History of Illicit Stimulant Use Is Not Associated with Long-Lasting Changes in Learning of Fine Motor Skills in Humans.

Little is known about the long-lasting effect of use of illicit stimulant drugs on learning of new motor skills. We hypothesised that abstinent individuals with a history of primarily methamphetamine and ecstasy use would exhibit normal learning of a visuomotor tracking task compared to controls. The study involved three groups: abstinent stimulant users (n = 21; 27 ± 6 yrs) and two gender-matched control groups comprising nondrug users (n = 16; 22 ± 4 yrs) and cannabis users (n = 16; 23 ± 5 yrs). Motor learning was assessed with a three-minute visuomotor tracking task. Subjects were instructed to follow a moving target on a computer screen with movement of the index finger. Metacarpophalangeal joint angle and first dorsal interosseous electromyographic activity were recorded. Pattern matching was assessed by cross-correlation of the joint angle and target traces. Distance from the target (tracking error) was also calculated. Motor learning was evident in the visuomotor task. Pattern matching improved over time (cross-correlation coefficient) and tracking error decreased. However, task performance did not differ between the groups. The results suggest that learning of a new fine visuomotor skill is unchanged in individuals with a history of illicit stimulant use.

Hand function is altered in individuals with a history of illicit stimulant use.

Use of illicit stimulant drugs such as methamphetamine, cocaine, and ecstasy are a significant worldwide problem. However, little is known about the effect of these drugs on movement. The aim of the current study was to investigate hand function in adults with a history of illicit stimulant use. We hypothesized that prior use of illicit stimulant drugs is associated with abnormal manipulation of objects. The study involved 22 subjects with a history of illicit stimulant use (aged 29±8 yrs; time since last use: 1.8±4.0 yrs) and two control groups comprising 27 non-drug users (aged 25±8 yrs) and 17 cannabis users with no history of stimulant use (aged 22±5 yrs). Each subject completed screening tests (neuropsychological assessment, medical history questionnaire, lifetime drug history questionnaire, and urine drug screen) prior to gripping and lifting a light-weight object with the dominant right hand. Horizontal grip force, vertical lift force, acceleration, and first dorsal interosseus electromyographic (EMG) activity were recorded during three trials. In trial one, peak grip force was significantly greater in the stimulant group (12.8±3.9 N) than in the control groups (non-drug: 10.3±4.6 N; cannabis: 9.4±2.9 N, P<0.022). However, peak grip force did not differ between groups in trials two and three. The results suggest that individuals with a history of stimulant use overestimate the grip force required to manipulate a novel object but, are able to adapt grip force in subsequent lifts. The results suggest that movement dysfunction may be an unrecognized consequence of illicit stimulant use.

Abnormal maximal finger tapping in abstinent cannabis users.

OBJECTIVE: To investigate movement speed and rhythmicity in abstinent cannabis users, we hypothesized that abstinent cannabis users exhibit decreased maximal finger tapping frequency and increased variability of tapping compared with non-drug users. METHODS: The study involved 10 healthy adult cannabis users and 10 age-matched and gender-matched controls with no history of illicit drug use. Subjects underwent a series of screening tests prior to participation. Subjects were then asked to tap a strain gauge as fast as possible with the index finger of their dominant hand (duration 5 s). RESULTS: The average intertap interval did not significantly differ between groups, but the coefficient of variation of the intertap interval was significantly greater in the cannabis group than in controls (p=0.011). The cannabis group also exhibited a slow tapping frequency at the beginning of the task. CONCLUSIONS: Rhythmicity of finger tapping is abnormal in individuals with a history of cannabis use. The abnormality appears to be long lasting and adds to the list of functional changes present in abstinent cannabis users.

Illicit stimulant use is associated with abnormal substantia nigra morphology in humans.

Use of illicit stimulants such as methamphetamine, cocaine, and ecstasy is an increasing health problem. Chronic use can cause neurotoxicity in animals and humans but the long-term consequences are not well understood. The aim of the current study was to investigate the long-term effect of stimulant use on the morphology of the human substantia nigra. We hypothesised that history of illicit stimulant use is associated with an abnormally bright and enlarged substantia nigra (termed 'hyperechogenicity') when viewed with transcranial sonography. Substantia nigra morphology was assessed in abstinent stimulant users (n = 36; 31±9 yrs) and in two groups of control subjects: non-drug users (n = 29; 24±5 yrs) and cannabis users (n = 12; 25±7 yrs). Substantia nigra morphology was viewed with transcranial sonography and the area of echogenicity at the anatomical site of the substantia nigra was measured at its greatest extent. The area of substantia nigra echogenicity was significantly larger in the stimulant group (0.273±0.078 cm(2)) than in the control (0.201±0.054 cm(2); P<0.001) and cannabis (0.202±0.045 cm(2); P<0.007) groups. 53% of stimulant users exhibited echogenicity that exceeded the 90(th) percentile for the control group. The results of the current study suggest that individuals with a history of illicit stimulant use exhibit abnormal substantia nigra morphology. Substantia nigra hyperechogenicity is a strong risk factor for developing Parkinson's disease later in life and further research is required to determine if the observed abnormality in stimulant users is associated with a functional deficit of the nigro-striatal system.

Illicit stimulant use in humans is associated with a long-term increase in tremor.

Use of illicit stimulants such as methamphetamine, cocaine, and ecstasy is a significant health problem. The United Nations Office on Drugs and Crime estimates that 14-57 million people use stimulants each year. Chronic use of illicit stimulants can cause neurotoxicity in animals and humans but the long-term functional consequences are not well understood. Stimulant users self-report problems with tremor whilst abstinent. Thus, the aim of the current study was to investigate the long-term effect of stimulant use on human tremor during rest and movement. We hypothesized that individuals with a history of stimulant use would exhibit abnormally large tremor during rest and movement. Tremor was assessed in abstinent ecstasy users (n = 9; 22 ± 3 yrs) and abstinent users of amphetamine-like drugs (n = 7; 33 ± 9 yrs) and in two control groups: non-drug users (n = 23; 27 ± 8 yrs) and cannabis users (n = 12; 24 ± 7 yrs). Tremor was measured with an accelerometer attached to the index finger at rest (30 s) and during flexion and extension of the index finger (30 s). Acceleration traces were analyzed with fast-Fourier transform. During movement, tremor amplitude was significantly greater in ecstasy users than in non-drug users (frequency range 3.9-13.3 Hz; P<0.05), but was unaffected in cannabis users or users of amphetamine-like drugs. The peak frequency of tremor did not significantly differ between groups nor did resting tremor. In conclusion, abstinent ecstasy users exhibit an abnormally large tremor during movement. Further work is required to determine if the abnormality translates to increased risk of movement disorders in this population.

Motor cortex and corticospinal excitability in humans with a history of illicit stimulant use.

Illicit use of stimulant drugs such as methamphetamine, ecstasy, and cocaine is a current and growing problem throughout the world. The aim of the current study was to investigate the long-term effect of illicit stimulant use on human motor cortical and corticospinal circuitry. We hypothesized that individuals with a history of primarily methamphetamine and ecstasy use would exhibit altered corticospinal excitability and intracortical inhibition within motor cortex. The study involved 52 healthy adults (aged 26 ± 7 yr) comprising 26 abstinent stimulant users, 9 cannabis users, and 17 nondrug users. The experiment involved a routine urine drug screen, drug history questionnaire, neuropsychological assessment, and single- and paired-pulse transcranial magnetic stimulation (TMS) over motor cortex. EMG responses to stimulation [motor evoked potentials (MEPs)] were recorded from the contralateral first dorsal interosseus. At a given stimulus intensity, MEP area was significantly larger in abstinent stimulant users than in nondrug users during both relaxation (P = 0.045) and muscle contraction (P < 0.001). MEP latency was also significantly longer in abstinent stimulant users (P < 0.009), and they exhibited significantly greater muscle activity during performance of a given task (P = 0.004). However, resting motor threshold and the response to paired-pulse TMS were unaffected. The results suggest that abstinent stimulant users exhibit long-term changes in the excitability of motor cortical and corticospinal circuitry and muscle activity during movement. These changes may partly underlie anecdotal and objective reports of movement dysfunction in chronic stimulant users.

Asymmetric activation of motor cortex controlling human anterior digastric muscles during speech and target-directed jaw movements.

Like most of the cranial muscles involved in speech, the trigeminally innervated anterior digastric muscles are controlled by descending corticobulbar projections from the primary motor cortex (M1) of each hemisphere. We hypothesized that changes in corticobulbar M1 excitability during speech production would show a hemispheric asymmetry favoring the left side, which is the dominant hemisphere for language processing in most strongly right handed subjects. Fifteen volunteers aged 24.5+/-5.3 (SD) yr participated. All subjects were strongly right handed as reported by questionnaire. A surface electromyograph (EMG) was recorded bilaterally from digastrics and jaw movement detected by an accelerometer attached to a lower incisor. Focal transcranial magnetic stimulation (TMS) was used to assess corticomotor excitability of the digastric representation in M1 of both hemispheres during four tasks: 1) static isometric contraction of digastrics; 2) speaking a single word; 3) visually guided, nonspeech jaw movement that matched the jaw kinematics recorded during task 2; and 4) reciting a sentence. Background EMG was well matched in all tasks and jaw kinematics were similar around the time of the TMS pulse for tasks 2-4. TMS resting thresholds and digastric muscle-evoked potential (MEP) size during isometric contraction did not differ for TMS over left versus right M1. MEPs elicited by TMS over left, but not right M1 increased in size during speech and nonspeech jaw movement compared with isometric contraction. We conclude that left corticobulbar M1 is preferentially engaged for descending control of digastric muscles during speech and the performance of a rapid jaw movement to match a target kinematic profile.

Priming theta-burst repetitive transcranial magnetic stimulation with low- and high-frequency stimulation.

Repetitive transcranial magnetic stimulation (rTMS) can be used to study metaplasticity in human motor cortex. The term metaplasticity describes a phenomenon where the prior synaptic history of a pathway can affect the subsequent induction of long-term potentiation or depression. In the current study, we investigated metaplasticity in human motor cortex with the use of inhibitory continuous theta-burst stimulation (cTBS). cTBS involves short bursts of high frequency (50 Hz) rTMS applied every 200 ms for 40 s. In the first series of experiments, cTBS was primed with 10 min of intermittent 2 or 6 Hz rTMS. Subjects (n = 20) received priming stimulation at 70% of active motor threshold or 90% of resting motor threshold. In another series of experiments, cTBS was primed with excitatory intermittent theta-burst stimulation (iTBS). iTBS involves a 2 s train of theta-burst stimulation delivered every 10 s for 190 s. Stimuli were delivered over the first dorsal interosseus motor area.. The effect of cTBS alone and primed cTBS on motor cortical excitability was investigated by recording motor-evoked potentials (MEP) in the first dorsal interosseus following single-pulse TMS. MEP area in the cTBS alone condition was not significantly different from cTBS primed with 2 or 6 Hz rTMS. However, priming cTBS with iTBS suppressed MEP area to a greater extent than in cTBS alone. Our results provide further evidence of metaplasticity in human motor cortex when appropriate priming protocols are employed.

Voluntary movement and repetitive transcranial magnetic stimulation over human motor cortex.

Repetitive transcranial magnetic stimulation (rTMS) can induce short-term reorganization of human motor cortex. Here, we investigated the effect of rTMS during relaxation and weak voluntary muscle contraction on motor cortex excitability and hand function. Subjects (n = 60) participated in one of four studies. Single transcranial magnetic stimuli were delivered over the motor area of the first dorsal interosseus for measurement of motor evoked potential (MEP) size before and after real or sham rTMS delivered at an intensity of 80% of active motor threshold. rTMS involved trains of stimuli applied at 6 Hz for 5 s and repeated every 30 s for 10 min. Resting MEP size was suppressed for 15 min after rTMS during relaxation. However, MEP suppression was abolished when additional brief voluntary contractions were performed before and after rTMS (study 1). Resting MEP size was suppressed for 30 min after rTMS during weak voluntary contraction. MEP suppression was present even though voluntary contractions were performed before and after rTMS (study 2). The MEP suppression most likely reflects a decrease in motor cortical excitability. Surprisingly, rTMS during voluntary contraction did not alter maximal finger tapping speed or performance on a grooved pegboard test, object grip and lift task (study 3), and visuomotor tracking task (study 4). These studies document the complex relationship between voluntary movement and rTMS-induced plasticity in motor cortex. This work has implications for the optimization of rTMS parameters for improved efficacy and potential therapeutic applications.

Transcranial magnetic stimulation reduces masseter motoneuron pool excitability throughout the cortical silent period.

OBJECTIVE: To evaluate the time-course of changes in masseter motoneuron pool excitability following transcranial magnetic stimulation of motor cortex, and relate this to the duration of the masseter cortical silent period (CSP). METHODS: Surface EMG was recorded bilaterally from masseter and digastric muscles in 13 subjects. Focal TMS was applied at 1.3x active motor threshold (AMT) to motor cortex of one hemisphere to elicit a muscle evoked potential (MEP) and silent period bilaterally in masseter as subjects maintained an isometric bite at approximately 10% maximum. With jaw muscles relaxed, a servo-controlled stretcher evoked a stretch reflex in masseter which was conditioned by TMS (1.3x AMT) at 14 different conditioning-testing intervals. There were 20 trials at each interval, in random order. TMS evoked no MEP in resting masseter, but often produced a small MEP in digastric. RESULTS: Mean (+/-SE) masseter CSP was 67+/-3ms. The masseter stretch reflex was facilitated when stretch preceded TMS by 8 and 10ms, which we attribute to spatial summation of corticobulbar and Ia-afferent excitatory inputs to masseter. Masseter stretch reflex amplitude was reduced when TMS was given up to 75ms before stretch, and for up to 2ms afterwards. CONCLUSIONS: We conclude that descending corticobulbar activity evoked by TMS acts bilaterally on brainstem interneurons that either inhibit masseter motoneurons or increase pre-synaptic inhibition of Ia-afferent terminals for up to 75ms after TMS. The reduction of masseter motoneuron pool excitability following TMS has a similar time-course to the CSP. SIGNIFICANCE: In contrast to the situation for spinal and facial (CN VII) muscles, the masseter CSP appears to have no component that can be attributed exclusively to cortical mechanisms. Abnormalities in the masseter cortical silent period observed in neurological conditions may be due to pathophysiological changes at cortical and/or sub-cortical levels.

Low-intensity repetitive transcranial magnetic stimulation decreases motor cortical excitability in humans.

Repetitive transcranial magnetic stimulation of the motor cortex (rTMS) can be used to modify motor cortical excitability in human subjects. At stimulus intensities near to or above resting motor threshold, low-frequency rTMS (approximately 1 Hz) decreases motor cortical excitability, whereas high-frequency rTMS (5-20 Hz) can increase excitability. We investigated the effect of 10 min of intermittent rTMS on motor cortical excitability in normal subjects at two frequencies (2 or 6 Hz). Three low intensities of stimulation (70, 80, and 90% of active motor threshold) and sham stimulation were used. The number of stimuli were matched between conditions. Motor cortical excitability was investigated by measurement of the motor-evoked potential (MEP) evoked by single magnetic stimuli in the relaxed first dorsal interosseus muscle. The intensity of the single stimuli was set to evoke baseline MEPs of approximately 1 mV in amplitude. Both 2- and 6-Hz stimulation, at 80% of active motor threshold, reduced the magnitude of MEPs for approximately 30 min (P < 0.05). MEPs returned to baseline values after a weak voluntary contraction. Stimulation at 70 and 90% of active motor threshold and sham stimulation did not induce a significant group effect on MEP magnitude. However, the intersubject response to rTMS at 90% of active motor threshold was highly variable, with some subjects showing significant MEP facilitation and others inhibition. These results suggest that, at low stimulus intensities, the intensity of stimulation may be as important as frequency in determining the effect of rTMS on motor cortical excitability.

Effect of human grip strategy on force control in precision tasks.

Alternate grip strategies are often used for object manipulation in individuals with sensorimotor deficits. To determine the effect of grip type on force control, ten healthy adult subjects were asked to grip and lift a small manipulandum using a traditional precision grip (lateral pinch), a pinch grip with the fingers oriented downwards (downward pinch) and a "key grip" between the thumb and the side of the index finger. The sequence of grip type and hand used was varied randomly after every ten lifts. Each of the three grips resulted in different levels of force, with the key grip strategy resulting in the greatest grip force and the downward pinch grip using the least amount of grip force to lift the device. Cross-correlation analysis revealed that the ability to scale accurately the rate of grip force and load force changes was lowest in the downward pinch grip. This was also associated with a more variable time-shift between the two forces, indicating that the precise anticipatory control when lifting an object is diminished in this grip strategy. There was a difference between hands across all grips, with the left non-dominant hand using greater grip force during the lift but not the hold phase. Further, in contrast with the right hand, the left hand did not reduce grip force during the lift or the hold phase over the ten lifts, suggesting that the non-dominant hand did not quickly learn to optimise grip force. These findings suggest that the alternate grip strategies used by patients with limited fine motor control, such as following stroke, may partly explain the disruption of force control during object manipulation.

Control of human mandibular posture during locomotion.

Mandibular movements and masseter muscle activity were measured in humans during hopping, walking and running to determine whether reflexes contribute to the maintenance of jaw position during locomotion. In initial experiments, subjects hopped so that they landed either on their toes or on their heel. Landing on the toes provoked only small mandibular movements and no reflex responses in the masseter electromyogram (EMG). Landing on the heels with the jaw muscles relaxed caused the mandible to move vertically downwards relative to the maxilla, and evoked a brisk reflex response in the masseter at monosynaptic latency. Neither this relative movement of the mandible nor the reflex was seen when the teeth were clenched: hence the reflex is not the result of vestibular activation during head movement. The same variables were measured in a second series of experiments while subjects stood, walked and ran at various speeds and at various inclinations on a treadmill. During walking, the vertical movements of the head and therefore the mandible were slow and small, and there was no tonic masseter EMG or gait-related activity in the jaw-closing muscles. When subjects ran, the vertical head and jaw movement depended on the running speed and the inclination of the treadmill. Landing on the heels induced larger movements than landing on the toes. About 10 ms after each foot-strike, the mandible moved downwards relative to the maxilla, thereby stretching the jaw-closing muscles and activating them at segmental reflex latency. This caused the mandible to move back upwards. The strength of the reflex response was related to the speed and amplitude of the vertical jaw movement following landing. It is concluded that, during walking, the small, slow movements of the mandible relative to the maxilla are subthreshold for stretch reflexes in the jaw muscles: i.e. the mandible is supported by visco-elasticity of the soft tissues in the masticatory system. However, the brisker downward movements of the mandible after heel-landing during hopping and running evoke segmental reflex responses which contribute to the active maintenance of the posture of the mandible. This is a unique demonstration of how a stretch reflex operates to maintain posture under entirely natural conditions.

Postural stability of the human mandible during locomotion.

Movements of the head and of the mandible relative to the head were measured in human subjects walking and running on a treadmill at various speeds and inclinations. A miniature magnet and piezo-electric accelerometer assembly was mounted on the mandibular incisors, and a Hall-effect sensor along with a second accelerometer mounted on a maxillary incisor along a common vertical axis. Signals from these sensors provided continuous records of vertical head and mandible acceleration, and relative jaw position. Landing on the heel or on the toe in different forms of locomotion was followed by rapid deceleration of the downward movement of the head and slightly less rapid deceleration of the downward movement of the mandible, i.e., the mandible moved downwards relative to the maxilla, then upwards again to near its normal posture within 200 ms. No tooth contact occurred in any forms of gait at any inclination. The movement of the mandible relative to the maxilla depended on the nature and velocity of the locomotion and their effects on head deceleration. The least deceleration and hence mandibular displacement occurred during toe-landing, for example, during "uphill" running. The maximum displacement of the mandible relative to the head was less than 1mm, even at the fastest running speed. The mechanisms that limit the vertical movements of the jaw within such a narrow range are not known, but are likely to include passive soft-tissue visco-elasticity and stretch reflexes in the jaw-closing muscles.

Pulsatile control of the human masticatory muscles.

Spectral analysis of jaw acceleration confirmed that the human mandible 'trembles' at a peak frequency around 6 Hz when held in its rest position and at other stationary jaw openings. The 6 Hz tremor increased during very slow movements of the mandible, but other lower-frequency peaks became prominent during more rapid jaw movements. These lower-frequency peaks are likely to be the result of asymmetries in the underlying, voluntarily produced, 'saw-tooth' movements. In comparison, finger tremor at rest and during slow voluntary movements had a mean peak frequency of about 8 Hz: this frequency did not change during rhythmical finger flexion and extension movements, but the power of the tremor increased non-linearly with the speed of the movement. The resting jaw tremor was weakly coherent with the activity of the masseter and digastric muscles at the tremor frequency in about half the subjects, but was more strongly coherent during voluntary movements in all subjects. The masseter activity was at least 150 deg out of phase with the digastric activity at the tremor frequency (and at all frequencies from 2.5-15 Hz). The alternating pattern of activity in antagonistic muscles at rest and during slow voluntary movements supports the idea that the masticatory system is subject to pulsatile control in a manner analogous to that seen in the finger.

A simple and inexpensive system for monitoring jaw movements in ambulatory humans.

A simple and inexpensive method for recording vertical movements of the human mandible relative to the maxilla is presented. Measurements are made from accelerometers and a Hall-effect device temporarily glued to the upper and lower anterior teeth. The accelerometer signals are integrated once to give velocity and a second time to give position. Movements of the mandible relative to the maxilla are obtained by integrating the difference between the two accelerometer signals. The (relative) velocity and position records derived in this way are linear, but subject to drift when the jaw is stationary. Steady mandibular position is obtained from the Hall-effect system, but this signal must be corrected for its inherent non-linearity. This device can record rapid movements of the mandible even when the head is unrestrained, and interferes minimally with normal jaw movements.