ELECTROPHYSIOLOGY OF BASAL GANGLIA (BG) CIRCUITRY AND DYSTONIA AS A MODEL OF MOTOR CONTROL DYSFUNCTION

The basal ganglia (BG) is a complex set of heavily interconnected nuclei located in the central part of the brain that receives inputs from the several areas of the cortex and projects via the thalamus back to the prefrontal and motor cortical areas. Despite playing a significant part in multiple brain functions, the physiology of the BG and associated disorders like dystonia remain poorly understood. Dystonia is a devastating condition characterized by ineffective, twisting movements, prolonged co-contractions and contorted postures. Evidences suggest that it occurs due to abnormal discharge patterning in BG-thalamocortocal (BGTC) circuitry. The central purpose of this study was to understand the electrophysiology of BGTC circuitry and its role in motor control and dystonia. Toward this goal, an advanced multi-target multi-unit recording and analysis system was utilized, which allows simultaneous collection and analysis of multiple neuronal units from multiple brain nuclei. Over the cause of this work, neuronal data from the globus pallidus (GP), subthalamic nucleus (STN), entopenduncular nucleus (EP), pallidal receiving thalamus (VL) and motor cortex (MC) was collected from normal, lesioned and dystonic rats under awake, head restrained conditions. The results have shown that the neuronal population in BG nuclei (GP, STN and EP) were characterized by a dichotomy of firing patterns in normal rats which remains preserved in dystonic rats. Unlike normals, neurons in dystonic rat exhibit reduced mean firing rate, increased irregularity and burstiness at resting state. The chaotic changes that occurs in BG leads to inadequate hyperpolarization levels within the VL thalamic neurons resulting in a shift from the normal bursting mode to an abnormal tonic firing pattern. During movement, the dystonic EP generates abnormally synchronized and elongated burst duration which further corrupts the VL motor signals. It was finally concluded that the loss of specificity and temporal misalignment between motor neurons leads to corrupted signaling to the muscles resulting in dystonic behavior. Furthermore, this study reveals the importance of EP output in controlling firing modes occurring in the VL thalamus

The Contribution of the Cerebello-thalamo-cortical Circuit to the Pathology of Non-dopaminergic Responsive Parkinson\u27s Disease Symptoms

It has been well established that motor symptoms in Parkinson’s disease (PD) are primarily associated with dopaminergic degeneration in the basal ganglia. However, symptoms which respond poorly to dopaminergic replacement, such as tremor, gait, and balance deficits, point to an alternative pathology to dysfunction of the basal ganglia. Over-activity of the cerebellum has been demonstrated in PD, however it is not entirely clear how the cerebellum might be affecting motor symptoms. A lack of consensus exists regarding how cerebellar over-activity might be influencing PD tremor, and whether resting and postural tremor are differentially influenced by cerebellar dysfunction. It is also unclear how cerebellar over-activity might be affecting gait and balance deficits in PD, even though the cerebellum is an important subcortical structure for the control of gait and balance. Thus, the aim of the current thesis was to assess how cerebellar over-activity may be influencing symptoms which respond poorly to dopamine replacement in PD by inhibiting cerebellar activity using repetitive transcranial magnetic stimulation (rTMS). Additionally, a direct comparison was made between the effects of stimulation targeted to the medial versus lateral cerebellum with the aim to localize the effect of cerebellar over-activity. Fifty PD participants were randomly assigned to receive stimulation over either the medial cerebellum (n=20), lateral cerebellum (n=20) or sham stimulation (n=10). 900 pulses at 1Hz were delivered at an intensity of 120% resting motor threshold determined from the first dorsal interosseous muscle representation in the primary motor cortex. Tremor was assessed quantitatively using a wireless finger accelerometer to record tremor. Balance was measured with objective, computerized protocols: modified clinical test of sensory integration and balance (m-CTSIB) and postural stability testing (PST). Spatiotemporal gait parameters were measured quantitatively during self-paced walking. All assessments were performed before and after either real or sham stimulation. Resting tremor frequency was reduced in tremor-dominant individuals, regardless of whether stimulation was applied over the medial (p=0.024) or lateral (p=0.033) cerebellum, but not in the sham group. Additionally, inhibition of the cerebellum did not result in modulation of gait and balance outcome measures. Hence, dysfunction of the cerebellum may be a contributing factor to resting tremor, but not gait and balance deficits in PD. Importantly, the improvements in resting tremor occurred without detriment to gait or balance, demonstrating the therapeutic potential of this stimulation protocol. Low frequency rTMS over the medial or lateral cerebellum provides promise of an alternative treatment for resting tremor in PD, a symptom that is poorly responsive to dopaminergic replacement

Sensorimotor integration in dystonia: pathophysiology and possible non-invasive approaches to therapy

Dystonia is a condition characterized by excessive and sustained muscle contractions causing abnormal postures and involuntary movements. The pathophysiology of dystonia includes loss of inhibition and abnormal plasticity in the somatosensory and motor systems; however, their contribution to the phenomenology of dystonia is still uncertain, and the possibility to target these abnormalities in an attempt to devise new treatments has not been thoroughly explored. This thesis describes how abnormal inhibition and plasticity in the somatosensory system of dystonic patients can be manipulated to ameliorate motor symptoms by means of peripheral stimulation. First, we characterized electrophysiological and behavioural markers of inhibition in the primary somatosensory cortex in a group of patients with idiopathic cervical dystonia (CD). Outcome measures included a) somatosensory temporal discrimination threshold (STDT); b) paired-pulse somatosensory evoked potentials (PP-SEP) tested with interstimulus intervals (ISIs) of 5, 20 and 40 ms; c) spatial somatosensory inhibition ratio (SIR) by measuring SEP interaction between simultaneous stimulation of the digital nerves in thumb and index finger; d) high-frequency oscillations (HFO) extracted from SEP obtained with stimulation of digital nerves of the index finger. This first investigation demonstrated that increased STDT in dystonia is related to reduced activity of inhibitory circuits within the primary somatosensory cortex, as reflected by reduced PP-SEP inhibition at ISI of 5 ms and reduced area of the late part of the HFO (l-HFO). In a second set of experiments, we applied high frequency repetitive somatosensory stimulation (HF-RSS), a patterned electric stimulation applied to the skin through surface electrodes, to the index finger in a sample of healthy subjects, with the aim to manipulate excitability and inhibition of the primary somatosensory (S1) and motor (M1) cortices. The former was assessed by the same methods used before (STDT, PP-SEP, HFO), with the addition of two psychophysical tasks designed to assess tactile spatial discrimination (grating orientation and bumps tests). Assessment of physiology of M1 was performed by means of short intracortical inhibition (SICI) assessed with TMS; this was performed with multiple conditioning stimulus (CS) intensities (70%, 80%, 90% of the active motor threshold) and with a insterstimulus interval (ISI) between conditioning and test stimulus of 3 ms. It was found that HF-RSS increased inhibition in S1 tested by PP-SEP and HFO; these changes were correlated with improvement in STDT. HF-RSS also enhanced bumps detection, while there was no change in grating orientation test. Finally, there was an increase in SICI, suggesting widespread changes in cortical sensorimotor interactions. Overall, these findings demonstrated that HF-RSS is able to modify the effectiveness of inhibitory circuitry in S1 and M1. The results obtained so far led us to hypothesize that HF-RSS could restore inhibition in dystonic patients, similar to what observed in healthy subjects. To test this, we applied HF-RSS on the index finger in a sample of patients with CD, and tested its effects with some of the outcome measures used before (STDT, PP-SEP, HFO, SIR, SICI). Unexpectedly, the results were opposite to what was predicted. Patients with CD showed a consistent, paradoxical response: after HF-RSS, they had reduced suppression of PP-SEP, as well as decreased HFO area and SICI, and increased SIR. STDT deteriorated after the stimulation protocol, and correlated with reduced measures of inhibition within S1 (PP-SEP at 5 ms ISI, l-HFO area). It was hypothesized that patients with CD have abnormal homeostatic inhibitory plasticity within the sensorimotor cortex and that this is responsible for their abnormal response to HF-RSS. Interestingly, this alteration in plasticity seems to be specific to idiopathic dystonia: when the same protocol was applied to patients with dystonia caused by lesions in the basal ganglia, the response was similar to healthy controls. This result suggests that reduced somatosensory inhibition and abnormal cortical plasticity are not strictly required for the clinical expression of dystonia, and that the abnormalities reported in idiopathic dystonia are not necessarily linked to basal ganglia damage. We then directed our attention to another form of peripheral electrical stimulation, delivered at low frequency (LF-RSS). Previous literature demonstrated that this pattern of stimulation had effects opposite to HF-RSS on tactile performance in healthy subjects; therefore, given the previous findings of abnormal response to HF-RSS in CD, we hypothesized that an inverse response might occur in these patients following LF-RSS as well. Our hypothesis was confirmed by the observation that LF-RSS, applied to the fingers in patients with CD, induced an increase in inhibition in the primary somatosensory and motor cortices. This was reflected by an improvement of STDT and an increase in PP-SEP suppression, HFO area and SICI. With this in mind, in the final project of the thesis, we tested the effects of HF-RSS and LF-RSS applied directly over two affected muscles in different groups of patients with focal hand dystonia (FHD), in an attempt to modulate involuntary muscle activity and, consequently, to ameliorate motor symptoms. Whereas HF-RSS was delivered synchronously over the two muscles, LF-RSS was given either synchronously or asynchronously. Outcome measures included a) PP-SEP obtained by direct stimulation of affected muscles, with ISIs of 5 and 30 ms; b) quantification of electromyographic (EMG) activity from tested muscles; c) SICI recorded from the affected muscles, with CS intensities ranging from 50% to 100% RMT and with an ISI of 3 ms; d) evaluation of hand function, assessed by the box and blocks test (BBT) and the nine-hole peg test (NHPT); e) SIR by measuring SEP interaction between simultaneous stimulation of the two muscles receiving repetitive stimulation. We confirmed the paradoxical response of dystonic patients to HF-RSS, which was reflected in decreased PP-SEP suppression and SICI and increased SIR. Importantly, this was paralleled by an increase in involuntary EMG activity and worse scores at the BBT and NHPT. This results were opposite when LF-RSS was delivered, either in its synchronous or asynchronous version, the latter being slightly more effective. Thus, LF-RSS was able to increase PP-SEP suppression and SICI, decrease SIR and reduce involuntary EMG activity, with consequent improvement in performance in the BBT and NHPT. Overall, our data provide novel insight into the neural mechanisms underlying loss of inhibition and deranged somatosensory plasticity in idiopathic dystonia and bring preliminary evidence that peripheral electrical stimulation can be used as a treatment in idiopathic focal hand dystonia

Oculomotor Deficits in Diseases of the Basal Ganglia: Parkinson\u27s and Huntington\u27s Diseases

Oculomotor deficits are now recognized as being present in several neurological diseases of the basal ganglia. The present report will focus primarily on those observed in Huntington\u27s and Parkinson\u27s diseases. Neuronal cell loss in the pars compacta of the substantia nigra, degeneration of the nigrostriatal pathway, and consequent depletion of the neurotransmitter dopamine is the most obvious etiological abnormality in Parkinson\u27s disease. Huntington\u27s disease, on the other hand, involves the selective genetically-driven atrophy of the striatum (caudate and putamen). In order to attempt to understand oculomotor dysfunction, as a component of basal ganglia disease, it is necessary to first establish a definition of the basal ganglia, its relevant connections, and their associated neurotransmitters and functions

Beta Oscillations in Working Memory, Executive Control of Movement and Thought, and Sensorimotor Function

Beta oscillations (~13 to 30Hz) have been observed during many perceptual, cognitive and motor processes in a plethora of brain recording studies. While the function of beta oscillations (hereafter ‘beta’ for short) is unlikely to be explained by any single monolithic description, we here discuss several convergent findings. In prefrontal cortex, increased beta appears at the end of a trial when working memory information needs to be erased. A similar clear-out function might apply during the stopping of action and the stopping of long-term memory retrieval (stopping thoughts), where increased prefrontal beta is also observed. A different apparent role for beta in prefrontal cortex occurs during the delay period of working memory tasks: it might serve to maintain the current contents and/or to prevent interference from distraction. We confront the challenge of relating these observations to the large literature on beta recorded from sensorimotor cortex. Potentially, the clear-out of working memory in prefrontal cortex has its counterpart in the post-movement clear-out of the motor plan in sensorimotor cortex. However, recent studies support alternative interpretations. In addition, we flag emerging research on different frequencies of beta and the relationship between beta and single neuron spiking. We also discuss where beta might be generated: basal ganglia, cortex, or both. We end by considering the clinical implications for adaptive deep brain stimulation