The promise and challenges of transcranial magnetic stimulation and deep brain stimulation as therapeutic options for obsessive-compulsive disorder.

INTRODUCTION: Obsessive compulsive disorder (OCD) represents a complex and often difficult to treat disorder. Pharmacological and psychotherapeutic interventions are often associated with sub-optimal outcomes, and 40-60% of patients are resistant to first line therapies and thus left with few treatment options. OCD is underpinned by aberrant neurocircuitry within cortical, striatal, and thalamic brain networks. Considering the neurocircuitry impairments that underlie OCD symptomology, neurostimulation therapies provide an opportunity to modulate psychopathology in a personalized manner. Also, by probing pathological neural networks, enhanced understanding of disease states can be obtained. AREAS COVERED: This perspective discusses the clinical efficacy of TMS and DBS therapies, treatment access options, and considerations and challenges in managing patients. Recent scientific progress is discussed, with a focus on neurocircuitry and biopsychosocial aspects. Translational recommendations and suggestions for future research are provided. EXPERT OPINION: There is robust evidence to support TMS and DBS as an efficacious therapy for treatment resistant OCD patients supported by an excellent safety profile and favorable health economic data. Despite a great need for alternative therapies for chronic and severe OCD patients, resistance toward neurostimulation therapies from regulatory bodies and the psychiatric community remains. The authors contend for greater access to TMS and DBS for treatment resistant OCD patients at specialized sites with appropriate clinical resources, particularly considering adjunct and follow-up care. Also, connectome targeting has shown robust predictive ability of symptom improvements and holds potential in advancing personalized neurostimulation therapies.

Clinical outcomes of deep brain stimulation for obsessive-compulsive disorder: Insight as a predictor of symptom changes.

AIM: Deep brain stimulation (DBS) is a safe and effective treatment option for people with refractory obsessive-compulsive disorder (OCD). Yet our understanding of predictors of response and prognostic factors remains rudimentary, and long-term comprehensive follow-ups are lacking. We aim to investigate the efficacy of DBS therapy for OCD patients, and predictors of clinical response. METHODS: Eight OCD participants underwent DBS stimulation of the nucleus accumbens (NAc) in an open-label longitudinal trial, duration of follow-up varied between 9 months and 7 years. Post-operative care involved comprehensive fine tuning of stimulation parameters and adjunct multidisciplinary therapy. RESULTS: Six participants achieved clinical response (35% improvement in obsessions and compulsions on the Yale Brown Obsessive Compulsive Scale (YBOCS)) within 6-9 weeks, response was maintained at last follow up. On average, the YBOCS improved by 45% at last follow up. Mixed linear modeling elucidated directionality of symptom changes: insight into symptoms strongly predicted (P = 0.008) changes in symptom severity during DBS therapy, likely driven by initial changes in depression and anxiety. Precise localization of DBS leads demonstrated that responders most often had their leads (and active contacts) placed dorsal compared to non-responders, relative to the Nac. CONCLUSION: The clinical efficacy of DBS for OCD is demonstrated, and mediators of changes in symptoms are proposed. The symptom improvements within this cohort should be seen within the context of the adjunct psychological and biopsychosocial care that implemented a shared decision-making approach, with flexible iterative DBS programming. Further research should explore the utility of insight as a clinical correlate of response. The trial was prospectively registered with the ANZCTR (ACTRN12612001142820).

Deep Brain Stimulation for Obsessive-Compulsive Disorder: Optimal Stimulation Sites.

BACKGROUND: Deep brain stimulation (DBS) is a promising treatment option for treatment-refractory obsessive-compulsive disorder (OCD). Several stimulation targets have been used, mostly in and around the anterior limb of the internal capsule and ventral striatum. However, the precise target within this region remains a matter of debate. METHODS: Here, we retrospectively studied a multicenter cohort of 82 patients with OCD who underwent DBS of the ventral capsule/ventral striatum and mapped optimal stimulation sites in this region. RESULTS: DBS sweet-spot mapping performed on a discovery set of 58 patients revealed 2 optimal stimulation sites associated with improvements on the Yale-Brown Obsessive Compulsive Scale, one in the anterior limb of the internal capsule that overlapped with a previously identified OCD-DBS response tract and one in the region of the inferior thalamic peduncle and bed nucleus of the stria terminalis. Critically, the nucleus accumbens proper and anterior commissure were associated with beneficial but suboptimal clinical improvements. Moreover, overlap with the resulting sweet- and sour-spots significantly estimated variance in outcomes in an independent cohort of 22 patients from 2 additional DBS centers. Finally, beyond obsessive-compulsive symptoms, stimulation of the anterior site was associated with optimal outcomes for both depression and anxiety, while the posterior site was only associated with improvements in depression. CONCLUSIONS: Our results suggest how to refine targeting of DBS in OCD and may be helpful in guiding DBS programming in existing patients.

Phenomenological Changes Associated with Deep Brain Stimulation for Obsessive Compulsive Disorder: A Cognitive Appraisal Model of Recovery.

The current scientific enquiry of deep brain stimulation (DBS) does not capture the breadth of DBS-induced changes to an individual's life. Considering that DBS is applied in severe and complex cases, it is ethically and clinically necessary to consider the patient perspective and personally relevant outcomes. This lived experience investigation of people with obsessive compulsive disorder (OCD) undergoing DBS aims to provide a comprehensive evaluation of DBS-induced effects associated with OCD psychopathology. Six patients and six carers completed semi-structured open-ended interviews. A blended approach of interpretative phenomenological, inductive, and thematic analysis techniques was employed. Profound psychopathological changes were expressed; individuals felt more alive, had improved cognitive affective control, greater engagement in the world, and were able to manage their OCD. Through suppression of the condition, self-constructs were able to re-emerge and develop. A framework describing the progression of phenomenological changes, and a theoretical model describing changes in the cognitive appraisal of intrusions influencing recovery are proposed. This is the first identified qualitative investigation of DBS-induced changes in psychiatric patients and carers. Findings have implications for patient education and recovery models of OCD, and scientific understanding of DBS effects.

Anatomical targeting for electrode localization in subthalamic nucleus deep brain stimulation: A comparative study.

BACKGROUND AND PURPOSE: In deep brain stimulation (DBS), accurate electrode placement is essential for optimizing patient outcomes. Localizing electrodes enables insight into therapeutic outcomes and development of metrics for use in clinical trials. Methods of defining anatomical targets have been described with varying accuracy and objectivity. To assess variability in anatomical targeting, we compare four methods of defining an appropriate target for DBS of the subthalamic nucleus for Parkinson's disease. METHODS: The methods compared are direct visualization, red nucleus-based indirect targeting, mid-commissural point-based indirect targeting, and automated template-based targeting. This study assessed 226 hemispheres in 113 DBS recipients (39 females, 73 males, 62.2 ± 7.7 years). We utilized the electrode placement error (the Euclidean distance between the defined target and closest DBS electrode) as a metric for comparative analysis. Pairwise differences in electrode placement error across the four methods were compared using the Kruskal-Wallis H-test and Wilcoxon signed-rank tests. RESULTS: Interquartile ranges of the differences in electrode placement error spanned 1.18-1.56 mm. A Kruskal-Wallis H-test reported a statistically significant difference in the median of at least two groups (H(5) = 41.052, p < .001). Wilcoxon signed-rank tests reported statistically significant difference in two comparisons: direct visualization versus red nucleus-based indirect, and direct visualization versus automated template-based methods (T < 9215, p < .001). CONCLUSIONS: All methods were similarly discordant in their relative accuracy, despite having significant technical differences in their application. The differing protocols and technical aspects of each method, however, have the implication that one may be more practical depending on the clinical or research application at hand.

Patient feedback and psychosocial outcomes of deep brain stimulation in people with obsessive-compulsive disorder.

Severe and refractory psychiatric patients can experience complex and profound changes in symptomology, functioning and well-being from deep brain stimulation (DBS) therapy. Currently, the efficacy of DBS is assessed by clinician rated scales of primary symptoms, yet this does not capture the multitude of DBS mediated changes or represent the patient perspective. We aimed to elucidate the patient perspective in psychiatric DBS application by investigating 1) symptomatic, and 2) psychosocial changes, 3) therapeutic expectations and satisfaction, 4) decision-making capacity, and 5) clinical care recommendations from treatment refractory obsessive-compulsive disorder (OCD) DBS patients. Participants enrolled in an open label clinical trial of DBS therapy for OCD who had reached clinical response were invited to participate in a follow up survey. Participants completed a 1) feedback survey relating to goals, expectations, and satisfaction of therapy, and 2) self-report questionnaires on psychosocial functioning including quality of life, cognitive insight, locus of control, rumination, cognitive flexibility, impulsivity, affect, and well-being. Greatest change was reported for quality of life, rumination, affect and cognitive flexibility. Participants reported realistic expectations, high satisfaction, adequate pre-operative education and decision-making capacity; and advocated for greater access to DBS care and more widespread support services. This is the first identified investigation on psychiatric patient perspectives of functioning and therapeutic outcomes following DBS. Insights from the study have implications for informing psychoeducation, clinical practices, and neuroethical debates. We encourage a greater patient-centred and biopsychosocial approach in evaluating and managing OCD DBS patients, by considering personally meaningful goals and addressing symptomatic and psychosocial recovery.

Clinical recommendations for the care of people with treatment-refractory obsessive-compulsive disorder when undergoing deep brain stimulation.

Deep brain stimulation is an emerging therapy for treatment-refractory obsessive-compulsive disorder patients. Yet, accessibility is limited, treatment protocols are heterogeneous and there is no guideline or consensus on the best practices. Here, we combine evidence from scientific investigations, expert opinions and our clinical expertise to propose several clinical recommendations from the pre-operative, surgical and post-operative phases of deep brain stimulation care for treatment-refractory obsessive-compulsive disorder patients. A person-centered and biopsychosocial approach is adopted. Briefly, we discuss clinical characteristics associated with response, the use of improved educational materials, an evaluative consent process, comprehensive programming by an expert clinician, a more global assessment of treatment efficacy, multi-disciplinary adjunct psychotherapy and the importance of peer support programs. Furthermore, where gaps are identified, future research suggestions are made, including connectome surgical targeting, scientific evaluation of hardware models and health economic data. In addition, we encourage collaborative groups of data and knowledge sharing by way of a clinical registry and a peer group of programming clinicians. We aim to commence a discussion on the determinants of deep brain stimulation efficacy for treatment-refractory obsessive-compulsive disorder patients, a rare and severe patient group, and contribute to more standardized and evidence-based practices.

Correction: Acevedo et al. Therapeutic Neurostimulation in Obsessive-Compulsive and Related Disorders: A Systematic Review. Brain Sci. 2021, 11, 948.

The authors wish to correct the following error in this paper [...].

Digital technology for addressing cognitive impairment in recent-onset psychosis: A perspective.

Cognitive impairments in psychosis negatively impact functional recovery and quality of life. Existing interventions for improving cognitive impairment in recent-onset psychosis show inconsistent treatment efficacy, small effects, suboptimal engagement and limited generalizability to daily life functioning. In this perspective we explore how digital technology has the potential to address these limitations in order to improve cognitive and functional outcomes in recent-onset psychosis. Computer programs can be used for standardized, automated delivery of cognitive remediation training. Virtual reality provides the opportunity for learning and practicing cognitive skills in real-world scenarios within a virtual environment. Smartphone apps could be used for notification reminders for everyday tasks to compensate for cognitive difficulties. Internet-based technologies can offer psychoeducation and training materials for enhancing cognitive skills. Early findings indicate some forms of digital interventions for cognitive enhancement can be effective, with well-established evidence for human-supported computer-based cognitive remediation in recent-onset psychosis. Emerging evidence regarding virtual reality is favorable for improving social cognition. Overall, blending digital interventions with human support improves engagement and effectiveness. Despite the potential of digital interventions for enhancing cognition in recent-onset psychosis, few studies have been conducted to date. Implementation challenges affecting application of digital technologies for cognitive impairment in recent-onset psychosis are sustained engagement, clinical integration, and lack of quality in the commercial marketplace. Future opportunities lie in including motivational frameworks and behavioral change interventions, increasing service engagement in young people and lived experience involvement in digital intervention development.

Electrically evoked and spontaneous neural activity in the subthalamic nucleus under general anesthesia.

OBJECTIVE: Deep brain stimulation (DBS) surgery is commonly performed with the patient awake to facilitate assessments of electrode positioning. However, awake neurosurgery can be a barrier to patients receiving DBS. Electrode implantation can be performed with the patient under general anesthesia (GA) using intraoperative imaging, although such techniques are not widely available. Electrophysiological features can also aid in the identification of target neural regions and provide functional evidence of electrode placement. Here we assess the presence and positional variation under GA of spontaneous beta and high-frequency oscillation (HFO) activity, and evoked resonant neural activity (ERNA), a novel evoked response localized to the subthalamic nucleus. METHODS: ERNA, beta, and HFO were intraoperatively recorded from DBS leads comprising four individual electrodes immediately after bilateral awake implantation into the subthalamic nucleus of 21 patients with Parkinson's disease (42 hemispheres) and after subsequent GA induction deep enough to perform pulse generator implantation. The main anesthetic agent was either propofol (10 patients) or sevoflurane (11 patients). RESULTS: GA reduced the amplitude of ERNA, beta, and HFO activity (p < 0.001); however, ERNA amplitudes remained large in comparison to spontaneous local field potentials. Notably, a moderately strong correlation between awake ERNA amplitude and electrode distance to an "ideal" therapeutic target within dorsal STN was preserved under GA (awake: ρ = -0.73, adjusted p value [padj] < 0.001; GA: ρ = -0.69, padj < 0.001). In contrast, correlations were diminished under GA for beta (awake: ρ = -0.45, padj < 0.001; GA: ρ = -0.13, padj = 0.12) and HFO (awake: ρ = -0.69, padj < 0.001; GA: ρ = -0.33, padj < 0.001). The largest ERNA occurred at the same electrode (awake vs GA) for 35/42 hemispheres (83.3%) and corresponded closely to the electrode selected by the clinician for chronic therapy at 12 months (awake ERNA 77.5%, GA ERNA 82.5%). The largest beta amplitude occurred at the same electrode (awake vs GA) for only 17/42 (40.5%) hemispheres and 21/42 (50%) for HFO. The electrode measuring the largest awake beta and HFO amplitudes corresponded to the electrode selected by the clinician for chronic therapy at 12 months in 60% and 70% of hemispheres, respectively. However, this correspondence diminished substantially under GA (beta 20%, HFO 35%). CONCLUSIONS: ERNA is a robust electrophysiological signal localized to the dorsal subthalamic nucleus subregion that is largely preserved under GA, indicating it could feasibly guide electrode implantation, either alone or in complementary use with existing methods.

Therapeutic Neurostimulation in Obsessive-Compulsive and Related Disorders: A Systematic Review.

Invasive and noninvasive neurostimulation therapies for obsessive-compulsive and related disorders (OCRD) were systematically reviewed with the aim of assessing clinical characteristics, methodologies, neuroanatomical substrates, and varied stimulation parameters. Previous reviews have focused on a narrow scope, statistical rather than clinical significance, grouped together heterogenous protocols, and proposed inconclusive outcomes and directions. Herein, a comprehensive and transdiagnostic evaluation of all clinically relevant determinants is presented with translational clinical recommendations and novel response rates. Electroconvulsive therapy (ECT) studies were limited in number and quality but demonstrated greater efficacy than previously identified. Targeting the pre-SMA/SMA is recommended for transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS). TMS yielded superior outcomes, although polarity findings were conflicting, and refinement of frontal/cognitive control protocols may optimize outcomes. For both techniques, standardization of polarity, more treatment sessions (>20), and targeting multiple structures are encouraged. A deep brain stimulation (DBS) 'sweet spot' of the striatum for OCD was proposed, and CBT is strongly encouraged. Tourette's patients showed less variance and reliance on treatment optimization. Several DBS targets achieved consistent, rapid, and sustained clinical response. Analysis of fiber connectivity, as opposed to precise neural regions, should be implemented for target selection. Standardization of protocols is necessary to achieve translational outcomes.

Objective measurement of tinnitus using functional near-infrared spectroscopy and machine learning.

Chronic tinnitus is a debilitating condition which affects 10-20% of adults and can severely impact their quality of life. Currently there is no objective measure of tinnitus that can be used clinically. Clinical assessment of the condition uses subjective feedback from individuals which is not always reliable. We investigated the sensitivity of functional near-infrared spectroscopy (fNIRS) to differentiate individuals with and without tinnitus and to identify fNIRS features associated with subjective ratings of tinnitus severity. We recorded fNIRS signals in the resting state and in response to auditory or visual stimuli from 25 individuals with chronic tinnitus and 21 controls matched for age and hearing loss. Severity of tinnitus was rated using the Tinnitus Handicap Inventory and subjective ratings of tinnitus loudness and annoyance were measured on a visual analogue scale. Following statistical group comparisons, machine learning methods including feature extraction and classification were applied to the fNIRS features to classify patients with tinnitus and controls and differentiate tinnitus at different severity levels. Resting state measures of connectivity between temporal regions and frontal and occipital regions were significantly higher in patients with tinnitus compared to controls. In the tinnitus group, temporal-occipital connectivity showed a significant increase with subject ratings of loudness. Also in this group, both visual and auditory evoked responses were significantly reduced in the visual and auditory regions of interest respectively. Naïve Bayes classifiers were able to classify patients with tinnitus from controls with an accuracy of 78.3%. An accuracy of 87.32% was achieved using Neural Networks to differentiate patients with slight/ mild versus moderate/ severe tinnitus. Our findings show the feasibility of using fNIRS and machine learning to develop an objective measure of tinnitus. Such a measure would greatly benefit clinicians and patients by providing a tool to objectively assess new treatments and patients' treatment progress.

Interaction of task-related learning and transcranial direct current stimulation of the prefrontal cortex in modulating executive functions.

The effects of transcranial direct-current stimulation (tDCS) on cognitive functions, such as response inhibition, might be mediated through plastic changes within the prefrontal cortex. Previous studies have also confirmed learning-related plasticity in prefrontal neurocircuitry. The susceptibility of prefrontal neurocircuitry for tDCS-induced plastic changes and consequent behavioural modulations might depend on the level of learning in a particular task. Variabilities in the cognitive outcome of tDCS might be related to the interaction of tDCS and task-relevant learning. 73 participants completed the Stop Task before and after tDCS over the dorsolateral prefrontal cortex. Participants had to deliver a speeded response upon the onset of a visual go-cue and inhibit the response when the go-cue was replaced by a stop signal. We measured response time (RT) in Go trials, and stop signal reaction time (SSRT) as an index of inhibition ability. A shorter SSRT indicates a better inhibition ability. Participants received either anodal or sham stimulation in two separate sessions (one week apart). RT was increased and SSRT became shorter from pre-stimulation to post-stimulation testing, indicating within-session learning. Furthermore, compared to the first week of testing, RT was increased and SSRT became shorter in the second week, indicating across-session learning. Within-session learning was significantly higher if anodal stimulation was given in the first week rather than the second week indicating that the behavioural effects of tDCS were dependent on the level of learning. Our findings indicate that tDCS effects on executive functions are dependent on the level of experience (learning) in the cognitive task.

Interactive effects of music and prefrontal cortex stimulation in modulating response inhibition.

Influential hypotheses propose that alterations in emotional state influence decision processes and executive control of behavior. Both music and transcranial direct current stimulation (tDCS) of prefrontal cortex affect emotional state, however interactive effects of music and tDCS on executive functions remain unknown. Learning to inhibit inappropriate responses is an important aspect of executive control which is guided by assessing the decision outcomes such as errors. We found that high-tempo music, but not low-tempo music or low-level noise, significantly influenced learning and implementation of inhibitory control. In addition, a brief period of tDCS over prefrontal cortex specifically interacted with high-tempo music and altered its effects on executive functions. Measuring event-related autonomic and arousal response of participants indicated that exposure to task demands and practice led to a decline in arousal response to the decision outcome and high-tempo music enhanced such practice-related processes. However, tDCS specifically moderated the high-tempo music effect on the arousal response to errors and concomitantly restored learning and improvement in executive functions. Here, we show that tDCS and music interactively influence the learning and implementation of inhibitory control. Our findings indicate that alterations in the arousal-emotional response to the decision outcome might underlie these interactive effects.