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Abstract Background Treatment effects of conventional approaches with antipsychotics or psychosocial interventions are limited when it comes to reducing negative and cognitive symptoms in schizophrenia. While there is emerging clinical evidence that new, augmented protocols based on theta-burst stimulation can increase rTMS efficacy dramatically in depression, data on similar augmented therapies are limited in schizophrenia. The different patterns of network impairments in subjects may underlie that some but not all patients responded to given stimulation locations. Methods Therefore, we propose an augmented theta-burst stimulation protocol in schizophrenia by stimulating both locations connected to negative symptoms: (1) the left dorsolateral prefrontal cortex (DLPFC), and (2) the vermis of the cerebellum. Ninety subjects with schizophrenia presenting negative symptoms and aging between 18 and 55 years will be randomized to active and sham stimulation in a 1:1 ratio. The TBS parameters we adopted follow the standard TBS protocols, with 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) and an intensity of 100% active motor threshold. We plan to deliver 1800 stimuli to the left DLPFC and 1800 stimuli to the vermis daily in two 9.5-min blocks for 4 weeks. The primary endpoint is the change in negative symptom severity measured by the Positive and Negative Syndrome Scale (PANSS). Secondary efficacy endpoints are changes in cognitive flexibility, executive functioning, short-term memory, social cognition, and facial emotion recognition. The difference between study groups will be analyzed by a linear mixed model analysis with the difference relative to baseline in efficacy variables as the dependent variable and treatment group, visit, and treatment-by-visit interaction as independent variables. The safety outcome is the number of serious adverse events. Discussion This is a double-blind, sham-controlled, randomized medical device study to assess the efficacy and safety of an augmented theta-burst rTMS treatment in schizophrenia. We hypothesize that social cognition and negative symptoms of patients on active therapy will improve significantly compared to patients on sham treatment. Trial registration The study protocol is registered at “ClinicalTrials.gov” with the following ID: NCT05100888. All items from the World Health Organization Trial Registration Data Set are registered. Initial release: 10/19/2021.

Background: Prior studies have demonstrated that early treatment response with transcranial magnetic stimulation (TMS) can predict overall response, yet none have directly compared that predictive capacity between intermittent theta-burst stimulation (iTBS) and 10 Hz repetitive transcranial magnetic stimulation (rTMS) for depression. Our study sought to test the hypothesis that early clinical improvement could predict ultimate treatment response in both iTBS and 10 Hz rTMS patient groups and that there would not be significant differences between the modalities. Methods: We retrospectively evaluated response to treatment in 105 participants with depression that received 10 Hz rTMS (n = 68) and iTBS (n = 37) to the dorsolateral prefrontal cortex (DLPFC). Percent changes from baseline to treatment 10 (t10), and to final treatment (tf), were used to calculate confusion matrices including negative predictive value (NPV). Treatment non-response was defined as <50% reduction in PHQ-9 scores according to literature, and population, data-driven non-response was defined as <40% for 10 Hz and <45% for iTBS. Results: For both modalities, the NPV related to degree of improvement at t10. NPV for 10 Hz was 74%, 82% and 73% at t10 in those who failed to improve >20, >10, and >0% respectively; while iTBS NPV rates were 65, 71, and 60%. There were not significant differences between protocols at any t1o cut-off assessed, whether research defined 50% improvement as response or data driven kernel density estimates (p = 0.46-0.79). Conclusion: Patients who fail to achieve >10% improvement by t10 with both 10 Hz rTMS and iTBS therapies have 70-80% chance of non-response to treatment. With no significant differences between predictive capacities, identifying patients at-risk for non-response affords psychiatrists greater opportunity to adapt treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Treatment effects of conventional approaches with antipsychotics or psychosocial interventions are limited when it comes to reducing negative and cognitive symptoms in schizophrenia. While there is emerging clinical evidence that new, augmented protocols based on theta-burst stimulation can increase rTMS efficacy dramatically in depression, data on similar augmented therapies are limited in schizophrenia. The different patterns of network impairments in subjects may underlie that some but not all patients responded to given stimulation locations. Methods: Therefore, we propose an augmented theta-burst stimulation protocol in schizophrenia by stimulating both locations connected to negative symptoms: (1) the left dorsolateral prefrontal cortex (DLPFC), and (2) the vermis of the cerebellum. Ninety subjects with schizophrenia presenting negative symptoms and aging between 18 and 55 years will be randomized to active and sham stimulation in a 1:1 ratio. The TBS parameters we adopted follow the standard TBS protocols, with 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) and an intensity of 100% active motor threshold. We plan to deliver 1800 stimuli to the left DLPFC and 1800 stimuli to the vermis daily in two 9.5-min blocks for 4 weeks. The primary endpoint is the change in negative symptom severity measured by the Positive and Negative Syndrome Scale (PANSS). Secondary efficacy endpoints are changes in cognitive flexibility, executive functioning, short-term memory, social cognition, and facial emotion recognition. The difference between study groups will be analyzed by a linear mixed model analysis with the difference relative to baseline in efficacy variables as the dependent variable and treatment group, visit, and treatment-by-visit interaction as independent variables. The safety outcome is the number of serious adverse events. Discussion: This is a double-blind, sham-controlled, randomized medical device study to assess the efficacy and safety of an augmented theta-burst rTMS treatment in schizophrenia. We hypothesize that social cognition and negative symptoms of patients on active therapy will improve significantly compared to patients on sham treatment. Trial registration: The study protocol is registered at "ClinicalTrials.gov" with the following ID: NCT05100888. All items from the World Health Organization Trial Registration Data Set are registered. Initial release: 10/19/2021. [ABSTRACT FROM AUTHOR]

Background: Prior studies have demonstrated that early treatment response with transcranial magnetic stimulation (TMS) can predict overall response, yet none have directly compared that predictive capacity between intermittent theta-burst stimulation (iTBS) and 10 Hz repetitive transcranial magnetic stimulation (rTMS) for depression. Our study sought to test the hypothesis that early clinical improvement could predict ultimate treatment response in both iTBS and 10 Hz rTMS patient groups and that there would not be significant differences between the modalities. Methods: We retrospectively evaluated response to treatment in 105 participants with depression that received 10 Hz rTMS (n = 68) and iTBS (n = 37) to the dorsolateral prefrontal cortex (DLPFC). Percent changes from baseline to treatment 10 (t10), and to final treatment (tf), were used to calculate confusion matrices including negative predictive value (NPV). Treatment non-response was defined as <50% reduction in PHQ-9 scores according to literature, and population, data-driven non-response was defined as <40% for 10 Hz and <45% for iTBS. Results: For both modalities, the NPV related to degree of improvement at t10. NPV for 10 Hz was 80%, 63% and 46% at t10 in those who failed to improve >20, >10, and >0% respectively; while iTBS NPV rates were 65, 50, and 35%. There were not significant differences between protocols at any t10 cut-off assessed, whether research defined 50% improvement as response or data driven kernel density estimates (p = 0.22–0.44). Conclusion: Patients who fail to achieve >20% improvement by t10 with both 10 Hz rTMS and iTBS therapies have ~70% chance of non-response to treatment. With no significant differences between predictive capacities, identifying patients at-risk for non-response affords psychiatrists greater opportunity to adapt treatment strategies. [ABSTRACT FROM AUTHOR]

BackgroundPrior studies have demonstrated that early treatment response with transcranial magnetic stimulation (TMS) can predict overall response, yet none have directly compared that predictive capacity between intermittent theta-burst stimulation (iTBS) and 10 Hz repetitive transcranial magnetic stimulation (rTMS) for depression. Our study sought to test the hypothesis that early clinical improvement could predict ultimate treatment response in both iTBS and 10 Hz rTMS patient groups and that there would not be significant differences between the modalities.MethodsWe retrospectively evaluated response to treatment in 105 participants with depression that received 10 Hz rTMS (n = 68) and iTBS (n = 37) to the dorsolateral prefrontal cortex (DLPFC). Percent changes from baseline to treatment 10 (t10), and to final treatment (tf), were used to calculate confusion matrices including negative predictive value (NPV). Treatment non-response was defined as 20, >10, and >0% respectively; while iTBS NPV rates were 65, 71, and 60%. There were not significant differences between protocols at any t10 cut-off assessed, whether research defined 50% improvement as response or data driven kernel density estimates (p = 0.46–0.79).ConclusionPatients who fail to achieve >10% improvement by t10 with both 10 Hz rTMS and iTBS therapies have 70–80% chance of non-response to treatment. With no significant differences between predictive capacities, identifying patients at-risk for non-response affords psychiatrists greater opportunity to adapt treatment strategies.

• 20 Hz-rTMS induced more pronounced pain-relief than iTBS. • Scores of chronic fatigue decreased to a greater extent after 20 Hz-rTMS than iTBS. • Matching of rTMS frequency and intrinsic cortical oscillations may potentiate efficacy. High-frequency repetitive transcranial magnetic stimulation (rTMS) has been shown to reduce neuropathic pain, but intermittent "theta-burst" stimulation (iTBS) could be a better alternative because of shorter duration and greater ability to induce cortical plasticity. Here we compared head-to-head the pain-relieving efficacy of the two modalities when applied daily for 5 days to patients with neuropathic pain. Forty-six patients received 20 Hz-rTMS and/or iTBS protocols and 39 of them underwent the full two procedures in a random cross-over design. They rated pain intensity, sleep quality, fatigue and general health status daily during 5 consecutive weeks. Pain relief during the month following stimulation was superior after 20 Hz-rTMS relative to iTBS (F(1,38) = 4.645; p = 0.037). Correlation between respective levels of maximal relief showed a significant deviation toward the 20 Hz-rTMS effect. A greater proportion of individuals responded to 20 Hz-rTMS (52% vs 32%, 95 %CI[0.095–3.27]; p = 0.06), and reports of fatigue significantly improved after 20 Hz-rTMS relative to iTBS (p = 0.01). General health and sleep quality scores did not differentiate both techniques. High-frequency rTMS appeared superior to iTBS for neuropathic pain relief. Adequate matching between the oscillatory activity of motor cortex and that of rTMS may increase synaptic efficacy, thus enhancing functional connectivity of motor cortex with distant structures involved in pain regulation. [ABSTRACT FROM AUTHOR]

The hippocampus supports episodic memory via interaction with a distributed brain network. Previous experiments using network- targeted noninvasive brain stimulation have identified episodic memory enhancements and modulation of activity within the hippocampal network. However, mechanistic insights were limited because these effects were measured long after stimulation and therefore could have reflected various neuroplastic aftereffects with extended time courses. In this experiment with human subjects of both sexes, we tested for immediate stimulation impact on encoding-related activity of the hippocampus and immediately adjacent medial-temporal cortex by delivering theta-burst transcranial magnetic stimulation (TBS) concurrent with fMRI, as an immediate impact of stimulation would suggest an influence on neural activity. We reasoned that TBS would be particularly effective for influencing the hippocampus because rhythmic neural activity in the theta band is associated with hippocampal memory processing. First, we demonstrated that it is possible to obtain robust fMRI correlates of task-related activity during concurrent TBS. We then identified immediate effects of TBS on encoding of visual scenes. Brief volleys of TBS targeting the hippocampal network increased activity of the targeted (left) hippocampus during scene encoding and increased subsequent recollection. Stimulation did not influence activity during an intermixed numerical task with no memory demand. Control conditions using beta band and out-of-network stimulation also did not influence hippocampal activity or recollection. TBS targeting the hippocampal network therefore immediately impacted hippocampal memory processing. This suggests direct, beneficial influence of stimulation on hippocampal neural activity related to memory and supports the role of theta-band activity in human episodic memory. [ABSTRACT FROM AUTHOR]

Introduction: Repetitive transcranial magnetic stimulation (TMS) is increasingly used to treat neurocognitive symptoms in mood disorders. Intermittent theta burst stimulation (iTBS) is a brief version of TMS that may preferentially target cognitive functions. This study evaluated whether iTBS leads to cognitive improvements and associated increased hippocampal volumes in bipolar depression., Methods: In a two-site double-blind randomised sham controlled trial (NCT02749006), 16 patients received active iTBS to the Left Dorsolateral Prefrontal Cortex (DLPF) and 15 patients received sham stimulation across four weeks. A composite neuropsychological score and declarative memory scores served as the cognitive outcomes. Hippocampal volumes were derived from T1 weighted MRI scans using the longitudinal ComBat method to harmonise data across sites., Results: No significant improvements were observed in any cognitive variables in the active relative to the sham group; however, there was a trend for increased left hippocampal volume in the former. Left hippocampal volume increases were associated with improvements in nonverbal memory in the active group., Conclusions: Although cognitive improvements were not associated with iTBS, the finding that hippocampal volume increases were associated with memory improvement suggests there may be some level of prefrontal-temporal neuroplasticity that could support cognitive change in future studies of iTBS in bipolar disorder.

Objectives: Repetitive transcranial magnetic stimulation (rTMS), a noninvasive method for altering cortical excitability, is becoming a therapeutic strategy in auditory research institutions worldwide. Application of inhibiting rTMS on these overactive cortical regions can result in effective tinnitus suppression. The aim of this study is to investigate the efficacy of theta-burst rTMS in patients with chronic tinnitus. Study Design: Parallel randomized control study. Setting: Tertiary referral center. Patients: We enrolled 2 female and 20 male patients in this study. The evaluative tools included tinnitus frequency- and loudness-matching, tinnitus questionnaires (TQ), and the Tinnitus Handicap Inventory (THI). Methods: The orthogonal projection of the auditory cortex on the scalp was focalized. A figure-eight coil was placed on the surface of the skull over the targeted region with the intensity setting at 80% of the resting motor threshold. We delivered 900 pulses of theta-burst rTMS daily for 10 business days. Main Outcome Measures: Nine of twelve patients (75%) in the active-stimulation group reported tinnitus suppression following treatment with rTMS. The treatment led to reductions of 8.58 and 8.33 in the mean TQ global and THI scores, respectively. Tinnitus loudness also decreased significantly after delivering rTMS. Results: Descriptive analysis of the TQs revealed that patients experienced significant improvements in emotional distress levels and somatic symptoms. Conclusions: Our preliminary results demonstrate that theta-burst rTMS treatments offer a method of modulating tinnitus. Patients could benefit from emotional improvements, even more than auditory perceptive relief. Further studies are needed to establish a standard protocol and to clarify nervous propagation along the auditory and psychological projection following treatment with rTMS. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A burst of action potentials in hippocampal neurons is followed by a slow afterhyperpolarization (sAHP) that serves to limit subsequent firing. A reduction in the sAHP accompanies acquisition of several types of learning, whereas increases in the sAHP are correlated with cognitive impairment. The present study demonstrates in vitro that activity-dependent bidirectional plasticity of the sAHP does not require synaptic activation, and depends on the pattern of action potential firing. Whole-cell current-clamp recordings from CA1 pyramidal neurons in hippocampal slices from young rats (postnatal days14-24) were performed in blockers of synaptic transmission. The sAHP was evoked by action potential firing at gamma-related (50 Hz, gamma-AHP) or theta frequencies (5 Hz, theta-AHP), two firing frequencies implicated in attention and memory. Interestingly, when the gamma-AHP and theta-AHP were evoked in the same cell, a gradual potentiation of the gamma-AHP (186 ± 31%) was observed that was blocked using Ca2+ channel blockers nimodipine (10 μ m) or ω-conotoxin MVIIC (1 μ m). In experiments that exclusively evoked the sAHP with 50 Hz firing, the gamma-AHP was similarly potentiated (198 ± 44%). However, theta-burst firing pattern alone resulted in a decrease (65 ± 19%) of the sAHP. In these experiments, application of the h-channel blocker ZD7288 (25 μ m) selectively prevented enhancement of the gamma-AHP. These data demonstrate that induction requirements for bidirectional AHP plasticity depend on the pattern of action potential firing, and result from distinct mechanisms. The identification of novel mechanisms underlying AHP plasticity in vitro provides additional insight into the dynamic processes that may regulate neuronal excitability during learning in vivo. [ABSTRACT FROM AUTHOR]

A burst of action potentials in hippocampal neurons is followed by a slow afterhyperpolarization (sAHP) that serves to limit subsequent firing. A reduction in the sAHP accompanies acquisition of several types of learning, whereas increases in the sAHP are correlated with cognitive impairment. The present study demonstrates in vitro that activity-dependent bidirectional plasticity of the sAHP does not require synaptic activation, and depends on the pattern of action potential firing. Whole-cell current-clamp recordings from CA1 pyramidal neurons in hippocampal slices from young rats (postnatal days14-24) were performed in blockers of synaptic transmission. The sAHP was evoked by action potential firing at gamma-related (50 Hz, gamma-AHP) or theta frequencies (5 Hz, theta-AHP), two firing frequencies implicated in attention and memory. Interestingly, when the gamma-AHP and theta-AHP were evoked in the same cell, a gradual potentiation of the gamma-AHP (186 ± 31%) was observed that was blocked using Ca2+ channel blockers nimodipine (10 μ m) or ω-conotoxin MVIIC (1 μ m). In experiments that exclusively evoked the sAHP with 50 Hz firing, the gamma-AHP was similarly potentiated (198 ± 44%). However, theta-burst firing pattern alone resulted in a decrease (65 ± 19%) of the sAHP. In these experiments, application of the h-channel blocker ZD7288 (25 μ m) selectively prevented enhancement of the gamma-AHP. These data demonstrate that induction requirements for bidirectional AHP plasticity depend on the pattern of action potential firing, and result from distinct mechanisms. The identification of novel mechanisms underlying AHP plasticity in vitro provides additional insight into the dynamic processes that may regulate neuronal excitability during learning in vivo. [ABSTRACT FROM AUTHOR]

Abstract: When an object is repetitively lifted, the scaling of grip force is influenced by the mechanical properties of the preceding lift, suggesting the formation of a sensorimotor memory. Similar effects on force scaling are observed when the subsequent lift is performed with the hand opposite to the preceding lift. We used neuronavigated rTMS over the hand area of the dominant primary motor cortex to investigate its role in setting up sensorimotor memory. After ten lifts of a novel object with the dominant hand either rTMS or a period of motor rest commenced, until another set of lifts was performed with either the same or opposite hand. Compared to motor rest, rTMS caused underestimation of the object''s weight when given 10 or 30s after the previous set of lifts, but overestimation of the object''s weight when applied 60 or 120s after the previous set of lifts, regardless of the hand performing the lift. Our interpretation of the data is that (a) the primary motor cortex is essential for setting up sensorimotor memory related to the mechanical object properties during manipulation and (b) rTMS can induce bidirectional changes of grip efficiency within the dynamics of sensorimotor integration. [Copyright &y& Elsevier]

Abstract: Theta-burst stimulation of the stratum radiatum induces a negative shift in the reversal potential (RP) of γ-aminobutyric acid (GABA)-ergic postsynaptic currents (PSCs) in hippocampal CA1 neurons in brain slices from rats of age groups 3–4 days, 6–9 days and 3–4 weeks. Furosemide reversed the shift in the RP. The amplitude of the evoked PSC appeared to increase following the theta-burst stimulation but this increase was secondary to the change in the RP. These results indicate that the RP for GABA-ergic PSCs undergoes an activity-dependent plasticity in not only neonatal but also adult neurons presumably through an up-regulation of a K+-Cl− co-transporter. This plasticity can have significant implications for neuronal network activity in the central nervous system. Furthermore, these results indicate that studies on GABA-ergic synaptic efficacy require a careful, parallel monitoring of the RP. [Copyright &y& Elsevier]

Abstract: Cannabinoid ligands alter cognition and prevent long-term potentiation (LTP) of synaptic transmission, but the influence of endogenously formed cannabinoids (eCBs) on hippocampal LTP remains ambiguous. In the accompanying study, we showed that eCB levels regulated by cyclooxygenase-2 (COX-2) tonically decrease basal excitatory transmission. Here, we investigated the influence of eCBs on LTP in CA1 hippocampus. LTP elicited by moderate stimulations (20 or 50 pulses) was facilitated in slices treated with a CB1 antagonist, whereas LTP elicited with robust stimulations (100 or 200 pulses) was unchanged by CB1 blockade. LTP elicited with theta-burst stimulations also was facilitated with CB1 blockade, revealing a tonic inhibitory influence of eCBs on LTP induction. Conversely, inhibition of COX-2 prevented LTP elicited with theta burst stimulations. Inhibition of COX-1 or other routes of eCB degradation did not affect LTP. We conclude that COX-2 regulates the formation of CB1 ligands that negatively regulate LTP. [Copyright &y& Elsevier]

Abstract: Down syndrome (DS) is the most common genetically defined cause of intellectual disabilities. Both hippocampal function and volume seem to be disproportionally reduced in individuals with DS and in at least one aneuploid murine model of DS, the Ts65Dn mouse. Two previous studies by one research group [R.J. Siarey, J. Stoll, S.I. Rapport, Z. Galdzicki, Altered long-term potentiation in the young and old Ts65Dn mouse, a model for Down syndrome, Neuropharmacology 36 (1997) 1549–1554; R.J. Siarey, E.J. Carlson, C.J. Epstein, A. Balbo, S.I. Rapport, Z. Galdzicki, Increased synaptic depression in the Ts65Dn mouse, a model for mental retardation in Down syndrome, Neuropharmacology 38 (1999) 1917–1920] have reported deficits in long-term potentiation (LTP) induced by in vitro high-frequency stimulation (HFS) of hippocampal CA1 synapses of adult Ts65Dn mice. Here, we report on the results of our own investigation on LTP in Ts65Dn mice. This study was designed to confirm the previous findings and possibly shed some light onto potential mechanisms underlying the reported deficit in this important form of long-term synaptic plasticity in a mouse model of DS. LTP was induced in area CA1 with either theta burst stimulation (TBS) or HFS. Contrary to the previous reports, our results showed no significant difference in HFS-induced LTP between Ts65Dn and euploid littermate mice. We have found, however, a significant reduction of the amount of TBS-induced LTP in Ts65Dn mice compared to euploid controls. Because this specific LTP deficit can be rescued by bath application of picrotoxin (10μM), we hypothesize that an increase in GABA(A)-mediated inhibition or in plasticity of the inhibitory circuitry in Ts65Dn mice may underlie the observed deficits. However, future experiments to examine the state of hippocampus CA1 GABAergic inhibition in Ts65Dn mice will be necessary to further explore these hypotheses. [Copyright &y& Elsevier]

By definition, lying involves withholding the truth. Response inhibition may therefore be the cognitive function at the heart of deception. Neuroimaging research has shown that the same brain region that is activated during response inhibition tasks, namely the inferior frontal region, is also activated during deception paradigms. This led to the hypothesis that the inferior frontal region is the neural substrate critically involved in withholding the truth. In the present study, we critically examine the functional necessity of the inferior frontal region in withholding the truth during deception. We experimentally manipulated the neural activity level in right inferior frontal sulcus (IFS) by means of neuronavigated continuous theta-burst stimulation (cTBS). Individual structural magnetic resonance brain images (MRI) were used to allow precise stimulation in each participant. Twenty-six participants answered autobiographical questions truthfully or deceptively before and after sham and real cTBS. Deception was reliably associated with more errors, longer and more variable response times than truth telling. Despite the potential role of IFS in deception as suggested by neuroimaging data, the cTBS-induced disruption of right IFS did not affect response times or error rates, when compared to sham stimulation. The present findings do not support the hypothesis that the right IFS is critically involved in deception.