Elisabeth Rounis

Theta Burst Stimulation of the Human Motor Cortex

It has been 30 years since the discovery that repeated electrical stimulation of neural pathways can lead to long-term potentiation in hippocampal slices. With its relevance to processes such as learning and memory, the technique has produced a vast literature on mechanisms of synaptic plasticity in animal models. To date, the most promising method for transferring these methods to humans is repetitive transcranial magnetic stimulation (rTMS), a noninvasive method of stimulating neural pathways in the brain of conscious subjects through the intact scalp. However, effects on synaptic plasticity reported are often weak, highly variable between individuals, and rarely last longer than 30 min. Here we describe a very rapid method of conditioning the human motor cortex using rTMS that produces a controllable, consistent, long-lasting, and powerful effect on motor cortex physiology and behavior after an application period of only 20-190 s.

Frequency specific changes in regional cerebral blood flow and motor system connectivity following rTMS to the primary motor cortex.

Repetitive transcranial magnetic stimulation (rTMS) to the human primary motor cortex (M1) causes bidirectional changes in corticospinal excitability depending on the stimulation frequency used. We used functional brain imaging to compare the effects of 5 Hz and 1 Hz-rTMS on local and inter-regional connectivity within the motor system. Regional cerebral blood flow (rCBF) was measured as a marker of synaptic activity at rest and during freely selected finger movements. We hypothesized that increased cortical excitability induced by 5 Hz-rTMS over M1 has an opposite effect on the synaptic activity and the connectivity of the motor network from the decreased cortical excitability induced by 1 Hz-rTMS. rTMS at both frequencies induced similar changes in rCBF at the site of stimulation and within areas of the motor network engaged by the task. The two frequencies showed different effects on movement-related coupling between motor areas. Connectivity analyses also indicated a differential effect of 5 and 1 Hz-rTMS on motor network connectivity, suggesting a role for an inferomedial portion of left M1 and left dorsal premotor cortex in maintaining performance. These results suggest that rapid reorganization of the motor system occurs to maintain task performance during periods of altered cortical excitability. This reorganization differs according to the modulation of excitability which is a function of rTMS frequency. This study extends the work of Lee et al. (Lee, L., Siebner, H.R., Rowe, J.B., Rizzo, V. Rothwell, J.C. Frackowiak, R.S. Friston, K.J., 2003. Acute remapping within the motor system induced by low-frequency repetitive transcranial magnetic stimulation. J. Neurosci. 23, 5308-5318.) by providing evidence that the pattern of acute reorganization in the motor network following rTMS depends on the direction of conditioning.

Acute Changes in Frontoparietal Activity after Repetitive Transcranial Magnetic Stimulation over the Dorsolateral Prefrontal Cortex in a Cued Reaction Time Task

Lesion and functional imaging studies in humans have suggested that the dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), and intraparietal sulcus (IPS) are involved in orienting attention. A functional magnetic resonance imaging study supplemented by a behavioral experiment examined the effects of 5 Hz repetitive transcranial magnetic stimulation (rTMS) conditioning to the right and left DLPFC on reaction times and synaptic activity as indexed by changes in the blood oxygenation level-dependent (BOLD) signal during a cued choice reaction time task. Orienting precues were either correct (valid) or incorrect (invalid) with respect to the subsequent move cue. The effects of real and sham rTMS were compared for each site of stimulation. Invalid trials showed a significant increase in response times and increases in the BOLD signal in right frontal and parietal regions when compared with valid trials. Conditioning left DLPFC with rTMS led to decreased BOLD signal during performance of this reorienting task in areas including left VLPFC and left IPS. Comparing invalid to valid trials after right DLPFC conditioning revealed decreased BOLD signal in right VLPFC. Data from the behavioral study showed that right DLPFC rTMS selectively increases response times in invalid trials. This effect was only present in the first 10 min after rTMS conditioning. No effect was found in either validly or invalidly cued trials with left DLPFC conditioning. These results suggest that 5 Hz rTMS over right DLPFC exerts remote effects on the activity of areas that functionally interact with the DLPFC during attentional processes, particularly when the reorienting of attention is more demanding as in invalid trials.

Altered Dorsal Premotor-Motor Interhemispheric Pathway Activity in Focal Arm Dystonia

Given the possible role of dorsal premotor cortex (PMd) in the pathophysiology of dystonia, we used transcranial magnetic stimulation (TMS) methods to study PMd and PMd–primary motor cortex (M1) interactions in patients with focal arm dystonia. Here, we tested the connectivity between left PMd and right M1 as well as the intracortical excitability of PMd in 11 right‐handed patients with focal arm/hand dystonia and nine age‐matched healthy controls. The results showed that excitability of the inhibitory connection between PMd and M1 was reduced in patients, but there was no significant difference to healthy subjects in the excitability of the facilitatory connection. A triple stimulation technique in which pairs of TMS pulses are given over PMd and their interaction measured in terms of the effect on the baseline PMd‐M1 connection failed to reveal the usual pattern of interaction between the pairs of PMd stimuli. Indeed, the results in patients were similar to those seen in a group of young healthy subjects after the excitability of PMd had been changed by pretreatment with high‐frequency rTMS. We suggest that reduced transcallosal inhibition from the PMd may be involved in the altered pattern of abnormal muscle contractions of agonists and antagonists (overflow).

Effects of rTMS Conditioning over the Fronto-parietal Network on Motor versus Visual Attention

Many studies have shown that visuospatial orienting attention depends on a network of frontal and parietal areas in the right hemisphere. Rushworth et al. [Rushworth, M. F., Krams, M., & Passingham, R. E. The attentional role of the left parietal cortex: The distinct lateralization and localization of motor attention in the human brain. Journal of Cognitive Neuroscience, 13, 698710, 2001] have recently provided evidence for a left-lateralized network of parietal areas involved in motor attention. Using two variants of a cued reaction time (RT) task, we set out to investigate whether high-frequency repetitive transcranial magnetic stimulation (rTMS; 5 Hz) delivered off-line in a virtual lesion paradigm over the right or left dorsolateral prefrontal cortex (DLPFC) or the posterior parietal cortex (PPC) would affect performance in a motor versus a visual attention task. Although rTMS over the DLPFC on either side did not affect RT performance on a spatial orienting task, it did lead to an increase in the RTs of invalidly cued trials in a motor attention task when delivered to the left DLPFC. The opposite effect was found when rTMS was delivered to the PPC: In this case, conditioning the right PPC led to increased RTs in invalidly cued trials located in the left hemispace, in the spatial orienting task. rTMS over the PPC on either side did not affect performance in the motor attention task. This double dissociation was evident in the first 10 min after rTMS conditioning. These results enhance our understanding of the networks associated with attention. They provide evidence of a role for the left DLPFC in the mechanisms of motor preparation, and confirm Mesulams original proposal for a right PPC dominance in spatial attention [Mesulam, M. M. A cortical network for directed attention and unilateral neglect. Annals of Neurology, 10, 309325, 1981].

Limb apraxia and the "affordance competition hypothesis".

Limb apraxia, a disorder of higher order motor control, has long been a challenge for clinical assessment and understanding (Leiguarda and Marsden, 2000). The deficits originally described in limb apraxia (Liepmann, 1920) have been classified by the nature of the errors made by the patients leading to, namely, ideational and ideomotor apraxia. The dual stream hypothesis (Goodale and Milner, 1992) has been used to explain these categories: ideational apraxia is thought to relate to a deficit in the concept of a movement (coded in the ventral stream). Patients have difficulty using objects, sequencing actions to interact with them or pantomiming their use. Ideomotor apraxia, on the other hand, is thought to arise from problems in the accurate implementation of movements within the dorsal stream. One of the limitations on understanding apraxia is the failure by the clinical literature to draw on knowledge of the factors determining actions in the environment. Here we emphasize the role of affordance. There is much recent work indicating that our responses to stimuli are strongly influenced by the actions that the objects “afford”, based on their physical properties and the intentions of the actor (e.g., Tucker and Ellis, 1998). The concept of affordance, originally suggested by Gibson (1979) has been incorporated in a recent model of interactive behavior that draws from findings in non-human primates, namely the “affordance competition hypothesis” (Cisek, 2007). This postulates that interactive behavior arises by a process of competition between possible actions elicited by the environment. In this paper we argue that “affordance competition” may play a role in apraxia. We review evidence that at least some aspects of apraxia may reflect an abnormal sensitivity to competition when multiple affordances are present (Riddoch et al., 1998) and/or a poor ability to exert cognitive control over this competition when it occurs. This framework suggests a new way of conceptualizing deficits in apraxia which invites further investigations in the field.

Factors influencing planning of a familiar grasp to an object: what it is to pick a cup.

We assessed the factors influencing the planning of actions required to manipulate one of two everyday objects with matching dimensions but openings at opposite ends: a cup and a vase. We found that, for cups, measures of movement preparation to reach and grasp the object were influenced by whether the grasp was made to the functional part of the object (wide opening) and whether the action would end in a supinated as opposed to a pronated grasp. These factors interacted such that effects of hand posture were found only when a less familiar grasp was made to the non-functional part of the cup (the base). These effects were not found with the vase, which has a less familiar location for grasping. We interpret the results in terms of a parallel model of action selection, modulated by both the familiarity of the grasp to a part of the object, likely to reflect object ‘affordances’ and the end state comfort of the action.

A direct effect of perception on action when grasping a cup

Affordances represent features of an object that trigger specific actions. Here we tested whether the presence and orientation of a handle on a cup could bias grasping movements towards it in conditions where subjects were explicitly told to ignore the handle. We quantified the grip aperture profile of twelve healthy participants instructed to grasp a cup from its body while it either had no handle, a handle pointing towards, or away from the grasping hand (3 ‘move’ conditions, with large grip aperture). To ensure the smaller grip aperture afforded by the handle was implicitly processed, we interspersed trials in which participants had to grasp the cup from its handle or a handle not attached to a cup with a small grip aperture. We found that grip aperture was smaller in the presence of a handle in the ‘move’ conditions, independently of its orientation. Our finding, of an effect of the handle during the execution of a grasp action, extends previous evidence of such an influence measured during motor preparation using simple reaction times. It suggests that the specific action elicited by an object’s attribute can affect movement performance in a sustained manner throughout movement execution.

To start immune therapy or not? An unusual presentation of longitudinally extensive transverse myelitis with pyrexia

We present the case of a patient with rapidly progressive transverse myelitis and fevers. A 26-year-old man, with no recent history of illnesses or foreign travel, was transferred to the John Radcliffe Hospital in Oxford with a 5-day history of bladder disturbance and loss of perineal sensation, followed by ascending sensorimotor deficits, beginning in his legs and spreading to his arms. Around 48–72 h after symptom onset, he developed fevers and became tachycardic. Neurological examination revealed increased tone in both legs with bilateral ankle clonus. He had pyramidal-pattern lower limb weakness. Reflexes were brisk throughout with crossed adductor jerks and extensor plantar responses. There was a sensory level to pin prick at T8. Vibration sense was reduced to the knees and joint position sense to the ankles bilaterally. He required catheterization after a bladder scan revealed a 500 ml post-void residual. During his admission, his temperature rose to more than 39 °C and was associated with symptoms of rigors and tachycardia. Blood tests revealed an elevated white cell count (22 × 109/L) with a neutrophilia (18 × 109) and a CRP of 100 mg/L. The patient had a series of blood cultures which did not grow any organisms. TB cultures from serum and Elispot IGRA were also negative. HIV, mycoplasma, borrelia and syphilis serology were all negative. His ANA, beta2 microglobulin, rheumatoid factor, complement levels and serum angiotensin converting enzyme were normal or negative. Initial cerebrospinal fluid (CSF) analysis revealed a white cell count of 379 × 106 (90% lymphocytes, 10% polymorphs; there were 356 × 106 red cells). No organisms were grown. The CSF protein was marginally elevated at 600 mg/L. CSF glucose was normal. Oligoclonal IgG bands were paired in CSF and serum. Histopathological analysis of his CSF revealed a lymphocytic inflammatory pleocytosis. TB Elispot and TB CSF PCR were subsequently negative. Flow cytometry was normal. A CT scan of his chest, abdomen and pelvis was also normal. The patient was treated with intravenous meropenem, ceftriaxone and acyclovir for a presumed systemic or central nervous system infection, whilst waiting for the results of his investigations. However, his fevers did not improve. After completing a course of antibiotics and with negative cultures and PCR for Herpes Simplex Virus, his antimicrobials and antivirals were stopped. His inflammatory markers normalized, but, nonetheless, he continued to experience a swinging pyrexia (Fig. 1). An initial unenhanced MRI scan of his whole spine demonstrated a longitudinally extensive transverse myelitis (LETM; Fig. 1a). A follow-up MRI of his brain and spine with gadolinium enhancement was performed 3 days later. This showed florid, patchy leptomeningeal enhancement along the cerebellar folia bilaterally. However, there was no leptomeningeal enhancement or parenchymal enhancement of the spinal cord. Antibody-testing demonstrated negative aquaporin 4, but positive anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in both serum and CSF, using an immunofluorescence assay previously described by our group [1]. He was initiated on immune therapy with intravenous immunoglobulins (IvIg). His temperature rapidly lysed and did not return * E. Rounis elisabeth.rounis@ndcn.ox.ac.uk