Invasive neurophysiology and whole brain connectomics for neural decoding in patients with brain implants.

Brain computer interfaces (BCI) provide unprecedented spatiotemporal precision that will enable significant expansion in how numerous brain disorders are treated. Decoding dynamic patient states from brain signals with machine learning is required to leverage this precision, but a standardized framework for identifying and advancing novel clinical BCI approaches does not exist. Here, we developed a platform that integrates brain signal decoding with connectomics and demonstrate its utility across 123 hours of invasively recorded brain data from 73 neurosurgical patients treated for movement disorders, depression and epilepsy. First, we introduce connectomics-informed movement decoders that generalize across cohorts with Parkinson's disease and epilepsy from the US, Europe and China. Next, we reveal network targets for emotion decoding in left prefrontal and cingulate circuits in DBS patients with major depression. Finally, we showcase opportunities to improve seizure detection in responsive neurostimulation for epilepsy. Our platform provides rapid, high-accuracy decoding for precision medicine approaches that can dynamically adapt neuromodulation therapies in response to the individual needs of patients.

Faster speed of onset of the depressive episode is associated with lower cytokine serum levels (IL-2, -4, -6, -10, TNF-α and IFN-γ) in patients with major depression.

INTRODUCTION: Cytokines might play a key role in the pathophysiology of major depressive disorder (MDD). The speed of onset of depressive episodes has been discussed as an important clinical parameter in MDD. The aim of this study was to investigate a potential influence of the speed of onset of the depressive episode on cytokine serum levels. METHOD: Serum level of the cytokines interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ) granulocyte and monocyte colony stimulating factor (GM-CSF) were measured in a total of 92 patients with MDD that did not respond to at least one previous antidepressant treatment. Patients were retrospectively divided in two groups: Faster (≤4 weeks) and slower (>4 weeks) onset of the depressive episode defined as the time passing from the first depressive symptoms to a full-blown depressive episode by using information from a clinical interview. RESULTS: We found significantly lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ in patients with a faster onset compared to patients with a slower onset of the depressive episodes. Furthermore, lower cytokine serum levels of IL-2, IL-8, IL-10 and IFN-γ were found in patients with a shorter duration (less than 6 months) compared to a longer duration (6-24 months) of the current depressive episode. This effect on cytokines was independent from the effect of the speed of onset of the depressive episode. CONCLUSIONS: Patients with faster onset of the depressive episode might represent a biological subtype of MDD with lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ.

Correction: Negative mood induction: Affective reactivity in recurrent, but not persistent depression.

[This corrects the article DOI: 10.1371/journal.pone.0208616.].

Negative mood induction: Affective reactivity in recurrent, but not persistent depression.

BACKGROUND: Despite the high clinical and epidemiological relevance of persistent depression, little is known about its specific psychopathology and whether it is distinct from recurrent depression. Depression in general has been associated with blunted affective reactivity but the evidence from previous studies is inconsistent. Here, we asked whether affective reactivity might differ between persistent and recurrent depression. METHODS: Twenty patients with persistent depression, 20 patients with recurrent depression and 20 healthy controls (HC) were recruited. Both patient groups showed moderate symptom severity. All participants underwent a sad mood induction procedure. Affective reactivity was assessed with the Positive and Negative Affect Schedule (PANAS) before and after mood induction. RESULTS: We found a striking difference in affective reactivity between patient groups. While the persistent group showed blunted reactivity to mood induction, the recurrent group demonstrated an affective response that was comparable to HC, with an increase in negative and a decrease in positive affect. Blunted affective reactivity was thus specifically associated with persistent in contrast to recurrent depression. CONCLUSIONS: These results highlight affective reactivity as an important psychopathological feature that differs between the two patient groups. Preserved affective reactivity to emotional stimuli in the recurrent group might reflect a resilience factor against persistence of depression.

Leptin gene polymorphisms are associated with weight gain during lithium augmentation in patients with major depression.

Weight gain is a common adverse effect of lithium augmentation. Previous studies indicate an impact of genetic variants at the leptin gene on weight gain as a consequence of psychopharmacological treatment. The primary aim of our study was to identify variants at the leptin locus that might predict lithium-induced weight gain. The secondary aim was to investigate if these variants modulate leptin levels. In 180 patients with acute major depressive disorder, body mass index was measured before and after 4 weeks of lithium augmentation, in a subsample also after 4 and/or 7 months. In a subsample of 89 patients, leptin serum concentrations were measured before and during lithium augmentation. We used linear mixed model analyzes to investigate the effects of 2 polymorphisms at the leptin locus (rs4731426 and rs7799039, employing the respective proxy SNPs rs2278815 and rs10487506) on changes in body mass index and leptin levels. For both polymorphisms, which are in high linkage disequilibrium, body mass index was significantly lower in homozygous A-allele carriers than in carriers of other genotypes at baseline. Over the follow-up period, body mass index increased less in homozygous A-allele carriers of rs4731426 than in carriers of other genotypes. This was not the case for rs7799039. Neither polymorphism modulated leptin protein expression. Our study strongly supports the hypothesis that genetic variability at the leptin locus is involved in lithium augmentation-associated weight gain in major depressive disorder. Furthermore, Genotype-Tissue Expression data provide strong evidence that rs4731426 influences the expression of leptin messenger ribonucleic acid in fibroblasts.

Deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: A double-blinded randomized controlled study and long-term follow-up in eight patients.

BACKGROUND: Deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) is an experimental approach in treatment-resistant depression (TRD). Short-term results of efficacy in DBS are incongruent and studies investigating long-term effects are warranted. METHODS: We assessed efficacy of SCG-DBS in eight patients randomized into a delayed-onset group (sham-DBS four weeks) and a non-delayed-onset group. The primary outcome measure was improvement on the Hamilton Depression Rating-Scale (HAMD-24-item-version). Response was defined as HAMD-24 reduction of at least 50% compared to baseline. Assessment was double-blind for a period of eight weeks and after 6,- 12,- 24,- and 28,- months open-label. RESULTS: The average improvement in HAMD-24 scores after 6,- 12,- and 24-months were 34%, 25%, and 37%. After 6 months, HAMD-24 revealed a significant difference (P = .022) and 37.5% of the patients were responders. After 12 months, HAMD-24 scores dropped, but no significant difference was observed. After 24 months, a significant improvement was found (P = .041). After the four weeks lasting sham vs. DBS-ON period, there was no group difference (P = .376) in HAMD-24 and patients did not improve during sham stimulation. Patients were followed until 28 months and two up to 4 years under SCG-DBS and average response rate was 51%, whereas two patients were remitters (33,3%). LIMITATIONS: The small sample size limited the statistical power and external validity. CONCLUSIONS: Long-term improvement after SCG-DBS revealed a stable effect. There was no significant difference in response rates between the delayed and non-delayed-onset group. DBS for TRD remains experimental and longitudinal investigations of large samples are needed.

Accepting unfairness by a significant other is associated with reduced connectivity between medial prefrontal and dorsal anterior cingulate cortex.

Conflict is a ubiquitous feature of interpersonal relationships, yet many of these relationships preserve their value following conflict. Our ability to refrain from punishment despite the occurrence of conflict is a characteristic of human beings. Using a combination of behavioral and neuroimaging techniques, we show that prosocial decision-making is modulated by relationship closeness. In an iterated social exchange, participants were more likely to cooperate with their partner compared to an unknown person by accepting unfair exchanges. Importantly, this effect was not influenced by how resources were actually being shared with one's partner. The medial prefrontal cortex (MPFC) was activated when the partner, rather than the unknown person, behaved unfairly and, in the same context, the MPFC demonstrated greater functional connectivity with the dorsal anterior cingulate cortex (DACC). MPFC-DACC connectivity was inversely associated with participants' tendency to "forgive" their partner for unfairness as well as performance outside the scanner on a behavioral measure of forgiveness. We conclude that relationship closeness modulates a neural network comprising the MPFC/DACC during economic exchanges.

Effects of subthalamic nucleus deep brain stimulation on emotional working memory capacity and mood in patients with Parkinson's disease.

BACKGROUND: In Parkinson's disease (PD), cognitive symptoms and mood changes may be even more distressing for the patient than motor symptoms. OBJECTIVE: Our aim was to determine the effects of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on working memory (WM) and mood. METHODS: Sixteen patients with PD were assessed with STN-DBS switched on (DBS-ON) and with dopaminergic treatment (Med-ON) compared to switched off (DBS-OFF) and without dopaminergic treatment (Med-OFF). The primary outcome measures were a Visual Analog Mood Scale (VAMS) and an emotional 2-back WM task at 12 months after DBS in the optimal DBS-ON/Med-ON setting compared to DBS-OFF/Med-OFF. RESULTS: Comparison of DBS-OFF/Med-OFF to DBS-ON/Med-ON revealed a significant increase in alertness (meanoff/off =51.59±24.54; meanon/on =72.75; P=0.016) and contentedness (meanoff/off =38.73±24.41; meanon/on =79.01±17.66; P=0.001, n=16), and a trend for reduction in sedation (P=0.060), which was related to stimulation as shown in a subgroup of seven patients. The N-back task revealed a significant increase in accuracy with DBS-ON/Med-ON compared to DBS-OFF/Med-OFF (82.0% vs 76.0%, respectively) (P=0.044), regardless of stimulus valence. CONCLUSION: In line with previous studies, we found that patients rated themselves subjectively as more alert, content, and less sedated during short-term DBS-ON. Accuracy in the WM task increased with the combination of DBS and medication, possibly related to higher alertness of the patients. Our results add to the currently mixed results described for DBS on WM and suggest that there are no deleterious DBS effects on this specific cognitive domain.

Probabilistic conversion of neurosurgical DBS electrode coordinates into MNI space.

In neurosurgical literature, findings such as deep brain stimulation (DBS) electrode positions are conventionally reported in relation to the anterior and posterior commissures of the individual patient (AC/PC coordinates). However, the neuroimaging literature including neuroanatomical atlases, activation patterns, and brain connectivity maps has converged on a different population-based standard (MNI coordinates). Ideally, one could relate these two literatures by directly transforming MRIs from neurosurgical patients into MNI space. However obtaining these patient MRIs can prove difficult or impossible, especially for older studies or those with hundreds of patients. Here, we introduce a methodology for mapping an AC/PC coordinate (such as a DBS electrode position) to MNI space without the need for MRI scans from the patients themselves. We validate our approach using a cohort of DBS patients in which MRIs are available, and test whether several variations on our approach provide added benefit. We then use our approach to convert previously reported DBS electrode coordinates from eight different neurological and psychiatric diseases into MNI space. Finally, we demonstrate the value of such a conversion using the DBS target for essential tremor as an example, relating the site of the active DBS contact to different MNI atlases as well as anatomical and functional connectomes in MNI space.

Processing of emotional stimuli is reflected by modulations of beta band activity in the subgenual anterior cingulate cortex in patients with treatment resistant depression.

Deep brain stimulation (DBS) of the subgenual anterior cingulate cortex (sgACC) has emerged as a new therapeutic option in patients with treatment resistant depression (TRD). At the same time, DBS offers a unique opportunity as an innovative research tool to study brain function in vivo Indirect measures of brain function such as positron-emission-tomography imaging findings have revealed a hypermetabolism in the sgACC area in patients with TRD that normalizes in parallel with treatment response to DBS. We used direct intracranial recordings via implanted DBS electrodes to study the neuronal oscillatory activity in the sgACC area during a picture viewing task including emotional and neutral stimuli in eight patients with TRD who underwent DBS.We found a stimulus-induced decrease in beta-band and increase in gamma-band activity, with a main effect of valence for event-related desynchronisation in the beta-frequency range (14-30 Hz). Unpleasant stimuli induced the strongest and most sustained beta-power decrease. The degree of beta-band modulation upon emotional stimuli correlated with the patients' rating of stimulus valence. Our findings confirm the involvement of the sgACC area in emotional processing that was more enhanced for unpleasant stimuli. Moreover, stimulus evaluation may be encoded by modulations of beta-band activity.

Deep brain stimulation of the posterior gyrus rectus region for treatment resistant depression.

BACKGROUND: Deep brain stimulation (DBS) represents an alternative symptomatic treatment for major depressive disorder in case of failure of pharmacotherapy. The sub-genual cingulate-Brodmann area 25 (CG-25), is one of the most widely used targets for electrode implantation. Given the diverging clinical outcome after DBS, there is a pressing need for in-depth study of brain anatomy and function allowing accurate and reliable prognosis before surgery. METHODS: We studied five treatment-resistant major depressive disorder patients planned to undergo DBS targeting the CG-25. Before surgery, we acquired high-resolution magnetic resonance (MR) diffusion-weighted images for each patient followed by post-surgery MRI for electrode localization. To estimate individual anatomical connectivity pattern of the active contact location we performed probabilistic diffusion tractography intra-individually. We then correlated connectivity patterns with outcome assessed with standardized clinical tests. Connectivity results were compared between DBS responders and non-responders. RESULTS: We observed in one patient an excellent clinical response after DBS of the bilateral posterior gyrus rectus rather than the initially targeted CG-25. The remaining four patients with DBS of the CG-25 were considered as non-responders. In the case patient, we demonstrate a strong connectivity of the stimulated regions to the medial prefrontal cortex (mPFC), which contrasted to the lower mPFC connectivity in non-responders. LIMITATIONS: Confirmation in larger cohorts is needed. CONCLUSIONS: We propose the posterior gyrus rectus as viable alternative new target for DBS in major depressive disorder. High connectivity between target and mPFC supports the pivotal role of this region in brain networks involved in mood processing.

Modulation of Beta-Band Activity in the Subgenual Anterior Cingulate Cortex during Emotional Empathy in Treatment-Resistant Depression.

Deep brain stimulation (DBS) is a promising approach in treatment-resistant depression (TRD). TRD is associated with problems in interpersonal relationships, which might be linked to impaired empathy. Here, we investigate the influence of DBS in the subgenual anterior cingulate cortex (sgACC) on empathy in patients with TRD and explore the pattern of oscillatory sgACC activity during performance of the multifaceted empathy test. We recorded local field potential activity directly from sgACC via DBS electrodes in patients. Based on previous behavioral findings, we expected disrupted empathy networks. Patients showed increased empathic involvement ratings toward negative stimuli as compared with healthy subjects that were significantly reduced after 6 months of DBS. Stimulus-related oscillatory activity pattern revealed a broad desynchronization in the beta (14-35 Hz) band that was significantly larger during patients' reported emotional empathy for negative stimuli than when patients reported to have no empathy. Beta desynchronization for empathic involvement correlated with self-reported severity of depression. Our results indicate a "negativity bias" in patients that can be reduced by DBS. Moreover, direct recordings show activation of the sgACC area during emotional processing and propose that changes in beta-band oscillatory activity in the sgACC might index empathic involvement of negative emotion in TRD.

Forgiving, fast and slow: validity of the implicit association test for predicting differential response latencies in a transgression-recall paradigm.

This study examined the role of automaticity in forgiving a real-life offense. As an alternative to self-report, an Implicit Association Test (IAT) of forgiveness was developed. Implicit (IAT-measured) and explicit (self-reported) forgiveness predicted shorter response times of state forgiveness ratings. The forgiveness IAT was highly reliable, moderately stable over time, and demonstrated incremental validity. Results suggest that the newly introduced forgiveness IAT could advance personality research beyond what is known from self-report measures, further corroborating the notion of implicit forgiveness. Implications for personality assessment are discussed.

Associations between obsessive-compulsive symptoms, revenge, and the perception of interpersonal transgressions.

Anger and aggression have only recently gained center stage in research on obsessive-compulsive disorder (OCD). An investigation of obsessive-compulsive (OC) symptoms focusing on the outcome of unresolved anger (i.e., revenge), however, is absent from the literature. The objective of the present research was therefore to provide a first step towards filling this gap and, hence, to systematically examine the associations between OC symptoms and different aspects of revenge (i.e., attitudes, dispositions, motivations). In three independent studies with nonclinical participants (N=504), we tested the hypothesis that OC symptoms relate to greater revenge. Individuals high in OC symptoms reported more positive attitudes toward revenge (Study 1), scored higher on a measure of trait revenge (Study 2), and reported increased revenge motivation regarding a real-life transgressor (Study 3). Furthermore, Study 4 (N=175) demonstrated that individuals high in OC symptoms perceived interpersonal transgressions more frequently in their daily lives. OC symptoms were positively related to the number of transgressions that respondents disclosed. Our results suggest that revenge and interpersonal hurt play a significant role in OCD.

Cognitive-behavioral therapy as continuation treatment to sustain response after electroconvulsive therapy in depression: a randomized controlled trial.

BACKGROUND: Although electroconvulsive therapy (ECT) is the most effective acute antidepressant intervention, sustained response rates are low. It has never been systematically assessed whether psychotherapy, continuation ECT, or antidepressant medication is the most efficacious intervention to maintain initial treatment response. METHODS: In a prospective, randomized clinical trial, 90 inpatients with major depressive disorder (MDD) were treated with right unilateral ultra-brief acute ECT. Electroconvulsive therapy responders received 6 months guideline-based antidepressant medication (MED) and were randomly assigned to add-on therapy with cognitive-behavioral group therapy (CBT-arm), add-on therapy with ultra-brief pulse continuation electroconvulsive therapy (ECT-arm), or no add-on therapy (MED-arm). After the 6 months of continuation treatment, patients were followed-up for another 6 months. The primary outcome parameter was the proportion of patients who remained well after 12 months. RESULTS: Of 90 MDD patients starting the acute phase, 70% responded and 47% remitted to acute ECT. After 6 months of continuation treatment, significant differences were observed in the three treatment arms with sustained response rates of 77% in the CBT-arm, 40% in the ECT-arm, and 44% in the MED-arm. After 12 months, these differences remained stable with sustained response rates of 65% in the CBT-arm, 28% in the ECT-arm, and 33% in the MED-arm. CONCLUSIONS: These results suggest that ultra-brief pulse ECT as a continuation treatment correlates with low sustained response rates. However, the main finding implicates cognitive-behavioral group therapy in combination with antidepressants might be an effective continuation treatment to sustain response after successful ECT in MDD patients.

Antidepressant effects after short-term and chronic stimulation of the subgenual cingulate gyrus in treatment-resistant depression.

BACKGROUND: Deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) is an experimental approach in treatment-resistant depression (TRD). Apart from its potential long-term antidepressant effects acute stimulation effects have been described. We investigated putative neuroanatomical clusters in which such acute effects accumulate and followed patients over the long-term. METHODS: We assessed safety and efficacy of DBS in six patients with TRD receiving bilateral DBS with electrodes implanted in the SCG. First, high intensity 130 Hz stimulation was applied on five consecutive days after surgery for 24 h comprising a sham condition in a double-blind, randomized design. Acute stimulation was conducted at all four homologous electrode contacts on both sides. Afterwards, chronic stimulation was initiated and the clinical effect was evaluated at 24-36 weeks compared to baseline (50% reduction in HAMD scores). The primary outcome criterion was depression severity as assessed with the Hamilton Depression Rating Scale (HAMD-24); secondary outcome parameters were the Montgomery-Åsberg Rating-Scale and Beck Depression Inventory following DBS. The clinical effect over the three scores was compared to sham stimulation and was correlated to the anatomical localization of active contacts by stereotactically delimiting the cluster of most effective contacts in responding patients. RESULTS: Acute 24 h of stimulation showed only moderate reductions in mean HAMD-24, MADRS and BDI scores. At the last observation (24-36 weeks), two patients were remitters (HAMD-24 < 10) and the four other patients were non-responders. CONCLUSIONS: Our results confirm that stimulation of the SCG is capable of exerting moderate acute and chronic antidepressant effects. The predictive value of these findings needs to be addressed in future studies.

Nightmares that mislead to diagnosis of reactivation of PTSD.

BACKGROUND: Sleep disturbance is a common characteristic of patients with post-traumatic stress disorder (PTSD). Besides the clinical descriptions of nightmares and insomnia, periodic limb movements (PLMs) are reported to co-occur in PTSD. Although the causal relationship between sleep disturbance and PTSD is not fully understood, sleep disturbance is an independent risk factor for the development and reactivation of PTSD. In contrast, the link between PTSD and REM sleep behaviour disorder (RBD) is less clear. METHOD: A case report is presented to illustrate differential diagnosis and time course of sleep disturbance in the context of PTSD. RESULT: A 63-year-old man who had been successfully treated for PTSD but who suffered the re-occurrence of disturbed sleep due to RBD and PLM, which was misdiagnosed as reactivation of PTSD. CONCLUSIONS: RBD can mimic PTSD-related nightmares. Accurate diagnosis of sleep disturbance in PTSD is relevant for treatment and prognostic evaluation.

Towards a multifaceted understanding of revenge and forgiveness.

We focus on two aspects: First, we argue that it is necessary to include implicit forgiveness as an additional adaptive behavioral option to the perception of interpersonal transgressions. Second, we present one possible way to investigate the cognitive-affective underpinnings of revenge and forgiveness: a functional MRI (fMRI) approach aiming at integrating forgiveness and revenge mechanisms into a single paradigm.

Gender differences in a clinical sample of patients with borderline personality disorder.

The aim of the study was to investigate gender differences and similarities in patients with borderline personality disorder (BPD) with respect to Axis I comorbidity, Axis II comorbidity, general psychopathology (Symptom Checklist 90-Revised), and dimensional personality traits (NEO-Personality-Inventory Revised [NEO-PI-R] and the Dimensional Assessment of Personality Profile Basic questionnaire [DAPP-BQ]). Fifty-seven men and 114 women with BPD were included in the study. Regarding Axis I and II disorders in an exploratory analysis, men with BPD more often fulfilled the diagnostic criteria for binge eating disorder, antisocial personality disorder, narcissistic personality disorder, and conduct disorder in childhood, whereas women had higher frequencies of bulimia nervosa, posttraumatic stress disorder, and panic disorder with agoraphobia. After correcting for multiple tests, only the gender differences in narcissistic and antisocial personality disorder remained significant. In the SCL-90-R profile, no significant gender differences could be identified. In the exploratory analysis of the dimensional personality traits, women showed higher rates on the NEO-PI-R main factors (Neuroticism and Agreeableness) compared to men. In the DAPP-BQ profile, men reached higher sores on the main factor, Dissocial Behavior. When correcting for multiple tests, gender differences still existed for Neuroticism and Dissocial Behavior. Our results argue for gender differences in Axis I and II comorbidity and dimensional personality traits in BPD. However, in general, more similarities than differences were shown in this study.