Kaviraja Udupa

Effects of subthalamic nucleus stimulation on motor cortex plasticity in Parkinson disease.

Objective: We hypothesized that subthalamic nucleus (STN) deep brain stimulation (DBS) will improve long-term potentiation (LTP)-like plasticity in motor cortex in Parkinson disease (PD). Methods: We studied 8 patients with PD treated with STN-DBS and 9 age-matched healthy controls. Patients with PD were studied in 4 sessions in medication (Med) OFF/stimulator (Stim) OFF, Med-OFF/Stim-ON, Med-ON/Stim-OFF, and Med-ON/Stim-ON states in random order. Motor evoked potential amplitude and cortical silent period duration were measured at baseline before paired associated stimulation (PAS) and at 3 different time intervals (T0, T30, T60) up to 60 minutes after PAS in the abductor pollicis brevis and abductor digiti minimi muscles. Results: Motor evoked potential size significantly increased after PAS in controls (+67.7% of baseline at T30) and in patients in the Med-ON/Stim-ON condition (+55.8% of baseline at T30), but not in patients in the Med-OFF/Stim-OFF (−0.4% of baseline at T30), Med-OFF/Stim-ON (+10.3% of baseline at T30), and Med-ON/Stim-OFF conditions (+17.3% of baseline at T30). Cortical silent period duration increased after PAS in controls but not in patients in all test conditions. Conclusions: Our findings suggest that STN-DBS together with dopaminergic medications restore LTP-like plasticity in motor cortex in PD. Restoration of cortical plasticity may be one of the mechanisms of how STN-DBS produces clinical benefit.

The Nature and Time Course of Cortical Activation Following Subthalamic Stimulation in Parkinson's Disease

We studied the time course and nature of interactions between the subthalamic nucleus (STN) and the motor cortex in 8 Parkinson disease (PD) patients with chronically implanted STN deep-brain stimulation (DBS) electrodes. We first identified the cortical evoked potentials following STN stimulation. The most consistent potential was positive wave with peak latency of 22.2 +/- 1.2 ms from stimulation of clinically effective contacts. We then stimulated the motor cortex with transcranial magnetic stimulation (TMS) at 2-15 ms and at the latency of the evoked potential ( approximately 23 ms) following STN DBS. TMS induced currents in 3 directions: lateral-medial (LM) direction activated corticospinal axons directly, posterior-anterior (PA), and anterior-posterior (AP) directions activated corticospinal neurons transynaptically. Motor-evoked potentials (MEP) elicited by AP and PA TMS were facilitated at short (2-4 ms) and medium latencies (21-24 ms). However, MEPs elicited by LM TMS were not modified by STN DBS. Short-latency antidromic stimulation of the corticosubthalamic projections and medium latency transmission likely through the basal ganglia-thalamocortical circuit led to cortical evoked potentials and increased motor cortex excitability at specific intervals following STN stimulation at clinically effective contacts. Cortical activation may be related to the clinical effects of STN DBS in PD.

Transcranial Magnetic Stimulation in Different Current Directions Activates Separate Cortical Circuits

Transcranial magnetic stimulation (TMS) to the primary motor cortex (M1) produces a series of corticospinal descending waves, with a direct (D) wave followed by several indirect (I) waves. TMS inducing posterior-anterior (PA) current in the brain predominantly recruits the early I1-wave, whereas anterior-posterior (AP) directed current preferentially recruits the late I3-wave. However, it is not known whether I-waves elicited by different current directions are mediated by the same neuronal populations. We studied the neuronal mechanisms mediating I-waves by examining the influence of short-latency afferent inhibition (SAI) on various I-waves. SAI was tested with electrical median nerve stimulation at the wrist followed by TMS to the contralateral M1 at different current directions. Surface electromyograms and single motor units were recorded from the first dorsal interosseous muscle. SAI was weaker for the AP compared with that for the PA current direction. With increasing median nerve stimulation intensities, SAI increased for the PA direction but showed a U-shaped relationship for the AP direction. SAI produced more inhibition of late I-waves generated by PA than those generated by AP current direction. We conclude that late I-waves generated by PA and AP current directions are mediated by different neuronal mechanisms.

The mechanisms of action of deep brain stimulation and ideas for the future development

Deep brain stimulation (DBS) has been used as a treatment of movement disorders such as Parkinsons disease, dystonia, and essential tremor for over twenty years, and is a promising treatment for depression and epilepsy. However, the exact mechanisms of action of DBS are still uncertain, although different theories have emerged. This review summarizes the current understanding in this field. Different modalities used to investigate DBS such as electrophysiological, imaging and biochemical studies have revealed different mechanisms of DBS. The mechanisms may also be different depending on the structure targeted, the disease condition or the animal model employed. DBS may inhibit the target neuronal networks but activate the efferent axons. It may suppress pathological rhythms or impose new rhythms associated with beneficial effects, and involves neuronal networks with widespread connections. Different neurotransmitter systems such as dopamine and GABA upregulation are involved in the effects of DBS. There are also technical advances to prolong the battery life and specific targeting based on new electrode designs with multiple contacts which have the ability to steer the current toward a specific direction. There is ongoing work in closed loop or adaptive DBS using neural oscillations to provide the feedback signals. These oscillations need to be better characterized in a wide variety of clinical settings in future studies. Individualization of DBS parameters based on neural oscillations may optimize the clinical benefits of DBS.

Motor cortical plasticity in Parkinson's disease

In Parkinson’s disease (PD), there are alterations of the basal ganglia (BG) thalamocortical networks, primarily due to degeneration of nigrostriatal dopaminergic neurons. These changes in subcortical networks lead to plastic changes in primary motor cortex (M1), which mediates cortical motor output and is a potential target for treatment of PD. Studies investigating the motor cortical plasticity using non-invasive transcranial magnetic stimulation (TMS) have found altered plasticity in PD, but there are inconsistencies among these studies. This is likely because plasticity depends on many factors such as the extent of dopaminergic loss and disease severity, response to dopaminergic replacement therapies, development of l-DOPA-induced dyskinesias (LID), the plasticity protocol used, medication, and stimulation status in patients treated with deep brain stimulation (DBS). The influences of LID and DBS on BG and M1 plasticity have been explored in animal models and in PD patients. In addition, many other factors such age, genetic factors (e.g., brain derived neurotropic factor and other neurotransmitters or receptors polymorphism), emotional state, time of the day, physical fitness have been documented to play role in the extent of plasticity induced by TMS in human studies. In this review, we summarize the studies that investigated M1 plasticity in PD and demonstrate how these afore-mentioned factors affect motor cortical plasticity in PD. We conclude that it is important to consider the clinical, demographic, and technical factors that influence various plasticity protocols while developing these protocols as diagnostic or prognostic tools in PD. We also discuss how the modulation of cortical excitability and the plasticity with these non-invasive brain stimulation techniques facilitate the understanding of the pathophysiology of PD and help design potential therapeutic possibilities in this disorder.

Direct demonstration of inhibitory interactions between long interval intracortical inhibition and short interval intracortical inhibition

Non‐technical summary  Motor cortical output is suppressed by two cortical inhibitory systems, short interval intracortical inhibition (SICI) and long interval intracortical inhibition (LICI). SICI is decreased in the presence of LICI. However, there is a long‐standing argument whether this is caused by a true interaction between them or is due to simple saturation of the inhibitory effects that occur at common cortical elements which both inhibitory systems target. We addressed this question by recording the descending corticospinal waves in the subjects with implanted epidural electrodes. The results suggest that there are inhibitory interactions between LICI and SICI.

Effect of long interval interhemispheric inhibition on intracortical inhibitory and facilitatory circuits

Stimulation of the primary motor cortex (M1) of one hemisphere of the brain inhibits the opposite M1, a process known as interhemispheric inhibition (IHI). An early phase of IHI peaks at about ∼10 ms after stimulation of the opposite hemisphere and is termed short latency interhemispheric inhibition (SIHI). A later phase peaks at about 40 ms and has been termed long latency interhemispheric inhibition (LIHI). The objective of the present study is to test how LIHI interacts with cortical inhibitory and facilitatory circuits, including short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and long interval intracortical inhibition (LICI). We studied 10 healthy volunteers. LIHI from right to left hemisphere was elicited by stimulating the right M1 at an interstimulus interval (ISI) of 40 ms before stimulation of the left M1. Conditioning and test stimuli to elicit SICI, ICF and LICI were given to left M1. The effects of different sizes of test motor‐evoked potential (MEP amplitudes; 0.2, 1 and 2 mV) were examined for SICI, ICF, LICI and LIHI. Using paired‐pulse and triple‐pulse protocols, how LIHI interacts with SICI, ICF and LICI were investigated. We found SICI increased, while LICI and LIHI decreased with increasing test MEP amplitude. The presence of LIHI did not change the degree of SICI and intracortical facilitation (ICF), and their effects of these circuits were additive. On the other hand, LICI and LIHI were reduced in the presence of each other. We conclude that different sets of cortical neurons mediate LIHI, SICI, ICF and LICI. GABAB‐mediated LICI and LIHI have inhibitory interactions with each other while LIHI has an additive effect with GABAA‐mediated SICI.

Cortical Plasticity Induction by Pairing Subthalamic Nucleus Deep-Brain Stimulation and Primary Motor Cortical Transcranial Magnetic Stimulation in Parkinson's Disease

Noninvasive brain stimulation studies have shown abnormal motor cortical plasticity in Parkinsons disease (PD). These studies used peripheral nerve stimulation paired with transcranial magnetic stimulation (TMS) to primary motor cortex (M1) at specific intervals to induce plasticity. Induction of cortical plasticity through stimulation of the basal ganglia (BG)–M1 connections has not been studied. In the present study, we used a novel technique of plasticity induction by repeated pairing of deep-brain stimulation (DBS) of the BG with M1 stimulation using TMS. We hypothesize that repeated pairing of subthalamic nucleus (STN)-DBS and M1-TMS at specific time intervals will lead to plasticity in the M1. Ten PD human patients with STN-DBS were studied in the on-medication state with DBS set to 3 Hz. The interstimulus intervals (ISIs) between STN-DBS and TMS that produced cortical facilitation were determined individually for each patient. Three plasticity induction conditions with repeated pairings (180 times) at specific ISIs (∼3 and ∼23 ms) that produced cortical facilitation and a control ISI of 167 ms were tested in random order. Repeated pairing of STN-DBS and M1-TMS at short (∼3 ms) and medium (∼23 ms) latencies increased M1 excitability that lasted for at least 45 min, whereas the control condition (fixed ISI of 167 ms) had no effect. There were no specific changes in motor thresholds, intracortical circuits, or recruitment curves. Our results indicate that paired-associative cortical plasticity can be induced by repeated STN and M1 stimulation at specific intervals. These results show that STN-DBS can modulate cortical plasticity. SIGNIFICANCE STATEMENT We introduced a new experimental paradigm to test the hypothesis that pairing subthalamic nucleus deep-brain stimulation (STN-DBS) with motor cortical transcranial magnetic stimulation (M1-TMS) at specific times can induce cortical plasticity in patients with Parkinsons disease (PD). We found that repeated pairing of STN-DBS with TMS at short (∼3 ms) and medium (∼23 ms) intervals increased cortical excitability that lasted for up to 45 min, whereas the control condition (fixed latency of 167 ms) had no effects on cortical excitability. This is the first demonstration of associative plasticity in the STN-M1 circuits in PD patients using this novel technique. The potential therapeutic effects of combining DBS and noninvasive cortical stimulation should be investigated further.

Stop-related subthalamic beta activity indexes global motor suppression in Parkinson's disease

Rapid action stopping leads to global motor suppression. This is shown by studies using transcranial magnetic stimulation to measure corticospinal excitability of task‐unrelated effectors (e.g., from the hand during speech stopping). We hypothesize that this global suppression relates to the STN of the basal ganglia. Several STN local field potential studies in PD patients have shown increased ß‐band power during successful stopping.

A comparative study of slow and fast suryanamaskar on physiological function

Background: Numerous scientific studies have reported beneficial physiological changes after short- and long-term yoga training. Suryanamaskar (SN) is an integral part of modern yoga training and may be performed either in a slow or rapid manner. As there are few studies on SN, we conducted this study to determine the differential effect of 6 months training in the fast and slow versions. Materials and Methods: 42 school children in the age group of 12–16 years were randomly divided into two groups of 21 each. Group I and Group II received 6 months training in performance of slow suryanamaskar (SSN) and fast suryanamaskar (FSN), respectively. Results: Training in SSN produced a significant decrease in diastolic pressure. In contrast, training in FSN produced a significant increase in systolic pressure. Although there was a highly significant increase in isometric hand grip (IHG) strength and hand grip endurance (HGE) in both the groups, the increase in HGE in FSN group was significantly more than in SSN group. Pulmonary function tests showed improvements in both the groups though intergroup comparison showed no significance difference. Maximum inspiratory pressure (MIP) and maximum expiratory pressure increased significantly in both the groups with increase of MIP in FSN group being more significant than in SSN. Conclusion: The present study reports that SN has positive physiological benefits as evidenced by improvement of pulmonary function, respiratory pressures, hand grip strength and endurance, and resting cardiovascular parameters. It also demonstrates the differences between SN training when performed in a slow and fast manner, concluding that the effects of FSN are similar to physical aerobic exercises, whereas the effects of SSN are similar to those of yoga training.