Studies on integrative functions of the human frontal association cortex with MEG

Our MEG studies on the human frontal association cortex are briefly reviewed. (1) The no-go potential was first found at go/no-go reaction-time hand movement task with discrimination between different colour light stimuli in the prefrontal cortex of monkeys. The potential was recorded in human subjects with EEG over the scalp, but its current dipoles could be localized only by use of MEG, in the dorsolateral part of the frontal association cortex in both cerebral hemispheres. The function for no-go decision and subsequent suppressor action was thus substantiated in the human frontal cortex. (2) Utterance of a short noun in Japanese was found to be initially preceded by an activity in the lower lateral part of the frontal lobe and then by that around the central sulcus. The area of the former, often in both hemispheres, appears to correspond to Broca's motor speech centre and that of the latter, always in both hemispheres, to correspond to the motor-somatosensory cortices. (3) Intensive and continuous concentration on mental calculation and some 'abstract' thinking for a few minutes were often associated with magnetic theta (5-7 Hz) wave bursts in the frontal part of the scalp. Dipole fitting suggested that the electrical current dipoles occur successively and scattered in wide areas of the frontal lobe on both sides. They are to be called "frontal mental theta wave", revealing dynamic and active participation of the frontal lobe in mental functions.     

Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation

We studied the effects of low-frequency transcranial magnetic stimulation (TMS) on motor cortex excitability in humans. TMS at 0.1 Hz for 1 hour did not change cortical excitability. Stimulation at 0.9 Hz for 15 minutes (810 pulses), similar to the parameters used to induce long-term depression (LTD) in cortical slice preparations and in vivo animal studies, led to a mean decrease in motor evoked potential (MEP) amplitude of 19.5%. The decrease in cortical excitability lasted for at least 15 minutes after the end of the 0.9 Hz stimulation. The mechanism underlying this decrease in excitability may be similar to LTD. TMS-induced reduction of cortical excitability has potential clinical applications in diseases such as epilepsy and myoclonus. Spread of excitation, which may be a warning sign for seizures, occurred in one subject and was not accompanied by increased MEP amplitude, suggesting that spread of excitation and amplitude changes are different phenomena and also indicating the need for adequate monitoring even with stimulations at low frequencies.     

Effects of lesions in the mesial frontal cortex on bimanual co-ordination in monkeys

The hypothesis was tested that the mesial frontal cortex, including the supplementary motor area, is engaged in bimanual co-ordination. Three monkeys, trained in a well-co-ordinated bimanual pull-and-grasp task, were subjected to unilateral or bilateral lesions of the mesial frontal cortex. With unilateral lesions, the deficit consisted in a delay in movement initiation of the contralateral arm. With a bilateral lesion, the deficit was more pronounced with marked bilateral delays in movement onset and slowing in reaching. However, in the three monkeys bimanual co-ordination at the moment of goal achievement remained intact with an excellent temporal co-variation of the two limbs. In the two unilateral cases, an adaptive strategy developed after a few sessions, either by catching up during reaching with the limb contralateral to the lesion (monkey M1) or by delaying movement initiation of the limb ipsilateral to the lesion (monkey M2). This outcome is discussed in terms of Lashley's principle of motor equivalence, i.e. invariant goal achievement with variable means. Bilateral lesions led to a transient and near-total impairment in movement self-initiation when all external cues were absent. It is concluded that in monkeys the mesial frontal cortex does not play a crucial role in bimanual co-ordination but rather in movement initiation, especially when sensory cues are absent.     

Effects of gaze on apparent visual responses of frontal cortex neurons

Previous reports have argued that single neurons in the ventral premotor cortex of rhesus monkeys (PMv, the ventrolateral part of Brodmann's area 6) typically show spatial response fields that are independent of gaze angle. We reinvestigated this issue for PMv and also explored the adjacent prearcuate cortex (PAv, areas 12 and 45). Two rhesus monkeys were operantly conditioned to press a switch and maintain fixation on a small visual stimulus (0.2 degree x 0.2 degree) while a second visual stimulus (1 degree x 1 degree or 2 degrees x 2 degrees) appeared at one of several possible locations on a video screen. When the second stimulus dimmed, after an unpredictable period of 0.4-1.2 s, the monkey had to quickly release the switch to receive liquid reinforcement. By presenting stimuli at fixed screen locations and varying the location of the fixation point, we could determine whether single neurons encode stimulus location in "absolute space" or any other coordinate system independent of gaze. For the vast majority of neurons in both PMv (90%) and PAv (94%), the apparent response to a stimulus at a given screen location varied significantly and dramatically with gaze angle. Thus, we found little evidence for gaze-independent activity in either PMv or PAv neurons. The present result in frontal cortex resembles that in posterior parietal cortex, where both retinal image location and eye position affect responsiveness to visual stimuli.     

Flavor and the frontal cortex.

Rats were trained to discriminate an aqueous compound of an odor and taste (amyl acetate and NaCl) from the components of the compound before removal of one olfactory bulb and the contralateral ventrolateral frontal cortex. In postoperative tests, experimental rats performed much more poorly than nonlesioned controls or controls which had all lesions made in the same hemisphere. However, there were no significant differences among groups on tests for detection of amyl acetate and NaCl. These results provide evidence that integration of taste and smell in the production of flavor occurs in the ventrolateral frontal cortex. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of lithium carbonate on memory and other cognitive functions

The authors studied the effects of lithium carbonate on memory and cognitive function in 16 psychiatric patients, who received lithium for 2 weeks and placebo for 2 weeks in a double-blind cross-over design. At the end of each treatment phase, subjects were administered a battery of memory and cognitive tests. As reported previously, lithium induced slowing of performance on certain of the perceptual motor tests; however, lithium did not cause memory impairment or a change in self-assessment of memory functions.     

Simultaneous recording of slow brain potentials and transcranial magnetic stimulation of hand area in human motor cortex

We have studied 60 ears initial stage professional acoustic trauma and a hearing loss in the 2,000 and 4,000 frequencies at 30-40 db. We also included in the study 60 normal ears as the control group. In the first group we investigated the recruitment by the SISI test. Watson and Tolan's test, vocal audiometry and Metz's test. Recruitment was considered positive when indicated so by two of four tests. In waves I and V of BERA we have obtained the following results compared to those of the normal ears: Amplitude is similar in both waves, whatever the intensity of the click. Latencies increase with weak clicks, more in wave V, while the become equal with stronger clicks, what means the existence of recruitment. While other tests are not useful or doubtful, BERA are of interest for the study on recruitment in deep hearing loss.     

Decreased dendritic branching in frontal, motor and limbic cortex in Rett syndrome compared with trisomy 21

Although some of the susceptibility to Graves' disease is conferred by genes in the human leucocyte antigen (HLA) region on the short arm of chromosome 6, other genetic factors must also predispose. Among the cytokines involved in thyroid autoimmunity interferon-gamma (IFN-gamma) plays a key role in the pathogenesis of Graves' disease. We therefore analyzed the first intron of the IFN-gamma gene for a dinucleotide (CA) repeat polymorphism on chromosome 12q. Two hundred two Caucasian patients with Graves' disease and 214 Caucasian controls were analyzed by polymerase chain reaction (PCR) and subsequent polyacrylamide gel electrophoresis technique: eight different alleles designated as IFN-gamma*1 to IFN-gamma*8 could be differentiated. Among Graves' disease patients IFN-gamma*5 (12.9% vs. 6.8%, p < 0.04) was significantly more frequent whereas IFN-gamma*2 (2.5% vs. 9.8%, p < 0.002) was significantly less frequent. Patients positive for the genetic susceptibility marker HLA DQA1*0501 had significantly more IFN-gamma*3 alleles (13.6% vs. 2.6%, p < 0.009) and IFN-gamma*5 alleles (22.1% vs. 7.6%, p < 0.03) compared with DQA1*0501 positive controls. Also, among patients with endocrine ophthalmopathy IFN-gamma*3 (17.9% vs. 4.2%, p < 8 x 10(-6)) and IFN-gamma*5 (18.9% vs. 7.0%, p < 0.003) were significantly more frequent compared with controls. Although a significant association of IFN-gamma microsatellite polymorphism was observed, only a small proportion of Graves' disease patients have these markers. Thus, it is likely that the detected microsatellite polymorphisms play only a minor role in the susceptibility to Graves' disease.     

Neuropsychology and pathology of the cerebral cortex

In all clinics we are faced with questions about certain aspects of cerebral dominance. We consider first the problem of recognition of faces where the right hemisphere plays a leading role. However, the disorders manifesting that function appear only bilateral lesions. This suggests that the left hemisphere participates in this process. The reception of language raises a problem which is analogous with the preceding: we propose the participation of both hemispheres in this activity: the left hemisphere is dominant in the analysis of phonemes and syntax, the right hemisphere seems implicated above all in the processing of prosodic aspects--in particular intonations and individual features of the voice.     

Multi-modality mapping of motor cortex: comparing echoplanar BOLD fMRI and transcranial magnetic stimulation. Short communication

Multiple non-invasive methods of imaging brain function are now available for presurgical planning and neurobiological research. As these new methods become available, it is important to understand their relative advantages and liabilities, as well as how the information gained compares across different methods. A current and future trend in neurobiological studies as well as presurgical planning is to combine information from different imaging techniques. Multi-modal integration may perhaps give more powerful information than each modality alone, especially when one of the methods is transcranial magnetic stimulation (TMS), with its ability to non-invasively activate the brain. As an initial venture in cross comparing new imaging methods, we performed the following 2 studies, locating motor cortex with echoplanar BOLD fMRI and TMS. The two methods can be readily integrated, with concurring results, although each have important limitations.     

Studies on the corticospinal control of human walking. I. Responses to focal transcranial magnetic stimulation of the motor cortex

Experiments were done to determine the extent to which the corticospinal tract is linked with the segmental motor circuits controlling ankle flexors and extensors during human walking compared with voluntary motor tasks requiring attention to the level of motor activity. The motor cortex was activated transcranially using a focal magnetic stimulation coil. For each subject, the entire input-output (I-O) curve [i.e., the integral of the motor evoked-potential (MEP) versus stimulus strength] was measured during a prescribed tonic voluntary contraction of either the tibialis anterior (TA) or the soleus. Similarly, I-O curves were measured in the early part of the swing phase, or in the early part of the stance phase of walking. The I-O data points were fitted by the Boltzmann sigmoidal function, which accounted for >/=80% of total data variance. There was no statistically significant difference between the I-O curves of the TA measured during voluntary ankle dorsiflexion or during the swing phase of walking, at matched levels of background electromyographic (EMG) activity. Additionally, there was no significant difference in the relation between the coefficient of variation and the amplitude of the MEPs measured in each task, respectively. In comparison, during the stance phase of walking the soleus MEPs were reduced on average by 26% compared with their size during voluntary ankle plantarflexion. Furthermore, during stance the MEPs in the inactive TA were enhanced relative to their size during voluntary ankle plantarflexion and in four of six subjects the TA MEPs were larger than those of the soleus. Finally, stimulation of the motor cortex at various phases of the step cycle did not reset the cycle. The time of the next step occurred at the expected moment, as determined from the phase-resetting curve. One interpretation of this result is that the motor cortex may not be part of the central neural system involved in timing the motor bursts during the step cycle. We suggest that during walking the corticospinal tract is more closely linked with the segmental motor circuits controlling the flexor, TA, than it is with those controlling the extensor, soleus. However, during voluntary tasks requiring attention to the level of motor activity, it is equally linked with the segmental motor circuits of ankle flexors or extensors.     

Effects of frontal cortex lesions on differentiation and extinction of the classically conditioned nictitating membrane response in rabbits.

In Exp I 8 male New Zealand rabbits with frontal lesions, compared to 10 Ss with Visual Area II lesions, were impaired in relearning an auditory differentiation involving a classically conditioned defensive response (movement of the nictitating membrane). In Exp II it was shown that frontal lesions in 6 additional Ss also produced perseveration of this response in extinction. Analysis of these findings suggests that frontal lesions impair the ability to suppress conditioned nictitating membrane responses. Results support the view that frontal ablation produces a general impairment in overcoming strong response tendencies independently of the kind of response or reinforcement. (16 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Distribution and latency of muscle responses to transcranial magnetic stimulation of motor cortex after spinal cord injury in humans

Noninvasive transcranial magnetic stimulation (TMS) of the motor cortex was used to evoke electromyographic (EMG) responses in persons with spinal cord injury (n = 97) and able-bodied subjects (n = 20, for comparative data). Our goal was to evaluate, for different levels and severity of spinal cord injury, potential differences in the distribution and latency of motor responses in a large sample of muscles affected by the injury. The spinal cord injury (SCI) population was divided into subgroups based upon injury location (cervical, thoracic, and thoracolumbar) and clinical status (motor-complete versus motor-incomplete). Cortical stimuli were delivered while subjects attempted to contract individual muscles, in order to both maximize the probability of a response to TMS and minimize the response latency. Subjects with motor-incomplete injuries to the cervical or thoracic spinal cord were more likely to demonstrate volitional and TMS-evoked contractions in muscles controlling their foot and ankle (i.e., distal lower limb muscles) compared to muscles of the thigh (i.e., proximal lower limb muscles). When TMS did evoke responses in muscles innervated at levels caudal to the spinal cord lesion, response latencies of muscles in the lower limbs were delayed equally for persons with injury to the cervical or thoracic spinal cord, suggesting normal central motor conduction velocity in motor axons caudal to the lesion. In fact, motor response distribution and latencies were essentially indistinguishable for injuries to the cervical or thoracic (at or rostral to T10) levels of the spine. In contrast, motor-incomplete SCI subjects with injuries at the thoracolumbar level showed a higher probability of preserved volitional movements and TMS-evoked contractions in proximal muscles of the lower limb, and absent responses in distal muscles. When responses to TMS were seen in this group, the latencies were not significantly longer than those of able-bodied (AB) subjects, strongly suggestive of "root sparing" as a basis for motor function in subjects with injury at or caudal to the T11 vertebral body. Both the distribution and latency of TMS-evoked responses are consistent with highly focal lesions to the spinal cord in the subjects examined. The pattern of preserved responsiveness predominating in the distal leg muscles is consistent with a greater role of corticospinal tract innervation of these muscles compared to more proximal muscles of the thigh and hip.     

Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis. Evidence from paired transcranial magnetic stimulation

We investigated 14 patients with amyotrophic lateral sclerosis (ALS) by paired conditioning-test transcranial magnetic stimulation to test the hypothesis that the motor cortex is hyperexcitable in ALS. Intracortical (corticocortical) inhibition was significantly less in the ALS group than in an age-matched healthy control group (85.3 +/- 27.0% versus 45.2 +/- 15.5%, respectively; p < 0.0001). In contrast, intracortical facilitation, motor threshold, and cortical silent period duration in the ALS patients were not different from the control group. We suggest that the selective abnormality of intracortical inhibition is best compatible with an impaired function of inhibitory interneuronal circuits in the motor cortex that in turn renders the corticomotoneuron hyperexcitable.     

Enhancement of human motor cortex inhibition by the dopamine receptor agonist pergolide: evidence from transcranial magnetic stimulation

The autoradiographic method with [L-35S]methionine was used to determine the effects of a 2 h acute immobilization stress followed by a 4 h recovery on local rates of protein synthesis in the adult rat brain. Methionine incorporation into proteins was significantly increased (from 17 to 86%) in 37 out of the 39 analyzed brain structures. These results show that the stress-induced activation of the overall rate of brain protein synthesis may persist for at least 4 h after cessation of the stimulus even though the stress-related physiological variables have returned to basal levels. They suggest that increased protein synthesis may play a key role in the molecular events which lead to the neuronal plastic changes following an acute stress.     

Effects of preliminary perceptual output on neuronal activity of the primary motor cortex.

Observations of single neurons in the primary motor cortex of 1 monkey provided evidence that preliminary perceptual information reaches the motor system before perceptual analysis is complete. Neurons were recorded during a task in which 1 stimulus was assigned to a wrist flexion response and another was assigned to wrist extension. Two stimuli were assigned to a no-go response; each was visually similar to either the flexion or the extension stimulus. When a no-go stimulus was presented, neurons responded with weaker versions of the discharge patterns exhibited to the visually similar stimulus requiring a movement, suggesting that neurons receive partial perceptual information favoring that movement. Functionally separate neuronal populations were identified, and differences in the activations of these provide evidence about the functional effects of preliminary perceptual output on movement control processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The interaction of ethanol and delta9-tetrahydrocannabinol in man: effects on perceptual, cognitive and motor functions

Twelve paid student volunteers (8 male, 4 female) were used in a double-blind crossover experiment to investigate the effects of delta9-tetrahydrocannabinol (THC) alone, and in combination with ethanol, on human perceptual, cognitive and motor functions. Both THC (10 mg/70 kg) and ethanol (0-5 g/kg) had little effect when administered alone. The combination of drugs, however, induced a significnat decrement in performance in some of the tests and this interaction was considered to be at least additive. The peak blood ethanol concentration was higher (P = 0-05) when subjects received both ethanol and THC than when they received ethanol alone.     

Effects of methylphenidate on preschool children with ADHD: cognitive and behavioral functions

OBJECTIVE: To report on implications for methylphenidate treatment of this very young age group and the need to examine factors related to achieving compliance. METHOD: Thirty-one children with attention-deficit hyperactivity disorder (ADHD), aged 4 to 6 years, participated in a double-blind, placebo-controlled study using placebo, 0.3 mg/kg, and 0.5 mg/kg of methylphenidate twice per day. RESULTS: Improvements related to medication were obtained on cognitive tests of attention and impulsivity as well as behaviors assessed by parent rating scales. In an interactive setting with their mothers, attentional abilities and the children's ability to work more productively also showed improvement. However, no changes were obtained with respect to the children's tendency to comply with parental requests. Side effects increased slightly with the high dosage of medication but remained mild. CONCLUSION: The results suggest that methylphenidate can be used to improve the functioning of preschool-age children with ADHD, in a manner similar to their school-age counterparts.