Connectivity-guided intermittent theta burst versus repetitive transcranial magnetic stimulation for treatment-resistant depression: a randomized controlled trial.

Disruption in reciprocal connectivity between the right anterior insula and the left dorsolateral prefrontal cortex is associated with depression and may be a target for neuromodulation. In a five-center, parallel, double-blind, randomized controlled trial we personalized resting-state functional magnetic resonance imaging neuronavigated connectivity-guided intermittent theta burst stimulation (cgiTBS) at a site based on effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. We tested its efficacy in reducing the primary outcome depression symptoms measured by the GRID Hamilton Depression Rating Scale 17-item over 8, 16 and 26 weeks, compared with structural magnetic resonance imaging (MRI) neuronavigated repetitive transcranial magnetic stimulation (rTMS) delivered at the standard stimulation site (F3) in patients with 'treatment-resistant depression'. Participants were randomly assigned to 20 sessions over 4-6 weeks of either cgiTBS (n = 128) or rTMS (n = 127) with resting-state functional MRI at baseline and 16 weeks. Persistent decreases in depressive symptoms were seen over 26 weeks, with no differences between arms on the primary outcome GRID Hamilton Depression Rating Scale 17-item score (intention-to-treat adjusted mean, -0.31, 95% confidence interval (CI) -1.87, 1.24, P = 0.689). Two serious adverse events were possibly related to TMS (mania and psychosis). MRI-neuronavigated cgiTBS and rTMS were equally effective in patients with treatment-resistant depression over 26 weeks (trial registration no. ISRCTN19674644).

Theta Burst Stimulation of the Human Motor Cortex Modulates Secondary Hyperalgesia to Punctate Mechanical Stimuli.

OBJECTIVES: Many chronic pain conditions show evidence of dysregulated synaptic plasticity, including the development and maintenance of central sensitization. This provides a strong rationale for neuromodulation therapies for the relief of chronic pain. However, variability in responses and low fidelity across studies remain an issue for both clinical trials and pain management, demonstrating insufficient mechanistic understanding of effective treatment protocols. MATERIALS AND METHODS: In a randomized counterbalanced crossover designed study, we evaluated two forms of patterned repetitive transcranial magnetic stimulation, known as continuous theta burst stimulation (TBS) and intermittent TBS, during normal and central sensitization states. Secondary hyperalgesia (a form of use-dependent central sensitization) was induced using a well-established injury-free pain model and assessed by standardized quantitative sensory testing involving light touch and pinprick pain thresholds in addition to stimulus-response functions. RESULTS: We found that continuous TBS of the human motor cortex has a facilitatory (pronociceptive) effect on the magnitude of perceived pain to secondary hyperalgesia, which may rely on induction and expression of neural plasticity through heterosynaptic long-term potentiation-like mechanisms. CONCLUSIONS: By defining the underlying mechanisms of TBS-driven synaptic plasticity in the nociceptive system, we offer new insight into disease mechanisms and provide targets for promoting functional recovery and repair in chronic pain. For clinical applications, this knowledge is critical for development of more efficacious and mechanisms-based neuromodulation protocols, which are urgently needed to address the chronic pain and opioid epidemics.

Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis.

Cognitive impairment in multiple sclerosis (MS) can adversely impact participation in employment, activities of daily living, and wider society. It affects 40-70% of people living with MS (pwMS). There are few effective treatments for cognitive impairment in people with MS. Neuromodulation with intermittent theta-burst stimulation (iTBS) has potential for treating cognitive impairment in pwMS. This single-centre mixed-methods feasibility randomised controlled trial (NCT04931953) will assess feasibility, acceptability, and tolerability of procedures used for applying iTBS for improving cognitive performance in pwMS. Participants will be randomised into three intervention groups with varying lengths of iTBS treatment (from 1 to 4 weeks) and a sham-control group. Quantitative data will be collected at three time points (baseline, end of intervention, and 8-week follow-up). End of the intervention semi-structured interviews will explore the views and experiences of the participants receiving the intervention, analysed using framework analysis. Quantitative and qualitative data will be synthesised to explore the impact of the iTBS intervention. Ethical approval has been received from the Health Research Authority (21/LO/0506) and recruitment started in June 2022. The results will inform the design of an RCT of the efficacy of iTBS as a therapeutic intervention for cognitive impairment in pwMS.

Brain connectivity-guided, Optimised theta burst transcranial magnetic stimulation to improve Central Pain Modulation in knee Osteoarthritis Pain (BoostCPM): protocol of a pilot randomised clinical trial in a secondary care setting in the UK.

INTRODUCTION: Chronic pain is a common health problem that is not efficiently managed by standard analgesic treatments. There is evidence that treatment resistance may result from maladaptive brain changes in areas that are fundamental to the perception of pain. Knee osteoarthritis is one of the most prevalent causes of chronic pain and commonly associated with negative affect. Chronic knee osteoarthritis pain is also associated with altered right anterior insula functional connectivity. We posit that reversal of these brain circuit alterations may be critical to alleviate chronic pain and associated negative affect, and that this can be achieved through non-invasive neuromodulation techniques. Despite growing interest in non-invasive neuromodulation for pain relief and proven efficacy in depression, results in chronic pain are mixed with limited high-quality evidence for clinical and mechanistic efficacy. Limitations include patient heterogeneity, imprecision of target selection, uncertain blinding and protocols that may deliver pulses at subclinical efficacy. METHODS AND ANALYSIS: We hence developed an optimised treatment protocol of connectivity-guided intermittent theta-burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex with accelerated delivery on four consecutive days (allowing 4 days within the same week as protocol variation) with five daily treatment sessions that will be piloted in a sham-controlled design in 45 participants with chronic knee pain. This pilot study protocol will assess feasibility, tolerability and explore mechanistic efficacy through serial functional/structural magnetic resonance imaging (MRI) and quantitative sensory testing. ETHICS AND DISSEMINATION: This pilot trial has been approved by the Ethics Committee Cornwall and Plymouth.Results of the pilot trial will be submitted to peer-reviewed journals, presented at research conferences and may be shared with participants and PPI/E advisors. TRIAL REGISTRATION NUMBER: ISRCTN15404076.

Connectivity guided theta burst transcranial magnetic stimulation versus repetitive transcranial magnetic stimulation for treatment-resistant moderate to severe depression: study protocol for a randomised double-blind controlled trial (BRIGhTMIND).

INTRODUCTION: The BRIGhTMIND study aims to determine the clinical effectiveness, cost-effectiveness and mechanism of action of connectivity guided intermittent theta burst stimulation (cgiTBS) versus standard repetitive transcranial magnetic stimulation (rTMS) in adults with moderate to severe treatment resistant depression. METHODS AND ANALYSIS: The study is a randomised double-blind controlled trial with 1:1 allocation to either 20 sessions of (1) cgiTBS or (2) neuronavigated rTMS not using connectivity guidance. A total of 368 eligible participants with a diagnosis of current unipolar major depressive disorder that is both treatment resistant (defined as scoring 2 or more on the Massachusetts General Hospital Staging Score) and moderate to severe (scoring >16 on the 17-item Hamilton Depression Rating Scale (HDRS-17)), will be recruited from primary and secondary care settings at four treatment centres in the UK. The primary outcome is depression response at 16 weeks (50% or greater reduction in HDRS-17 score from baseline). Secondary outcomes include assessments of self-rated depression, anxiety, psychosocial functioning, cognition and quality of life at 8, 16 and 26 weeks postrandomisation. Cost-effectiveness, patient acceptability, safety, mechanism of action and predictors of response will also be examined. ETHICS AND DISSEMINATION: Ethical approval was granted by East Midlands Leicester Central Research Ethics Committee (ref: 18/EM/0232) on 30 August 2018. The results of the study will be published in relevant peer-reviewed journals, and then through professional and public conferences and media. Further publications will explore patient experience, moderators and mediators of outcome and mechanism of action. TRIAL REGISTRATION NUMBER: ISRCTN19674644.

Effects of intermittent theta burst stimulation applied to the left dorsolateral prefrontal cortex on empathy and impulsivity in healthy adult males.

Impulsivity and empathy are clinically relevant multi-dimensional concepts. Existing evidence suggests the left dorsolateral prefrontal cortex (LDLPFC) plays a crucial role in impulsivity and empathy. However, the neuromodulation effect of excitatory repetitive transcranial magnetic stimulation at the LDLPFC is insufficiently explored in the current literature. To address this important gap in the literature, we aimed to examine the effects of intermittent theta burst stimulation (iTBS) at the LDLPFC on impulsivity and empathy. A single-blind sham-controlled randomised crossover trial involving twenty-three healthy male adults was conducted. The iTBS protocol delivered 1800 pulses to the LDLPFC at 80% of the motor threshold in each condition. Trait impulsivity and empathy were measured at baseline using the Barrett Impulsiveness Scale and UPPS-P Impulsiveness Scale. The Reading the Mind in the Eyes Test, Information Sampling Task, and Adjusting Amount Task serving as behavioural measures of empathy, cognitive and temporal impulsivity respectively were administered before and after iTBS sessions. No significant changes were found on any of the measures after iTBS at the LDLPFC compared to the sham stimulation. Neuromodulation at the LDLPFC using iTBS may not alter cognitive empathy and temporal and cognitive impulsivity. Further research is required using amended protocols in a large-scaled sample.

Patients with depression who self-refer for transcranial magnetic stimulation treatment: exploratory qualitative study.

Aims and methodAs part of a larger clinical trial concerning the use of transcranial magnetic stimulation (TMS) for treatment-resistant depression, the current study aimed to examine referral emails to describe the clinical characteristics of people who self-refer and explore the reasons for self-referral for TMS treatment. We used content analysis to explore these characteristics and thematic analysis to explore the reasons for self-referral. RESULTS: Of the 98 referrals, 57 (58%) were for women. Depressive disorder was the most commonly cited diagnosis, followed by bipolar affective disorder. Six themes emerged from the thematic analysis: treatment resistance, side-effects of other treatments, desperation for relief, proactively seeking information, long-term illness and illness getting worse.Clinical implicationsTMS has recently been recommended in the UK for routine use in clinical practice. Therefore, the number of people who self-refer for TMS treatment is likely to increase as its availability increases.Declaration of interestNone.

Targeted transcranial theta-burst stimulation alters fronto-insular network and prefrontal GABA.

Repetitive transcranial magnetic stimulation (rTMS) has been used worldwide to treat depression. However, the exact physiological effects are not well understood. Pathophysiology of depression involves crucial limbic structures (e.g. insula), and it is still not clear if these structures can be modulated through neurostimulation of surface regions (e.g. dorsolateral prefrontal cortex, DLPFC), and whether rTMS-induced excitatory/inhibitory transmission alterations relate to fronto-limbic connectivity changes. Therefore, we sought proof-of-concept for neuromodulation of insula via prefrontal intermittent theta-burst stimulation (iTBS), and how these effects relate to GABAergic and glutamatergic systems. In 27 healthy controls, we employed a single-blind crossover randomised-controlled trial comparing placebo and real iTBS using resting-state functional MRI and magnetic resonance spectroscopy. Granger causal analysis was seeded from right anterior insula (rAI) to locate individualized left DLPFC rTMS targets. Effective connectivity coefficients within rAI and DLPFC were calculated, and levels of GABA/Glx, GABA/Cr and Glx/Cr in DLPFC and anterior cingulate voxels were also measured. ITBS significantly dampened fronto-insular connectivity and reduced GABA/Glx in both voxels. GABA/Glx had a significant mediating effect on iTBS-induced changes in DLPFC-to-rAI connectivity. We demonstrate modulation of the rAI using targeted iTBS through alterations of excitatory/inhibitory interactions, which may underlie therapeutic effects of rTMS, offering promise for rTMS treatment optimization.

Transcranial magnetic stimulation for geriatric depression: Promises and pitfalls.

As the global population gets older, depression in the elderly is emerging as an important health issue. A major challenge in treating geriatric depression is the lack of robust efficacy for many treatments that are of significant benefit to depressed working age adults. Repetitive transcranial magnetic stimulation (rTMS) is a novel physical treatment approach used mostly in working age adults with depression. Many TMS trials and clinics continue to exclude the elderly from treatment citing lack of evidence in this age group. In this review, we appraise the evidence regarding the safety and efficacy of rTMS in the elderly. A consistent observation supporting a high degree of tolerability and safety among the elderly patients emerged across the Randomised Controlled Trials and the uncontrolled trials. Further, there is no reliable evidence negating the utility of rTMS in the elderly with depression. We also identified several factors other than age that moderate the observed variations in the efficacy of rTMS in the elderly. These factors include but not limited to: (1) brain atrophy; (2) intensity and number of pulses (dose-response relationship); and (3) clinical profile of patients. On the basis of the current evidence, the practice of excluding elderly patients from TMS clinics and trials cannot be supported.

The role of the cerebellum in sub- and supraliminal error correction during sensorimotor synchronization: evidence from fMRI and TMS.

Our ability to interact physically with objects in the external world critically depends on temporal coupling between perception and movement (sensorimotor timing) and swift behavioral adjustment to changes in the environment (error correction). In this study, we investigated the neural correlates of the correction of subliminal and supraliminal phase shifts during a sensorimotor synchronization task. In particular, we focused on the role of the cerebellum because this structure has been shown to play a role in both motor timing and error correction. Experiment 1 used fMRI to show that the right cerebellar dentate nucleus and primary motor and sensory cortices were activated during regular timing and during the correction of subliminal errors. The correction of supraliminal phase shifts led to additional activations in the left cerebellum and right inferior parietal and frontal areas. Furthermore, a psychophysiological interaction analysis revealed that supraliminal error correction was associated with enhanced connectivity of the left cerebellum with frontal, auditory, and sensory cortices and with the right cerebellum. Experiment 2 showed that suppression of the left but not the right cerebellum with theta burst TMS significantly affected supraliminal error correction. These findings provide evidence that the left lateral cerebellum is essential for supraliminal error correction during sensorimotor synchronization.

The functional anatomical distinction between truth telling and deception is preserved among people with schizophrenia.

BACKGROUND: A recently emergent functional neuroimaging literature has described the functional anatomical correlates of deception among healthy volunteers, most often implicating the ventrolateral prefrontal and anterior cingulate cortices. To date, there have been no such imaging studies of people with severe mental illness. AIMS: To discover whether the brains of people with schizophrenia would manifest a similar functional anatomical distinction between the states of truthfulness and deceit. It is hypothesised that, as with healthy people, persons with schizophrenia will show activation in the ventrolateral prefrontal and anterior cingulate cortices when lying. METHOD: Fifty-two people satisfying Diagnostic and Statistical Manual of Mental Disorder-IV criteria for schizophrenia or schizoaffective disorder underwent functional magnetic resonance imaging at 3 T while responding truthfully or with lies to questions concerning their recent actions. Half the sample was concurrently experiencing delusions. RESULTS: As hypothesised, patients exhibited greater activity in ventrolateral prefrontal cortices while lying. Truthful responses were not associated with any areas of relatively increased activation. The presence or absence of delusions did not substantially affect these findings, although subtle laterality effects were discernible upon post hoc analyses. CONCLUSIONS: As in healthy cohorts, the brains of people with schizophrenia exhibit a functional anatomical distinction between the states of truthfulness and deceit. Furthermore, this distinction pertains even in the presence of delusions.

If brain scans really detected deception, who would volunteer to be scanned?

Recent neuroimaging studies investigating the neural correlates of deception among healthy people, have raised the possibility that such methods may eventually be applied during legal proceedings. Were this so, who would volunteer to be scanned? We report a "natural experiment" casting some light upon this question. Following broadcast of a television series describing our team's investigative neuroimaging of deception in 2007, we received unsolicited (public) correspondence for 12 months. Using a customized template to examine this material, three independent assessors unanimously rated 30 of an initial 56 communications as unequivocally constituting requests for a "scan" (to demonstrate their author's "innocence"). Compared with the rest, these index communications were more likely to originate from incarcerated males, who were also more likely to engage in further correspondence. Hence, in conclusion, if neuroimaging were to become an acceptable means of demonstrating innocence then incarcerated males may well constitute those volunteering for such investigation.

'Munchausen's syndrome by proxy' or a 'miscarriage of justice'? An initial application of functional neuroimaging to the question of guilt versus innocence.

'Munchausen's syndrome by proxy' characteristically describes women alleged to have fabricated or induced illnesses in children under their care, purportedly to attract attention. Where conclusive evidence exists the condition's aetiology remains speculative, where such evidence is lacking diagnosis hinges upon denial of wrong-doing (conduct also compatible with innocence). How might investigators obtain objective evidence of guilt or innocence? Here, we examine the case of a woman convicted of poisoning a child. She served a prison sentence but continues to profess her innocence. Using a modified fMRI protocol (previously published in 2001) we scanned the subject while she affirmed her account of events and that of her accusers. We hypothesized that she would exhibit longer response times in association with greater activation of ventrolateral prefrontal and anterior cingulate cortices when endorsing those statements she believed to be false (i.e., when she 'lied'). The subject was scanned 4 times at 3 Tesla. Results revealed significantly longer response times and relatively greater activation of ventrolateral prefrontal and anterior cingulate cortices when she endorsed her accusers' version of events. Hence, while we have not 'proven' that this subject is innocent, we demonstrate that her behavioural and functional anatomical parameters behave as if she were.