a statistically significant positive correlation between mean baseline PD duration and major depressive disorder frequency. CONCLUSION: The current meta-analysis found a global frequency of depressive disorders of 30.7% and major depressive disorder of 14.0%. Study design influenced the frequency of depressive disorders in PD. Mean baseline PD duration and major depressive disorder frequency were positively correlated.

Mesial Prefrontal Cortex and Alcohol Misuse: Dissociating Cross-sectional and Longitudinal Relationships in UK Biobank.

BACKGROUND: Alcohol misuse is a major global public health issue. The disorder is characterized by aberrant neural networks interacting with environment and genetics. Dissecting the neural substrates and functional networks that relate to longitudinal changes in alcohol use from those that relate to alcohol misuse cross-sectionally is important to elucidate therapeutic approaches. METHODS: To assess how neuroimaging data, including T1, resting-state functional magnetic resonance imaging, and diffusion-weighted imaging, relate to alcohol misuse cross-sectionally and longitudinally in the UK Biobank, this study analyzed range of alcohol misuse in a population-based normative sample of 24,784 participants, ages 45 to 81 years old, in a cross-sectional analysis and a sample of 3070 participants in a longitudinal analysis 2 years later. RESULTS: Cross-sectional analysis showed that alcohol use is associated with a reduction in dorsal anterior cingulate cortex and dorsomedial prefrontal cortex gray matter concentration and functional resting-state connectivity (nodal degree: t24,422 = -12.99, p < 1 × 10-17). Reduced dorsal anterior cingulate cortex/dorsomedial prefrontal cortex functional connections to the ventrolateral prefrontal cortex, amygdala, and striatum relate to greater alcohol use. In a longitudinal analysis, higher resting-state nodal degree (t3036 = -3.27, p = .0011) and T1 gray matter concentration in the ventromedial prefrontal cortex relate to reduced alcohol intake frequency 2 years later. Higher ventromedial prefrontal cortex and frontoparietal executive network functional connectivity is associated with lower subsequent drinking longitudinally. CONCLUSIONS: Dorsal versus ventromedial prefrontal regions are differentially related to alcohol misuse cross-sectionally or longitudinally in a large UK Biobank normative dataset. Our study provides a comprehensive understanding of the neurobiological substrates of alcohol use as a state or prospectively, thereby providing potential targets for clinical treatment.