Plasticity and dystonia: a hypothesis shrouded in variability.

Studying plasticity mechanisms with Professor John Rothwell was a shared highlight of our careers. In this article, we discuss non-invasive brain stimulation techniques which aim to induce and quantify plasticity, the mechanisms and nature of their inherent variability and use such observations to review the idea that excessive and abnormal plasticity is a pathophysiological substrate of dystonia. We have tried to define the tone of our review by a couple of Professor John Rothwell's many inspiring characteristics; his endless curiosity to refine knowledge and disease models by scientific exploration and his wise yet humble readiness to revise scientific doctrines when the evidence is supportive. We conclude that high variability of response to non-invasive brain stimulation plasticity protocols significantly clouds the interpretation of historical findings in dystonia research. There is an opportunity to wipe the slate clean of assumptions and armed with an informative literature in health, re-evaluate whether excessive plasticity has a causal role in the pathophysiology of dystonia

Is negative self-referent bias an endophenotype for depression? An fMRI study of emotional self-referent words in twins at high vs. low risk of depression

Background: Negative cognitive bias and aberrant neural processing of self-referent emotional words seem to be trait-marks of depression. However, it is unclear whether these neurocognitive changes are present in unaffected first-degree relatives and constitute an illness endophenotype. Methods: Fifty-three healthy, never-depressed monozygotic or dizygotic twins with a co-twin history of depression (high-risk group: n = 26) or no first-degree family history of depression (low-risk group: n = 27) underwent neurocognitive testing and functional magnetic imaging (fMRI) as part of a follow-up cohort study. Participants performed a self-referent emotional word categorisation task and free word recall task followed by a recognition task during fMRI. Participants also completed questionnaires assessing mood, personality traits and coping strategies. Results: High-risk and low-risk twins (age, mean ± SD: 40 ± 11) were well-balanced for demographic variables, mood, coping and neuroticism. High-risk twins showed lower accuracy during self-referent categorisation of emotional words independent of valence and more false recollections of negative words than low-risk twins during free recall. Functional MRI yielded no differences between high-risk and low-risk twins in retrievalspecific neural activity for positive or negative words or during the recognition of negative versus positive words within the hippocampus or prefrontal cortex. Conclusions: The subtle display of negative recall bias is consistent with the hypothesis that self-referent negative memory bias is an endophenotype for depression. High-risk twins’ lower categorisation accuracy adds to the evidence for valence-independent cognitive deficits in individuals at familial risk for depression

Ergodicity-breaking reveals time optimal decision making in humans

Ergodicity describes an equivalence between the expectation value and the time average of observables. Applied to human behaviour, ergodic theories of decision-making reveal how individuals should tolerate risk in different environments. To optimise wealth over time, agents should adapt their utility function according to the dynamical setting they face. Linear utility is optimal for additive dynamics, whereas logarithmic utility is optimal for multiplicative dynamics. Whether humans approximate time optimal behavior across different dynamics is unknown. Here we compare the effects of additive versus multiplicative gamble dynamics on risky choice. We show that utility functions are modulated by gamble dynamics in ways not explained by prevailing decision theories. Instead, as predicted by time optimality, risk aversion increases under multiplicative dynamics, distributing close to the values that maximise the time average growth of in-game wealth. We suggest that our findings motivate a need for explicitly grounding theories of decision-making on ergodic considerations

Short-term effects of repetitive transcranial magnetic stimulation on sleep bruxism:a pilot study

The purpose of this study was to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on patients with sleep bruxism (SB). Twelve patients with SB were included in an open, single-intervention pilot study. rTMS at 1 Hz and an intensity of 80% of the active motor threshold was applied to the ‘hot spot' of the masseter muscle representation at the primary motor cortex bilaterally for 20 min per side each day for 5 consecutive days. The jaw-closing muscle electromyographic (EMG) activity during sleep was recorded with a portable EMG recorder at baseline, during rTMS treatment and at follow-up for 5 days. In addition, patients scored their jaw-closing muscle soreness on a 0–10 numerical rating scale (NRS). Data were analysed with analysis of variance. The intensity of the EMG activity was suppressed during and after rTMS compared to the baseline (P = 0.04; P = 0.02, respectively). The NRS score of soreness decreased significantly during and after rTMS compared with baseline (P < 0.01). These findings indicated a significant inhibition of jaw-closing muscle activity during sleep along with a decrease of muscle soreness. This pilot study raises the possibility of therapeutic benefits from rTMS in patients with bruxism and calls for further and more controlled studies

Left Dorsal Premotor Cortex and Supramarginal Gyrus Complement Each Other during Rapid Action Reprogramming

The ability to discard a prepared action plan in favor of an alternative action is critical when facing sudden environmental changes. We tested whether the functional contribution of left supramarginal gyrus (SMG) during action reprogramming depends on the functional integrity of left dorsal premotor cortex (PMd). Adopting a dual-site repetitive transcranial magnetic stimulation (rTMS) strategy, we first transiently disrupted PMd with “offline” 1Hz rTMS and then applied focal “online” rTMS to SMG whilst human subjects performed a spatially-precued reaction time task. Effective online rTMS of SMG but not sham rTMS of SMG increased errors when subjects had to reprogram their action in response to an invalid precue regardless of the type of preceding offline rTMS. This suggests that left SMG primarily contributes to the online updating of actions by suppressing invalidly prepared responses. Online rTMS of SMG additionally increased reaction times for correct responses in invalidly-precued trials, but only after offline rTMS of PMd. We infer that offline rTMS caused an additional dysfunction of PMd which increased the functional relevance of SMG for rapid activation of the correct response, and sensitized SMG to the disruptive effects of online rTMS. These results not only provide causal evidence that left PMd and SMG jointly contribute to action reprogramming, but also that the respective functional weight of these areas can be rapidly redistributed. This mechanism might constitute a generic feature of functional networks that allows for rapid functional compensation in response to focal dysfunctions

Unmixing oscillatory brain activity by EEG source localization and empirical mode decomposition

Neuronal activity is composed of synchronous and asynchronous oscillatory activity at different frequencies. The neuronal oscillations occur at time scales well matched to the temporal resolution of electroencephalography (EEG); however, to derive meaning from the electrical brain activity as measured from the scalp, it is useful to decompose the EEG signal in space and time. In this study, we elaborate on the investigations into source-based signal decomposition of EEG. Using source localization, the electrical brain signal is spatially unmixed and the neuronal dynamics from a region of interest are analyzed using empirical mode decomposition (EMD), a technique aimed at detecting periodic signals. We demonstrate, first in simulations, that the EMD is more accurate when applied to the spatially unmixed signal compared to the scalp-level signal. Furthermore, on EEG data recorded simultaneously with transcranial magnetic stimulation (TMS) over the hand area of the primary motor cortex, we observe a link between the peak to peak amplitude of the motor-evoked potential (MEP) and the phase of the decomposed localized electrical activity before TMS onset. The results thus encourage combination of source localization and EMD in the pursuit of further insight into the mechanisms of the brain with respect to the phase and frequency of the electrical oscillations and their cortical origin

Transcranial Magnetic Stimulation for the treatment of tinnitus: Effects on cortical excitability

<p>Abstract</p> <p>Background</p> <p>Low frequency repetitive transcranial magnetic stimulation (rTMS) has been proposed as an innovative treatment for chronic tinnitus. The aim of the present study was to elucidate the underlying mechanism and to evaluate the relationship between clinical outcome and changes in cortical excitability. We investigated ten patients with chronic tinnitus who participated in a sham-controlled crossover treatment trial. Magnetic-resonance-imaging and positron-emission-tomography guided 1 Hz rTMS were performed over the auditory cortex on 5 consecutive days. Active and sham treatments were separated by one week. Parameters of cortical excitability (motor thresholds, intracortical inhibition, intracortical facilitation, cortical silent period) were measured serially before and after rTMS treatment by using single- and paired-pulse transcranial magnetic stimulation. Clinical improvement was assessed with a standardized tinnitus-questionnaire.</p> <p>Results</p> <p>We noted a significant interaction between treatment response and changes in motor cortex excitability during active rTMS. Specifically, clinical improvement was associated with an increase in intracortical inhibition, intracortical facilitation and a prolongation of the cortical silent period. These results indicate that intraindividual changes in cortical excitability may serve as a correlate of response to rTMS treatment.</p> <p>Conclusion</p> <p>The observed alterations of cortical excitability suggest that low frequency rTMS may evoke long-term-depression like effects resulting in an improvement of subcortical inhibitory function.</p

Handwriting performance in the absence of visual control in writer's cramp patients: Initial observations

BACKGROUND: The present study was aimed at investigating the writing parameters of writer's cramp patients and control subjects during handwriting of a test sentence in the absence of visual control. METHODS: Eight right-handed patients with writer's cramp and eight healthy volunteers as age-matched control subjects participated in the study. The experimental task consisted in writing a test sentence repeatedly for fifty times on a pressure-sensitive digital board. The subject did not have visual control on his handwriting. The writing performance was stored on a PC and analyzed off-line. RESULTS: During handwriting all patients developed a typical dystonic limb posture and reported an increase in muscular tension along the experimental session. The patients were significantly slower than the controls, with lower mean vertical pressure of the pen tip on the paper and they could not reach the endmost letter of the sentence in the given time window. No other handwriting parameter differences were found between the two groups. CONCLUSION: Our findings indicate that during writing in the absence of visual feedback writer's cramp patients are slower and could not reach the endmost letter of the test sentence, but their level of automatization is not impaired and writer's cramp handwriting parameters are similar to those of the controls except for even lower vertical pressure of the pen tip on the paper, which is probably due to a changed strategy in such experimental conditions

Simply longer is not better: reversal of theta burst after-effect with prolonged stimulation

From all rTMS protocols at present, the theta burst stimulation (TBS) is considered the most efficient in terms of number of impulses and intensity required during a given stimulation. The aim of this study was to investigate the effects of inhibitory and excitatory TBS protocols on motor cortex excitability when the duration of stimulation was doubled. Fourteen healthy volunteers were tested under four conditions: intermittent theta bust stimulation (iTBS), continuous theta burst stimulation (cTBS), prolonged intermittent theta bust stimulation (ProiTBS) and prolonged continuous theta burst stimulation (ProcTBS). The prolonged paradigms were twice as long as the conventional TBS protocols. Conventional facilitatory iTBS converted into inhibitory when it was applied for twice as long, while the normally inhibitory cTBS became facilitatory when the stimulation duration was doubled. Our results show that TBS-induced plasticity cannot be deliberately enhanced simply by prolonging TBS protocols. Instead, when stimulating too long, after-effects will be reversed. This finding supplements findings at the short end of the stimulation duration range, where it was shown that conventional cTBS is excitatory in the first half and switches to inhibition only after the full length protocol. It is relevant for clinical applications for which an ongoing need for further protocol improvement is imminent

Altered orbitofrontal sulcogyral patterns in gambling disorder: a multicenter study

Gambling disorder is a serious psychiatric condition characterized by decision-making and reward processing impairments that are associated with dysfunctional brain activity in the orbitofrontal cortex (OFC). However, it remains unclear whether OFC functional abnormalities in gambling disorder are accompanied by structural abnormalities. We addressed this question by examining the organization of sulci and gyri in the OFC. This organization is in place very early and stable across life, such that OFC sulcogyral patterns (classified into Types I, II, and III) can be regarded as potential pre-morbid markers of pathological conditions. We gathered structural brain data from nine existing studies, reaching a total of 165 individuals with gambling disorder and 159 healthy controls. Our results, supported by both frequentist and Bayesian statistics, show that the distribution of OFC sulcogyral patterns is skewed in individuals with gambling disorder, with an increased prevalence of Type II pattern compared with healthy controls. Examination of gambling severity did not reveal any significant relationship between OFC sulcogyral patterns and disease severity. Altogether, our results provide evidence for a skewed distribution of OFC sulcogyral patterns in gambling disorder and suggest that pattern Type II might represent a pre-morbid structural brain marker of the disease. It will be important to investigate more closely the functional implications of these structural abnormalities in future work