Danny I. Cunic

Interhemispheric and ipsilateral connections in Parkinson's disease: Relation to mirror movements

Mirror movements (MM) occur in early, asymmetric Parkinsons disease (PD). To examine the pathophysiology of MM in PD, we studied 13 PD patients with MM (PD‐MM), 7 PD patients without MM (PD‐NM), and 14 normal subjects. Cross‐correlogram did not detect common synaptic input to motoneuron pools innervating homologous hand muscles in PD‐MM patients. Transcranial magnetic stimulation studies showed no significant difference in ipsilateral motor‐evoked potentials between PD‐MM patients and normal subjects. The MM side of PD‐MM patients showed a slower increase in ipsilateral silent period area with higher level of muscle contraction than the non‐MM side and normal subjects. There was less interhemispheric inhibition (IHI) at long interstimulus intervals of 20 to 50 ms in PD‐MM than PD‐NM. IHI reduced short interval intracortical inhibition in normal subjects and PD‐NM, but not in PD‐MM. IHI significantly increased intracortical facilitation in PD‐MM and PD‐NM patients, but not in normal subjects. Our results suggest that MM in PD is due to activation of the contralateral motor cortex. PD‐MM patients had reduced transcallosal inhibitory effects on cortical output neurons and on intracortical inhibitory circuits compared to PD‐NM patients and controls. These deficits in transcallosal inhibition may contribute to MM in PD patients.

Effects of peripheral sensory input on cortical inhibition in humans

Cortical inhibitory systems play an important role in motor output. The motor cortex can be inhibited by intracortical mechanisms and by peripheral sensory inputs. We examined whether cortical inhibition from peripheral sensory input is mediated through previously identified intracortical inhibitory systems and how these inhibitory systems interact. Two types of intracortical inhibition were assessed by paired‐pulse transcranial magnetic stimulation (TMS). Short‐interval intracortical inhibition (SICI) was determined with a subthreshold conditioning stimulus (CS) followed by a test stimulus 2 ms later and long‐interval intracortical inhibition (LICI) with suprathreshold conditioning and test stimuli 100 ms apart. Cortical inhibition from peripheral sensory input was induced by median nerve stimulation (MNS) of the right hand and followed by a suprathreshold TMS over the left motor cortex 200 ms later. The first set of experiments tested the effects of different test stimulus intensities on SICI, LICI and cortical inhibition induced by median nerve stimulation (MNSI). With higher test stimulus intensities, LICI and MNSI decreased whereas SICI showed a trend towards an increase. The extent of SICI, LICI and MNSI did not correlate. The second experiment assessed the interaction between MNSI and LICI. The results of applying MNSI and LICI simultaneously were compared with MNSI and LICI alone. MNSI was virtually abolished in the presence of LICI and LICI was also significantly decreased in the presence of MNSI. Thus, the effects of MNSI and LICI when applied together were much less than their expected additive effects when applied alone. The degree of interaction between MNSI and LICI was related to the combined strength of MNSI and LICI but not to the strength of LICI alone. The third experiment investigated the interaction between SICI and MNSI. MNSI and SICI were applied together and the results were compared with MNSI and SICI alone. SICI remained unchanged in the presence of MNSI. We conclude that MNSI is mediated by circuits distinct from those mediating LICI or SICI. The MNSI circuits seem to have an inhibitory interaction with the LICI circuits, whereas the SICI and MNSI circuits do not seem to interact.

Involvement of the Basal Ganglia and Cerebellar Motor Pathways in the Preparation of Self-Initiated and Externally Triggered Movements in Humans

The subthalamic nucleus (STN) is part of the cortico-basal ganglia (BG)–thalamocortical circuit, whereas the ventral lateral nucleus of the thalamus (VL) is a relay nucleus in the cerebello-dentato-thalamocortical (CTC) pathway. Both pathways have been implicated in movement preparation. We compared the involvement of the STN and VL in movement preparation in humans by recording local field potentials (LFPs) from seven patients with Parkinsons disease with deep-brain stimulation (DBS) electrodes in the STN and five patients with tremor and electrodes in VL. LFPs were recorded from DBS electrodes and scalp electrodes simultaneously while the patients performed self-paced and externally cued (ready, go/no-go) movements. For the self-paced movement, a premovement-related potential was observed in all patients from scalp, STN (phase reversal, five of six patients), and VL (phase reversal, five of five patients) electrodes. The onset times of the potentials were similar in the cortex, STN, and VL, ranging from 1.5 to 2 s before electromyogram onset. For the externally cued movement, an expectancy potential was observed in all patients in cortical and STN electrodes (phase reversal, six of six patients). The expectancy potential was recorded from the thalamic electrodes in four of five patients. However, phase reversal occurred only in one case, and magnetic resonance imaging showed that this contact was outside the VL. The cortico-BG–thalamocortical circuit is involved in the preparation of both self-paced and externally cued movements. The CTC pathway is involved in the preparation of self-paced but not externally cued movements, although the pathway may still be involved in the execution of these movements.

Changes in motor cortex excitability with stimulation of anterior thalamus in epilepsy.

Background: Deep brain stimulation (DBS) is an effective treatment for movement disorders and pain. Recently, bilateral DBS of the anterior nucleus of thalamus (AN) was performed for the treatment of intractable epilepsy. This surgery reduced seizure frequency in an initial group of patients. However, its physiologic effects on the cortex and mechanisms of action remain poorly understood. Different classes of antiepileptic drugs (AEDs) have distinct effects on the excitatory and inhibitory circuits in the motor cortex, which can be studied noninvasively by transcranial magnetic stimulation (TMS). Objective: To examine the effects of bilateral AN DBS on motor cortex excitability in epilepsy and compare these to the known effects of AEDs. Methods: Cortical excitability was assessed in five medicated epilepsy patients with bilateral stimulators implanted in the anterior thalamus and nine healthy controls. Single and paired TMS were used to examine cortical inhibitory and facilitatory circuits. Electromyography was recorded from the dominant hand, and TMS was applied over the contralateral motor cortex. Patients were studied during DBS turned off (OFF condition), DBS with cycling stimulation mode (1 minute on, 5 minutes off; CYCLE), and DBS with continuous stimulation (CONTINUOUS) in random order on 3 consecutive days. Results: Motor thresholds were increased in the patients regardless of DBS condition. Active short-interval intracortical inhibition (SICI) was significantly reduced in the OFF and CYCLE conditions but returned toward normal levels in the CONTINUOUS condition. Rest SICI, long interval intracortical inhibition, and silent period duration were unchanged. Conclusions: Increased short-interval intracortical inhibition with continuous deep brain stimulation (DBS) suggests that thalamic DBS might drive cortical inhibitory circuits, similar to antiepileptic drugs that enhance γ-aminobutyric acid inhibition.

Subthalamic nucleus stimulation modulates afferent inhibition in Parkinson disease

Background: Peripheral sensory stimulation at the wrist inhibits the motor cortex as measured by transcranial magnetic stimulation at interstimulus intervals of approximately 20 ms (short latency afferent inhibition [SAI]) and 200 ms (long latency afferent inhibition [LAI]). Previous studies suggested that reduced SAI in Parkinson disease (PD) reflects adverse effect of dopaminergic medications and reduced LAI may be related to nondopaminergic manifestations of PD. We hypothesize that subthalamic nucleus (STN) deep brain stimulation (DBS) may correct these deficiencies. Methods: We studied the effects of STN DBS on SAI and LAI in seven PD patients and age-matched controls. PD patients were studied in an off medication followed by an on medication session, with the stimulator switched on or off in random order in each session. Results: In the on medication session, SAI was reduced in the stimulator off condition and was restored by STN DBS. LAI was partially normalized by STN DBS in the medication on condition. Conclusions: Subthalamic nucleus (STN) stimulation improves short latency afferent inhibition, suggesting that it could normalize pathways that are adversely affected by dopaminergic medications. The effect of STN stimulation on long latency afferent inhibition suggests that it may influence nondopaminergic pathways involved in sensorimotor integration.

Representation of facial muscles in human motor cortex

Whether there is a projection from the primary motor cortex (M1) to upper facial muscles and how the facial M1 area is modulated by intracortical inhibitory and facilitatory circuits remains controversial. To assess these issues, we applied transcranial magnetic stimulation (TMS) to the M1 and recorded from resting and active contralateral (C‐OOc) and ipsilateral orbicularis oculi (I‐OOc), and contralateral (C‐Tr) and ipsilateral triangularis (I‐Tr) muscles in 12 volunteers. In five subjects, the effects of stimulating at different scalp positions were assessed. Paired TMS at interstimulus intervals (ISIs) of 2 ms were used to elicit short interval intracortical inhibition (SICI) and ISI of 10 ms for intracortical facilitation (ICF). Long interval intracortical inhibition (LICI) was evaluated at ISIs between 50 and 200 ms, both at rest and during muscle activation. The silent period (SP) was also determined. C‐OOc and I‐OOc responses were recorded in all subjects. The optimal position for eliciting C‐OOc responses was lateral to the hand representation in all subjects and MEP amplitude markedly diminished when the coil was placed 2 cm away from the optimal position. For the I‐OOc, responses were present in more scalp sites and the latency decreased with more anterior placement of the coil. C‐Tr response was recorded in 10 out of 12 subjects and the I‐Tr muscle showed either no response or low amplitude response, probably due to volume conduction. SICI and ICF were present in the C‐OOc and C‐Tr, but not in the I‐OOc muscle. Muscle activation attenuated SICI and ICF. LICI at rest showed facilitation at 50 ms ISI in all muscles, but there was no significant inhibition at other ISIs. There was no significant inhibition or facilitation with the LICI protocol during muscle contraction. The SP was present in the C‐OOc, C‐Tr and I‐OOc muscles and the mean durations ranged from 92 to 104 ms. These findings suggest that the I‐OOc muscle response is probably related to the first component (R1) of the blink reflex. There is M1 projection to the contralateral upper and lower facial muscles in humans and the facial M1 area is susceptible to cortical inhibition and facilitation, similar to limb muscles.

Changes in cortical excitability with thalamic deep brain stimulation

Background: Deep brain stimulation (DBS) is an effective treatment for several movement disorders. However, its mechanism of action is largely unknown. Both lesioning and DBS of the ventralis intermedius (VIM) nucleus of thalamus improve essential tremor. Although DBS was initially thought to inhibit the target neurons, recent studies suggest that DBS activates neurons. Objective: To test the hypothesis that thalamic DBS activates the target area in patients with essential tremor. Methods: Cortical excitability was assessed in seven unmedicated patients with essential tremor using unilateral stimulators implanted in the VIM of the dominant hemisphere and in 11 healthy controls using transcranial magnetic stimulation (TMS). Patients were studied during optimal DBS (ON condition), half the optimal frequency (HALF), and with DBS off (OFF) in random order. Tremor was assessed after a change in DBS setting. Electromyography was recorded from the dominant hand, and TMS was applied over the contralateral motor cortex using single and paired pulses to elicit motor evoked potentials (MEPs). MEP recruitment was determined using stimulus intensities from 100% to 150% of motor threshold. Results: Tremor scores were significantly improved with DBS ON. Analysis of variance showed a significant interaction between condition (ON, HALF, OFF, Normal) and stimulus intensity on MEP amplitude. During DBS ON MEP amplitudes were significantly higher compared with controls at high but not at low TMS intensities. Conclusion: Because the ventralis intermedius (VIM) projects directly to the motor cortex, the high motor evoked potential amplitude with deep brain stimulation ON suggests that VIM DBS activates rather than inhibits the target area.

Changes in cortical and pallidal oscillatory activity during the execution of a sensory trick in patients with cervical dystonia.

We examined the effects of a sensory trick (SeT) on cortical EEG and globus pallidus (GP) local field potentials in four cervical dystonia patients, two of whom had an effective SeT and two who did not. The application of an effective SeT was associated with bilateral desynchronization in the 6-8 Hz and beta bands in the GP and sensorimotor cortical regions. In contrast, mimicking an SeT led to a worsening of dystonia, which was associated with desynchronization of the beta band and synchronization in the 4-6 Hz range. These preliminary findings suggest a role for 4-8 Hz frequency synchronization in the pathophysiology of dystonia.

Electrophysiological features of myoclonus-dystonia.

Inherited myoclonus‐dystonia (M‐D) is an autosomal dominant disorder characterized by myoclonus and dystonia that often improves with alcohol. To examine the electrophysiologic characteristics of M‐D, we studied 6 patients from 4 different families and 9 age‐matched healthy subjects. Neurophysiological studies performed include electromyography (EMG)‐electroencephalography (EEG) polygraphy, jerk‐locked back‐averaged EEG, somatosensory evoked potentials (SEP), long‐latency reflex (LLR) to median and digital nerve stimulation, and transcranial magnetic stimulation studies with short‐interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long‐interval intracortical inhibition (LICI). All 6 patients showed myoclonus and dystonia on clinical examination and EMG testing. The EMG burst durations ranged from 30.4 to 750.6 milliseconds (mean, 101.5 milliseconds). Jerk‐locked back‐averaged EEG failed to reveal any preceding cortical correlates. Median nerve SEP revealed no giant potential. No patients had exaggerated LLR to median or digital nerve stimulation. There was no significant difference in SICI, ICF, and LICI between M‐D patients and normal subjects. Myoclonus in inherited M‐D is likely of subcortical origin. Normal intracortical inhibition and facilitation suggest that the GABAergic circuits in the motor cortex are largely intact and that the mechanisms of myoclonus and dystonia are different from those for cortical myoclonus and other dystonic disorders.

Involvement of Subcortical Structures in the Preparation of Self-Paced Movement

Abstract Although it has long been suggested that the basal ganglia and thalamus are involved in movement planning and preparation, there was little direct evidence in humans to support this hypothesis. Deep brain stimulation (DBS) is a well-established treatment for movement disorders such as Parkinsons disease, tremor, and dystonia. In patients undergoing DBS surgery, we recorded simultaneously from scalp contacts and from electrodes surgically implanted in the subthalamic nucleus (STN) of 13 patients with Parkinsons disease and in the “cerebellar” thalamus of 5 patients with tremor. The aim of our studies was to assess the role of the cortico-basal ganglia-thalamocortical loop through the STN and the cerebello-thalamocortical circuit through the “cerebellar” thalamus in movement preparation. The patients were asked to perform self-paced wrist extension movements. All subjects showed a cortical readiness potential (RP) with onset ranging between 1.5 to 2s before the onset of movement. Subcortical RPs ...