Long-lasting TMS motor threshold elevation in mild traumatic brain injury.

OBJECTIVES: Mild traumatic brain injury (mTBI) is very common, and part of the patients experience persistent symptoms. These may be caused by diffuse neuronal damage and could therefore affect cortical excitability. The motor threshold (MT), measured by transcranial magnetic stimulation (TMS), is a measure of cortical excitability and cortico-spinal tract integrity. MATERIALS AND METHODS: We used navigated TMS (nTMS) and electromyography to determine subjects' left hemisphere MTs. Nineteen subjects with mTBI (11 with persistent symptoms and eight fully recovered) and nine healthy controls were tested. The injuries had occurred on average 5 years earlier. All participants had normal brain MRIs, that is, no signs of injury. None used centrally acting medication. RESULTS: The mean MT in controls was 43.0% (SD 2.5) of maximum stimulator output. The mTBI subjects mean MT was 53.4% (SD 9.7), being higher than the controls' threshold. Subjective recovery did not correlate with MT. CONCLUSIONS: The results show chronic MT elevation in a sample of subjects with symptomatic or recovered mTBI. This suggests that mTBI may be compensated, although not fully recovered, years after the injury. While the cause for MT elevation cannot be concluded from these preliminary observations, possible explanations include decreased cortical excitability and impaired subcortical conduction.

What do ERPs and ERFs reveal about the effect of antipsychotic treatment on cognition in schizophrenia?

Cognitive dysfunction is considered to be a core feature in schizophrenia. It is believed that antipsychotic drugs, especially atypical ones, could improve cognitive functions in schizophrenia patients. Auditory event-related potentials (ERPs) such as mismatch negativity (MMN) and P300 response are potential candidates for objective investigation of pre-attentional and attention-dependent processing in schizophrenia patients, respectively. Both these responses were found to be altered in schizophrenia. Moreover, neurotransmitters play important role in generation of MMN and P300 components. Therefore, these ERPs are potential candidates for monitoring the cognitive changes caused by neurochemical modulation during antipsychotic treatment in schizophrenia patients. In addition, neurochemical ERP generation mechanisms discovered during drug-challenge studies in healthy subjects could explain these ERP findings in patients. To date, no effect of antipsychotic treatment on MMN was observed, whereas certain antipsychotics (e.g. clozapine) could modulate P300 response. At the same time, adjunctive glutamate-system affecting therapy seems to influence MMN response. The explanation of these phenomena could be a weak relationship between dopaminergic activities and MMN response and a strong connection between glutamate NMDA receptors and MMN generation. As to the P300 component, because of the multiple generators, it is more sensitive to the influences of different neurochemical activities. In the future, the combination of transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) with electroencephalography (EEG) will open new possibilities for understanding the drug-induced changes on the neural substrates of information processing in schizophrenia patients.

Reorganization of the composition of brain oscillations and their temporal characteristics during opioid withdrawal.

Majority of the opioid-dependence and withdrawal studies are dominated with many inconsistencies and contradictions. One of the reasons for such inconsistencies may be methodological while performing EEG analysis. To overcome methodological limitations, in the present study we examined the composition of electroencephalographic (EEG) brain oscillations in broad frequency band (0.5-30 Hz) in 13 withdrawal opioid-dependent patients and 14 healthy subjects during resting condition (closed eyes). The exact compositions of brain oscillations and their temporal behaviour were assessed by the probability-classification analysis of short-term EEG spectral patterns (SPs). It was reported that early withdrawal had a generalized effect: the activity in all EEG channels was affected nearly equally. EEG of withdrawal patients was characterized by (a) different dominant SP types (had unique SP types which describe beta-frequency band), (b) increased number of SP types observed in each EEG channel, (c) a larger percentage of alpha(2)-, beta- and poly-rhythmic activity, and by a smaller percentage of delta-, - and alpha(1)-rhythmic activity, (d) predominantly right-sided asymmetry and (e) longer periods of temporal stabilization for alpha- and beta-brain oscillations and by shorter periods of temporal stabilization for -activity when compared with control subjects. When taken together, these findings suggest a considerable reorganization of composition of brain oscillations, which reflects a disorganization process and an allostatic state with neuronal activation in EEG of opioid withdrawal patients.

Prefrontal transcranial magnetic stimulation produces intensity-dependent EEG responses in humans.

The reactivity of the prefrontal cortex (PFC) was studied by measuring electroencephalographic (EEG) responses to transcranial magnetic stimulation (TMS) with different stimulus intensities. Focal TMS at intensities of 60%, 80%, 100%, and 120% of the motor threshold was delivered to the left middle frontal gyrus identified individually from magnetic resonance images (MRI) in seven healthy subjects. EEG was simultaneously recorded with 60 scalp electrodes. Stimulation evoked clear responses at all intensities. Left prefrontal TMS evoked an averaged EEG response consisting of five deflections at 27 +/- 3 ms (peak I), 39 +/- 3 ms (II), 52 +/- 7 ms (III), 105 +/- 14 ms (IV), and 193 +/- 15 ms (V) at the Fz/FCz electrodes. The slope of the almost linear dependence of the overall response on stimulus intensity varied with latency. Potential distributions were relatively similar for the four intensities, suggesting that the same cortical structures may be activated. Intensity dependence function to TMS may be an indicator of cortical activation in humans.

Combination of magneto- and electroencephalography in studies of monoamine modulation on attention.

The brain monoamines serotonin and dopamine have an important role in the regulation of human cognitive functions. Neural correlates of attention can be studied in millisecond resolution with magnetoencephalography (MEG) and electroencephalography (EEG), which provide complementary views on attentional processing. During "selective attention", a processing negativity (PN) overlaps EEG response to the attended tones. This component can be modulated with drugs affecting dopamine transmission in the brain, such as haloperidol and droperidol, whereas no effects seem to be caused by acute tryptophan depletion (ATD), decreasing serotonin synthesis in the brain. Distinct responses are associated with "involuntary attention". Responses reflecting sound-change detection and initiation of involuntary attention, the mismatch negativity and its magnetic counterpart, appear to be modulated by ATD, but not with haloperidol. Subsequent P3a elicited by actual attention shifting, as well as reorienting negativity reflecting orienting back to a relevant task, are in turn decreased by haloperidol, but not affected by ATD or other serotonin modulators. Serotonin may affect the earliest "preattentive" phases on auditory processing, indexed by mid-latency magnetic responses and NIm, but haloperidol's effects on these parameters are insignificant. Taken together, serotonin and dopamine may have differential effects on attentional processing depending on time after stimulus presentation.

No evidence for dependence of early cortical auditory processing on dopamine D(2)-receptor modulation: a whole-head magnetoencephalographic study.

Magnetoencephalography (MEG) was used to determine the effect of neuroleptic challenge on brain responses in healthy subjects. In a double-blind, randomized, placebo-controlled, cross-over design study, the dopamine D(2) receptor antagonist haloperidol (2 mg) was given orally to 12 healthy volunteers. The middle-latency auditory evoked magnetic fields (MAEF) were recorded 3 h after administration of haloperidol or placebo with a whole-head 122-channel MEG. Haloperidol did not significantly affect MAEF responses. The dipole moments and source locations of the responses were not significantly influenced by haloperidol. These results suggest that dopamine D(2) receptors are not involved in the early phases of auditory cortical processing.

Effects of haloperidol on selective attention: a combined whole-head MEG and high-resolution EEG study.

We used 122-channel magnetoencephalography (MEG) and 64-channel electroencephalogrphy (EEG) simultaneously to study the effects of dopaminergic transmission on human selective attention in a randomized, double-blind placebo-controlled cross-over design. A single dose of dopamine D2 receptor antagonist haloperidol (2 mg) or placebo was given orally to 12 right-handed healthy volunteers 3 hours before measurement. In a dichotic selective attention task, subjects were presented with two trains of standard (700 Hz to the left ear, 1,100 Hz to the right ear) and deviant (770 and 1,210 Hz, respectively) tones. Subjects were instructed to count the tones presented to one ear; whereas, the tones presented to the other ear were to be ignored. Haloperidol significantly attenuated processing negativity (PN), an event-related potential (ERP) component elicited by selectively attended standard tones at 300-500 ms after stimulus presentation. These results, indicating impaired selective attention by a blockade of dopamine D2 receptors, were further accompanied with increased mismatch negativity (MMN), elicited by involuntary detection of task-irrelevant deviants. Taken together, haloperidol seemed to induce functional changes in neural networks accounting for both selective and involuntary attention, suggesting modulation of these functions by dopamine D2 receptors.

Ethanol modulates cortical activity: direct evidence with combined TMS and EEG.

The motor cortex of 10 healthy subjects was stimulated by transcranial magnetic stimulation (TMS) before and after ethanol challenge (0.8 g/kg resulting in blood concentration of 0.77 +/- 0.14 ml/liter). The electrical brain activity resulting from the brief electromagnetic pulse was recorded with high-resolution electroencephalography (EEG) and located using inversion algorithms. Focal magnetic pulses to the left motor cortex were delivered with a figure-of-eight coil at the random interstimulus interval of 1.5-2.5 s. The stimulation intensity was adjusted to the motor threshold of abductor digiti minimi. Two conditions before and after ethanol ingestion (30 min) were applied: (1) real TMS, with the coil pressed against the scalp; and (2) control condition, with the coil separated from the scalp by a 2-cm-thick piece of plastic. A separate EMG control recording of one subject during TMS was made with two bipolar platinum needle electrodes inserted to the left temporal muscle. In each condition, 120 pulses were delivered. The EEG was recorded from 60 scalp electrodes. A peak in the EEG signals was observed at 43 ms after the TMS pulse in the real-TMS condition but not in the control condition or in the control scalp EMG. Potential maps before and after ethanol ingestion were significantly different from each other (P = 0.01), but no differences were found in the control condition. Ethanol changed the TMS-evoked potentials over right frontal and left parietal areas, the underlying effect appearing to be largest in the right prefrontal area. Our findings suggest that ethanol may have changed the functional connectivity between prefrontal and motor cortices. This new noninvasive method provides direct evidence about the modulation of cortical connectivity after ethanol challenge.

Suppression of transient 40-Hz auditory response by haloperidol suggests modulation of human selective attention by dopamine D2 receptors.

Cognitive processes including selective attention may depend on synchronous activity of neurons at the gamma-band (around 40Hz). To determine the effect of neuroleptic challenge on transient auditory evoked 40-Hz response, simultaneous measurement of 122-channel magnetoencephalogram (MEG) and 64-channel electroencephalogram (EEG) was used. Either 2mg of dopamine D(2)-receptor antagonist haloperidol or a placebo was administered orally to 11healthy subjects in a double-blind randomized crossover design in two separate sessions. The subjects attended to tones presented to one ear and ignored those presented to the other ear. Haloperidol significantly suppressed the transient 40-Hz electric response to the attended stimuli, while no significant effect was observed in the electric responses to the unattended tones or in the magnetic responses. The present result suggests that dopamine D(2) receptors modulate selective attention.