Continuous Theta-Burst Stimulation of the Contralesional Primary Motor Cortex for Promotion of Upper Limb Recovery After Stroke: A Randomized Controlled Trial.

BACKGROUND: Despite improvements in acute stroke therapies and rehabilitation strategies, many stroke patients are left with long-term upper limb motor impairment. We assessed whether an inhibitory repetitive transcranial magnetic stimulation treatment paradigm started within 3 weeks after stroke onset promotes upper limb motor recovery. METHODS: We performed a single-center randomized, sham-controlled clinical trial. Patients with ischemic stroke or intracerebral hemorrhage and unilateral upper limb motor impairment were randomized to 10 daily sessions of active or sham continuous theta-burst stimulation (cTBS) of the contralesional primary motor cortex combined with standard upper limb therapy, started within 3 weeks after stroke onset. The primary outcome was the change in the Action Research Arm Test score from baseline (pretreatment) at 3 months after stroke. Secondary outcomes included the score on the modified Rankin Scale at 3 months and the length of stay at the rehabilitation center. Statistical analyses were performed using mixed models for repeated measures. RESULTS: We enrolled 60 patients between April 2017 and February 2021, of whom 29 were randomized to active cTBS and 31 to sham cTBS. One patient randomized to active cTBS withdrew consent before the intervention and was excluded from the analyses. The mean difference in the change in Action Research Arm Test score from baseline at 3 months poststroke was 9.6 points ([95% CI, 1.2-17.9]; P=0.0244) in favor of active cTBS. Active cTBS was associated with better scores on the modified Rankin Scale at 3 months (OR, 0.2 [95% CI, 0.1-0.8]; P=0.0225) and with an 18 days shorter length of stay at the rehabilitation center than sham cTBS ([95% CI, 0.0-36.4]; P=0.0494). There were no serious adverse events. CONCLUSIONS: Ten daily sessions of cTBS of the contralesional primary motor cortex combined with upper limb training, started within 3 weeks after stroke onset, promote recovery of the upper limb, reduce disability and dependence and leads to earlier discharge from the rehabilitation center. REGISTRATION: URL: https://trialsearch.who.int/; Unique identifier: NTR6133.

Structural Thalamofrontal Hypoconnectivity Is Related to Oculomotor Corollary Discharge Dysfunction in Schizophrenia.

By predicting sensory consequences of actions, humans can distinguish self-generated sensory inputs from those that are elicited externally. This is one mechanism by which we achieve a subjective sense of agency over our actions. Corollary discharge (CD) signals-"copies" of motor signals sent to sensory areas-permit such predictions, and CD abnormalities are a hypothesized mechanism for the agency disruptions in schizophrenia that characterize a subset of symptoms. Indeed, behavioral evidence of altered CD, including in the oculomotor system, has been observed in schizophrenia patients. A pathway projecting from the superior colliculus to the frontal eye fields (FEFs) via the mediodorsal thalamus (MD) conveys oculomotor CD associated with saccadic eye movements in nonhuman primates. This animal work provides a promising translational framework in which to investigate CD abnormalities in clinical populations. In the current study, we examined whether structural connectivity of this MD-FEF pathway relates to oculomotor CD functioning in schizophrenia. Twenty-two schizophrenia patients and 24 healthy control participants of both sexes underwent diffusion tensor imaging, and a large subset performed a trans-saccadic perceptual task that yields measures of CD. Using probabilistic tractography, we identified anatomical connections between FEF and MD and extracted indices of microstructural integrity. Patients exhibited compromised microstructural integrity in the MD-FEF pathway, which was correlated with greater oculomotor CD abnormalities and more severe psychotic symptoms. These data reinforce the role of the MD-FEF pathway in transmitting oculomotor CD signals and suggest that disturbances in this pathway may relate to psychotic symptom manifestation in patients.SIGNIFICANCE STATEMENT People with schizophrenia sometimes experience abnormalities in a sense of agency, which may stem from abnormal sensory predictions about their own actions. Consistent with this notion, the current study found reduced structural connectivity in patients with schizophrenia in a specific brain pathway found to transmit such sensorimotor prediction signals in nonhuman primates. Reduced structural connectivity was correlated with behavioral evidence for impaired sensorimotor predictions and psychotic symptoms.

Functional connectivity of the frontotemporal network in preattentive detection of abstract changes: Perturbs and observes with transcranial magnetic stimulation and event-related optical signal.

Current theories of automatic or preattentive change detection suggest a regularity or prediction violation mechanism involving functional connectivity between the inferior frontal cortex (IFC) and the superior temporal cortex (STC). By disrupting the IFC function with transcranial magnetic stimulation (TMS) and recording the later STC mismatch response with event-related optical signal (EROS), previous study demonstrated a causal IFC-to-STC functional connection in detecting a pitch or physical change. However, physical change detection can be achieved by memory comparison of the physical features and may not necessarily involve regularity/rule extraction and prediction. The current study investigated the IFC-STC functional connectivity in detecting rule violation (i.e., an abstract change). Frequent standard tone pairs with a constant relative pitch difference, but varying pitches, were presented to establish a pitch interval rule. This abstract rule was violated by deviants with reduced relative pitch intervals. The EROS STC mismatch response to the deviants was abolished by the TMS applied at the IFC 80 ms after deviance onset, but preserved in the spatial (TMS on vertex), auditory (TMS sound), and temporal (200 ms after deviance onset) control conditions. These results demonstrate the IFC-STC connection in preattentive abstract change detection and support the regularity or prediction violation account.

Design and Evaluation of a Rodent-Specific Transcranial Magnetic Stimulation Coil: An In Silico and In Vivo Validation Study.

BACKGROUND: Rodent models are fundamental in unraveling cellular and molecular mechanisms of transcranial magnetic stimulation (TMS)-induced effects on the brain. However, proper translation of human TMS protocols to animal models have been restricted by the lack of rodent-specific focal TMS coils. OBJECTIVE: We aimed to improve TMS focalization in rodent brain with a novel small, cooled, and rodent-specific TMS coil. METHODS: A rodent-specific 25-mm figure-of-eight TMS coil was developed. Stimulation focalization was simulated in silico for the rodent coil and a commercial human 50-mm figure-of-eight TMS coil. Both coils were also compared in vivo by electromyography measurements of brachialis motor evoked potential (MEP) responses to TMS at different brain sites in anesthetized rats (n = 6). Focalization was determined from the coils' level of stimulation laterality. Differences in MEPs were statistically analyzed with repeated-measures, within-subjects, ANOVA. RESULTS: In silico simulation results deemed the human coil insufficient for unilateral stimulation of the rat motor cortex, whereas lateralized electrical field induction was projected attainable with the rodent coil. Cortical, in vivo MEP amplitude measurements from multiple points in each hemisphere, revealed unilateral activation of the contralateral brachialis muscle, in absence of ipsilateral brachialis activation, with both coils. CONCLUSION: Computer simulations motivated the design of a smaller rodent-specific TMS coil, but came short in explaining the capability of a larger commercial human coil to induce unilateral MEPs in vivo. Lateralized TMS, as demonstrated for both TMS coils, corroborates their use in translational rodent studies, to elucidate mechanisms of action of therapeutic TMS protocols.

A novel concurrent TMS-fMRI method to reveal propagation patterns of prefrontal magnetic brain stimulation.

Major depressive disorder (MDD) is a severe mental disorder associated with high morbidity and mortality rates, which remains difficult to treat, as both resistance and recurrence rates are high. Repetitive transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (DLPFC) provides a safe and effective treatment for selected patients with treatment-resistant MDD. Little is known about the mechanisms of action of TMS provided to the left DLPFC in MDD and we can currently not predict who will respond to this type of treatment, precluding effective patient selection. In order to shed some light on the mechanism of action, we applied single pulse TMS to the left DLPFC in 10 healthy participants using a unique TMS-fMRI set-up, in which we could record the direct effects of TMS. Stimulation of the DLPFC triggered activity in a number of connected brain regions, including the subgenual anterior cingulate cortex (sgACC) in four out of nine participants. The sgACC is of particular interest, because normalization of activity in this region has been associated with relief of depressive symptoms in MDD patients. This is the first direct evidence that TMS pulses delivered to the DLPFC can propagate to the sgACC. The propagation of TMS-induced activity from the DLPFC to sgACC may be an accurate biomarker for rTMS efficacy. Further research is required to determine whether this method can contribute to the selection of patients with treatment resistant MDD who will respond to rTMS treatment.

Children with ADHD symptoms show decreased activity in ventral striatum during the anticipation of reward, irrespective of ADHD diagnosis.

BACKGROUND: Changes in reward processing are thought to be involved in the etiology of attention-deficit/hyperactivity disorder (ADHD), as well as other developmental disorders. In addition, different forms of therapy for ADHD rely on reinforcement principles. As such, improved understanding of reward processing in ADHD could eventually lead to more effective treatment options. However, differences in reward processing may not be specific to ADHD, but may be a trans-diagnostic feature of disorders that involve ADHD-like symptoms. METHODS: In this event-related fMRI study, we used a child-friendly version of the monetary incentive delay task to assess performance and brain activity during reward anticipation. Also, we collected questionnaire data to assess reward sensitivity in daily life. For final analyses, data were available for 27 typically developing children, 24 children with ADHD, and 25 children with an autism spectrum disorder (ASD) and ADHD symptoms. RESULTS: We found decreased activity in ventral striatum during anticipation of reward in children with ADHD symptoms, both for children with ADHD as their primary diagnosis and in children with autism spectrum disorder and ADHD symptoms. We found that higher parent-rated sensitivity to reward was associated with greater anticipatory activity in ventral striatum for children with ADHD symptoms. In contrast, there was no relationship between the degree of ADHD symptoms and activity in ventral striatum. CONCLUSIONS: We provide evidence of biological and behavioral differences in reward sensitivity in children with ADHD symptoms, regardless of their primary diagnosis. Ultimately, a dimensional brain-behavior model of reward sensitivity in children with symptoms of ADHD may be useful to refine treatment options dependent on reward processing.

What to expect and when to expect it: an fMRI study of expectancy in children with ADHD symptoms.

Changes in cognitive control and timing have both been implicated in ADHD. Both are involved in building and monitoring expectations about the environment, and altering behavior if those expectations are violated. In ADHD, problems with expectations about future events have high face validity, as this would be associated with behavior that is inappropriate only given a certain context, similar to symptoms of the disorder. In this fMRI study, we used a timing manipulated go/nogo task to assess brain activity related to expectations about what (cognitive control) and when (timing) events would occur. We hypothesized that problems in building expectations about the environment are a more general, trans-diagnostic characteristic of children with hyperactive, impulsive and inattentive symptoms. To address this, we included children with ASD and symptoms of ADHD, in addition to children with ADHD and typically developing children. We found between-group differences in brain activity related to expectations about when (timing), but not what events will occur (cognitive control). Specifically, we found timing-related hypo-activity that was in part unique to children with a primary diagnosis of ADHD (left pallidum) and in part shared by children with similar levels of ADHD symptoms and a primary diagnosis of ASD (left subthalamic nucleus). Moreover, we found poorer task performance related to timing, but only in children with ASD and symptoms of ADHD. Ultimately, such neurobiological changes in children with ADHD symptoms may relate to a failure to build or monitor expectations and thereby hinder the efficiency of their interaction with the environment.

Speed of saccade execution and inhibition associated with fractional anisotropy in distinct fronto-frontal and fronto-striatal white matter pathways.

Fast cancellation or switching of action plans is a critical cognitive function. Rapid signal transmission is key for quickly executing and inhibiting responses, and the structural integrity of connections between brain regions plays a crucial role in signal transmission speed. In this study, we used the search-step task, which has been used in nonhuman primates to measure dynamic alteration of saccade plans, in combination with functional and diffusion-weighted MRI. Functional MRI results were used to identify brain regions involved in the reactive control of gaze. Probabilistic tractography was used to identify white matter pathways connecting these structures, and the integrity of these connections, as indicated by fractional anisotropy (FA), was correlated with search-step task performance. Average FA from tracts between the right frontal eye field (FEF) and both right supplementary eye field (SEF) and the dorsal striatum were associated with faster saccade execution. Average FA of connections between the dorsal striatum and both right SEF and right inferior frontal cortex (IFC) as well as between SEF and IFC predicted the speed of inhibition. These relationships were largely behaviorally specific, despite the correlation between saccade execution and inhibition. Average FA of connections between the IFC and both SEF and the dorsal striatum specifically predicted the speed of inhibition, and connections between the FEF and SEF specifically predicted the speed of execution. In addition, these relationships were anatomically specific; correlations were observed after controlling for global FA. These data suggest that networks supporting saccade initiation and inhibition are at least partly dissociable. Hum Brain Mapp 37:2811-2822, 2016. © 2016 Wiley Periodicals, Inc.

Proactive control of sequential saccades in the human supplementary eye field.

Our ability to regulate behavior based on past experience has thus far been examined using single movements. However, natural behavior typically involves a sequence of movements. Here, we examined the effect of previous trial type on the concurrent planning of sequential saccades using a unique paradigm. The task consisted of two trial types: no-shift trials, which implicitly encouraged the concurrent preparation of the second saccade in a subsequent trial; and target-shift trials, which implicitly discouraged the same in the next trial. Using the intersaccadic interval as an index of concurrent planning, we found evidence for context-based preparation of sequential saccades. We also used functional MRI-guided, single-pulse, transcranial magnetic stimulation on human subjects to test the role of the supplementary eye field (SEF) in the proactive control of sequential eye movements. Results showed that (i) stimulating the SEF in the previous trial disrupted the previous trial type-based preparation of the second saccade in the nonstimulated current trial, (ii) stimulating the SEF in the current trial rectified the disruptive effect caused by stimulation in the previous trial, and (iii) stimulating the SEF facilitated the preparation of second saccades based on previous trial type even when the previous trial was not stimulated. Taken together, we show how the human SEF is causally involved in proactive preparation of sequential saccades.

Frontal-subcortical circuits involved in reactive control and monitoring of gaze.

Rapid and reactive control of movement is essential in a dynamic environment and is disrupted in several neuropsychiatric disorders. Nonhuman primate neurophysiology studies have made significant contributions to our understanding of how saccadic eye movements can be rapidly inhibited, changed, and monitored. These results highlight a frontostriatal network involved in gaze control and provide a strong basis for understanding how cognitive control of action is implemented in the human brain. The goal of the present study was to bridge human and nonhuman primate studies by investigating reactive control of eye movements during fMRI using a task that has been used in neurophysiology studies: the search-step task. This task requires a speeded response to a visual target (no-step trial). On a minority (40%) of trials, the target jumps to a new location and participants are instructed to inhibit the initially planned saccade and redirect gaze toward the new location (redirect trial). Compared with no-step trials, greater activation in a frontal oculomotor network, including frontal and supplementary eye fields (SEFs), and the striatum was observed during correctly executed redirect trials. Individual differences in stopping efficiency were related to striatal activation. Further, greater activation in SEF was in a region anterior to that activated during visually guided saccades and scaled positively with error magnitude, suggesting a prominent role in response monitoring. Combined, these data lend new evidence for a role of the striatum in reactive saccade control and further clarify the role of SEF in action inhibition and performance monitoring.

Failure to use corollary discharge to remap visual target locations is associated with psychotic symptom severity in schizophrenia.

Corollary discharge (CD) refers to "copies" of motor signals sent to sensory areas, allowing prediction of future sensory states. They enable the putative mechanisms supporting the distinction between self-generated and externally generated sensations. Accordingly, many authors have suggested that disturbed CD engenders psychotic symptoms of schizophrenia, which are characterized by agency distortions. CD also supports perceived visual stability across saccadic eye movements and is used to predict the postsaccadic retinal coordinates of visual stimuli, a process called remapping. We tested whether schizophrenia patients (SZP) show remapping disturbances as evidenced by systematic transsaccadic mislocalizations of visual targets. SZP and healthy controls (HC) performed a task in which a saccadic target disappeared upon saccade initiation and, after a brief delay, reappeared at a horizontally displaced position. HC judged the direction of this displacement accurately, despite spatial errors in saccade landing site, indicating that their comparison of the actual to predicted postsaccadic target location relied on accurate CD. SZP performed worse and relied more on saccade landing site as a proxy for the presaccadic target, consistent with disturbed CD. This remapping failure was strongest in patients with more severe psychotic symptoms, consistent with the theoretical link between disturbed CD and phenomenological experiences in schizophrenia.

Feasibility of a randomized, sham-controlled pilot study for accelerated rTMS-treatment of the cerebellum plus physiotherapy in CANVAS patients.

BACKGROUND: Cerebellar ataxia, neuropathy and bilateral vestibular areflexia (CANVAS) is a rare neurodegenerative disease affecting the cerebellum, the peripheral nervous system and the vestibular system. Due to the lack of approved drugs, therapy comprises physiotherapy and speech therapy. Transcranial magnetic stimulation is a promising non-invasive therapeutic option to complement classical symptomatic therapies. OBJECTIVE: To test feasibility of the combination of transcranial magnetic stimulation using an accelerated protocol and standard symptomatic therapy in patients with CANVAS. METHODS: Eight patients with genetically confirmed CANVAS were assigned to either verum or sham cerebellar transcranial magnetic stimulation using an accelerated protocol. Treatment duration was limited to 5 days. Additionally, patients in both groups received symptomatic therapy (speech and physiotherapy) for the duration of the study. RESULTS: All patients completed the stimulation protocol. Adverse events were rare. Ataxia severity improved in the verum group only. CONCLUSION: The combination of transcranial magnetic stimulation and classic symptomatic therapy is feasible in a neuro-rehabilitation setting and potentially ameliorates ataxia severity.

Expectations and violations: delineating the neural network of proactive inhibitory control.

The ability to stop a prepared response (reactive inhibition) appears to depend on the degree to which stopping is expected (proactive inhibition). Functional MRI studies have shown that activation during proactive and reactive inhibition overlaps, suggesting that the whole neural network for reactive inhibition becomes already activated in anticipation of stopping. However, these studies measured proactive inhibition as the effect of stop-signal probability on activation during go trials. Therefore, activation could reflect expectation of a stop-signal (evoked by the stop-signal probability cue), but also violation of this expectation because stop-signals do not occur on go trials. We addressed this problem, using a stop-signal task in which the stop-signal probability cue and the go-signal were separated in time. Hence, we could separate activation during the cue, reflecting expectation of the stop-signal, from activation during the go-signal, reflecting expectation of the stop-signal or violation of that expectation. During the cue, the striatum, the supplementary motor complex (SMC), and the midbrain activated. During the go-signal, the right inferior parietal cortex (IPC) and the right inferior frontal cortex (IFC) activated. These findings suggest that the neural network previously associated with proactive inhibition can be subdivided into two components. One component, including the striatum, the SMC, and the midbrain, activated during the cue, implicating this network in proactive inhibition. Another component, consisting of the right IPC and the right IFC, activated during the go-signal. Rather than being involved in proactive inhibition, this network appears to be involved in processes associated with violation of expectations.

Aberrations in the arcuate fasciculus are associated with auditory verbal hallucinations in psychotic and in non-psychotic individuals.

The pathophysiology of auditory verbal hallucinations (AVH) is still unclear. Cognitive as well as electrophysiological studies indicate that a defect in sensory feedback (corollary discharge) may contribute to the experience of AVH. This could result from disruption of the arcuate fasciculus, the major tract connecting frontal and temporo-parietal language areas. Previous diffusion tensor imaging studies indeed demonstrated abnormalities of this tract in schizophrenia patients with AVH. It is, however, difficult to disentangle specific associations with AVH in this patient group as many other factors, such as other positive and negative symptoms, medication or halted education could likewise have affected tract integrity. We therefore investigated AVH in relative isolation and studied a group of non-psychotic individuals with AVH as well as patients with AVH and non-hallucinating matched controls. We compared tract integrity of the arcuate fasiculus and of three other control tracts, between 35 non-psychotic individuals with AVH, 35 schizophrenia patients with AVH, and 36 controls using diffusion tensor imaging and magnetization transfer imaging. Both groups with AVH showed an increase in magnetization transfer ratio (MTR) in the arcuate fasciculus, but not in the other control tracts. In addition, a general decrease in fractional anisotropy (FA) for almost all bundles was observed in the patient group, but not in the non-psychotic individuals with AVH. As increased MTR in the arcuate fasciculus was present in both hallucinating groups, a specific association with AVH seems plausible. Decreases in FA, on the other hand, seem to be related to other disease processes of schizophrenia.

Bilateral low-frequency repetitive transcranial magnetic stimulation of the auditory cortex in tinnitus patients is not effective: a randomised controlled trial.

BACKGROUND: Although some therapies may be beneficial for some patients in reducing tinnitus, there is no curative therapy. Repetitive transcranial magnetic stimulation (rTMS) has been applied as a treatment for chronic tinnitus, but the effect remains controversial. MATERIAL AND METHODS: Fifty patients were treated with rTMS or placebo. Treatment consisted of 2,000 TMS pulses on each auditory cortex, at a rate of 1 Hz and an intensity of 110% of the individual motor threshold, on 5 consecutive days. rTMS and placebo effects were evaluated directly after treatment, after 1 week, and after 1, 3 and 6 months. Primary outcome was the Tinnitus Questionnaire (TQ). Secondary outcomes were the Tinnitus Handicap Inventory (THI) and a visual analogue scale. RESULTS: At none of the follow-up evaluation moments a significant difference between rTMS and placebo was observed with respect to changes in TQ or THI scores relative to pretreatment scores. Multilevel modelling (MLM) analyses did not show a global treatment effect either. Patients with a higher degree of burden showed slightly greater improvement after rTMS (only significant on the THI with MLM analyses). CONCLUSION: Bilateral low-frequency rTMS of the auditory cortex was not effective in treating tinnitus.

Transcranial magnetic stimulation and motor plasticity in human lateral cerebellum: dual effect on saccadic adaptation.

The cerebellum is a key area for movement control and sensory-motor plasticity. Its medial part is considered as the exclusive cerebellar center controlling the accuracy and adaptive calibration of saccadic eye movements. However, the contribution of other zones situated in its lateral part is unknown. We addressed this question in healthy adult volunteers by using magnetic resonance imaging (MRI)-guided transcranial magnetic stimulation (TMS). The double-step target paradigm was used to adaptively lengthen or shorten saccades. TMS pulses over the right hemisphere of the cerebellum were delivered at 0, 30, or 60 ms after saccade detection in separate recording sessions. The effects on saccadic adaptation were assessed relative to a fourth session where TMS was applied to Vertex as a control site. First, TMS applied upon saccade detection before the adaptation phase reduced saccade accuracy. Second, TMS applied during the adaptation phase had a dual effect on saccadic plasticity: adaptation after-effects revealed a potentiation of the adaptive lengthening and a depression of the adaptive shortening of saccades. For the first time, we demonstrate that TMS on lateral cerebellum can influence plasticity mechanisms underlying motor performance. These findings also provide the first evidence that the human cerebellar hemispheres are involved in the control of saccade accuracy and in saccadic adaptation, with possibly different neuronal populations concerned in adaptive lengthening and shortening. Overall, these results require a reappraisal of current models of cerebellar contribution to oculomotor plasticity.

Decreased language lateralization is characteristic of psychosis, not auditory hallucinations.

Decreased language lateralization is a well-replicated finding in psychotic patients. It is currently unclear, however, whether this abnormality is related to a particular symptom of psychosis or to psychosis in general. It has been argued that decreased language lateralization may be related to auditory verbal hallucinations. To elucidate this, these hallucinations should be studied in isolation. Thirty-five patients with a psychotic disorder, 35 non-psychotic subjects with relatively isolated auditory verbal hallucinations and 35 healthy control subjects participated in this study. All subjects were scanned on a 3T magnetic resonance imaging scanner, while covertly performing a paced verbal fluency task. In order to measure performance on the task, one additional task block was presented during which subjects had to generate words overtly. In addition to calculating language lateralization indices, group-wise brain activation during verbal fluency was compared between the three groups. Task performance was nearly maximal for all groups and did not differ significantly between the groups. Compared with the healthy control subjects and non-psychotic subjects with auditory verbal hallucinations, language lateralization was significantly reduced for the patient group. In addition, the patients displayed significantly greater activity in the right precentral gyrus and left insula when compared with the healthy control subjects and the non-psychotic subjects with auditory verbal hallucinations. Furthermore, the patients showed greater activity in the right superior parietal lobule when compared with the healthy control subjects. Lateralization indices did not differ significantly between the non-psychotic subjects with auditory verbal hallucinations and the healthy control subjects. Moreover, there were no significant differences in brain activation during verbal fluency between the two non-psychotic groups. As language lateralization was not significantly reduced in the non-psychotic individuals with auditory verbal hallucinations, a direct relationship between auditory verbal hallucinations and decreased language lateralization can not be established at present.

Altered effective connectivity within an oculomotor control network in individuals with schizophrenia.

Rapid inhibition or modification of actions is a crucial cognitive ability, which is impaired in persons with schizophrenia (SZP). Primate neurophysiology studies have identified a network of brain regions that subserves control over gaze. Here, we examine effective connectivity within this oculomotor control network in SZP and healthy controls (HC). During fMRI, participants performed a stop-signal task variant in which they were instructed to saccade to a visual target (no-step trials) unless a second target appeared (redirect trials); on redirect trials, participants were instructed to inhibit the planned saccade and redirect to the new target. We compared functional responses on redirect trials to no-step trials and used dynamic causal modelling (DCM) to examine group differences in network effective connectivity. Behaviorally, SZP were less efficient at inhibiting, which was related to their employment status. Compared to HC, they showed a smaller difference in activity between redirect trials and no-step trials in frontal eye fields (FEF), supplementary eye fields (SEF), inferior frontal cortex (IFC), thalamus, and caudate. DCM analyses revealed widespread group differences in effective connectivity across the task, including different patterns of self-inhibition in many nodes in SZP. Group differences in how effective connectivity was modulated on redirect trials revealed differences between the FEF and SEF, between the SEF and IFC, between the superior colliculus and the thalamus, and self-inhibition within the FEF and caudate. These results provide insight into the neural mechanisms of inefficient inhibitory control in individuals with schizophrenia.

Altered Effective Connectivity within an Oculomotor Control Network in Unaffected Relatives of Individuals with Schizophrenia.

The ability to rapidly stop or change a planned action is a critical cognitive process that is impaired in schizophrenia. The current study aimed to examine whether this impairment reflects familial vulnerability to schizophrenia across two experiments comparing unaffected first-degree relatives to healthy controls. First, we examined performance on a saccadic stop-signal task that required rapid inhibition of an eye movement. Then, in a different sample, we investigated behavioral and neural responses (using fMRI) during a stop-signal task variant that required rapid modification of a prepared eye movement. Here, we examined differences between relatives and healthy controls in terms of activation and effective connectivity within an oculomotor control network during task performance. Like individuals with schizophrenia, the unaffected relatives showed behavioral evidence for more inefficient inhibitory processes. Unlike previous findings in individuals with schizophrenia, however, the relatives showed evidence for a compensatory waiting strategy. Behavioral differences were accompanied by more activation among the relatives in task-relevant regions across conditions and group differences in effective connectivity across the task that were modulated differently by the instruction to exert control over a planned saccade. Effective connectivity parameters were related to behavioral measures of inhibition efficiency. The results suggest that individuals at familial risk for schizophrenia were engaging an oculomotor control network differently than controls and in a way that compromises inhibition efficiency.

Antidepressant efficacy of low-frequency repetitive transcranial magnetic stimulation in antidepressant-nonresponding bipolar depression: a single-blind randomized sham-controlled trial.

BACKGROUND: To examine the antidepressant efficacy and response predictors of R-DLPFC-LF rTMS for antidepressant-nonresponding BD. METHODS: We conducted a single-blind randomized sham-controlled trial for 54 (28 sham, 26 active) patients with antidepressant-nonresponding BD (baseline MADRS ≥ 20). Patients received 15 daily sessions of active or sham neuronavigated rTMS (Figure-of-8 coil, five 1 Hz 60 s 110% RMT trains). Outcome measures included depressive response (≥ 50% MADRS reduction, CGI ≤ 2) and remission (MADRS < 7, CGI = 1) rates, treatment emergent hypo/mania (YMRS), depressive and anxiety symptoms (HAM-A). RESULTS: 48 patients (25 sham, 23 active) completed treatment, with 3 drop-outs each in active and sham groups. Active rTMS did not produce superior response or remission rates at endpoint or 6 or 12 weeks (ps > 0.05). There was no significant group * time interaction (ps > 0.05) in a multivariate ANOVA with MADRS, HAMA and YMRS as dependent variables. Exploratory analysis found MADRS improvement to be moderated by baseline anxiety (p = 0.02) and melancholia (p = 0.03) at week 3, and depressive onset at weeks 6 (p = 0.03) and 12 (p = 0.04). In subjects with below-mean anxiety (HAMA < 20.7, n = 24), MADRS improvement from active rTMS was superior to sham at week 3 (ITT, t = 2.49, p = 0.04, Cohen's d = 1.05). No seizures were observed. Groups did not differ in treatment-emergent hypomania (p = 0.1). LIMITATIONS: Larger sample size might be needed to power subgroup analyses. Moderation analyses were exploratory. Single-blind design. Unblinding before follow-up assessments due to ethical reasons. CONCLUSIONS: 1-Hz 110% RMT (5 × 60 s trains) R-DLPFC-LF rTMS was not effective for antidepressant non-responding BD but may be further investigated at increased dosage and/or in BD patients with low anxiety. Trial registration CCRB Clinical Trials Registry, CUHK, CUHK_CCT00440. Registered 04 December 2014, https://www2.ccrb.cuhk.edu.hk/registry/public/279.