Hitoshi Mochizuki

Consensus paper: Combining transcranial stimulation with neuroimaging

In the last decade, combined transcranial magnetic stimulation (TMS)-neuroimaging studies have greatly stimulated research in the field of TMS and neuroimaging. Here, we review how TMS can be combined with various neuroimaging techniques to investigate human brain function. When applied during neuroimaging (online approach), TMS can be used to test how focal cortex stimulation acutely modifies the activity and connectivity in the stimulated neuronal circuits. TMS and neuroimaging can also be separated in time (offline approach). A conditioning session of repetitive TMS (rTMS) may be used to induce rapid reorganization in functional brain networks. The temporospatial patterns of TMS-induced reorganization can be subsequently mapped by using neuroimaging methods. Alternatively, neuroimaging may be performed first to localize brain areas that are involved in a given task. The temporospatial information obtained by neuroimaging can be used to define the optimal site and time point of stimulation in a subsequent experiment in which TMS is used to probe the functional contribution of the stimulated area to a specific task. In this review, we first address some general methodologic issues that need to be taken into account when using TMS in the context of neuroimaging. We then discuss the use of specific brain mapping techniques in conjunction with TMS. We emphasize that the various neuroimaging techniques offer complementary information and have different methodologic strengths and weaknesses.

Influence of Genetic Variations of Ethanol‐Metabolizing Enzymes on Phenotypes of Alcohol‐Related Disorders

Abstract: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase‐2 (ALDH2) play central roles in the metabolism of ethanol and its metabolite, acetaldehyde, in the liver. In ADH2, one nucleotide replacement causes either a super‐active beta 2 subunit encoded by the ADH2*2 allele or a less active beta 1 subunit (ADH2*1 allele). In the same way, a G/A replacement at codon 487 of the ALDH2 gene produces an inactive form of the enzyme. Because the geno‐types of these genes may explain individual differences in concentration and elimination of ethanol and acetaldehyde in the blood after drinking, they could be used as models to elucidate the contribution of these substances to the development of addiction and various types of organ damage. We have examined the influence of genetic variations of these enzymes on alcohol‐related disorders in the Japanese. The results revealed that (1) the less active allele of the ADH2 gene (ADH2*1) is associated with an increased risk for alcohol dependence, alcohol‐induced persistent amnestic disorder, alcohol withdrawal syndrome, and cancer of the upper GI tract; (2) the inactive allele of the ALDH2 gene (ALDH2*2) is associated with a decreased risk for alcohol dependence, and an increased risk for alcoholic polyneuropathy and cancer in the same region; and (3) these genetic variations modify clinical features of alcohol dependence. Possible mechanisms of altered risk for these disorders are discussed.

Benign type of central pontine myelinolysis in alcoholism: Clinical, neuroradiological and electrophysiological findings

Abstract.Nine alcoholic patients with central pontine myelinolysisn(CPM),who showed a favorable prognosis, are reported. Thenmajority of them had taken part in binge drinking and had ansubsequent consciousness disturbance for 18.1±10.9 (mean±SD)ndays. None of the patients had had acute correction ofnhyponatremia. Truncal ataxia and gait instability were presentnin most of the patients after recovery from the disturbance ofnconsciousness. Most of them eventually gained independence, andnmagnetic resonance imaging showed that their pontine lesionsntended to shrink. Electrophysiological studies detectednprolonged latency between the I and III waves in auditorynbrainstem responses and between N11 and P13/14 onsets in thensomatosensory evoked potentials. These clinical, radiologicalnand electrophysiological findings should be of use in diagnosingnCPM.

Intracortical inhibition of the motor cortex is normal in chorea

Intracortical inhibition of the motor cortex was investigated using a paired pulse magnetic stimulation method in 14 patients with chorea caused by various aetiologies (six patients with Huntington’s disease, one with chorea acanthocytosis, a patient with systemic lupus erythematosus with a vascular lesion in the caudate, three with senile chorea and three with chorea of unknown aetiology). The time course and amount of inhibition was the same in the patients as in normal subjects, suggesting that the inhibitory mechanisms of the motor cortex studied with this method are intact in chorea. This is in striking contrast with the abnormal inhibition seen in patients with Parkinson’s disease or focal hand dystonia, or those with a lesion in the putamen or globus pallidus. It is concluded that the pathophysiological mechanisms responsible for chorea are different from those producing other involuntary movements.

Decreased resting energy expenditure in patients with Duchenne muscular dystrophy.

BACKGROUNDnSkeletal muscle metabolism is a major determinant of resting energy expenditure (REE). Although the severe muscle loss that characterizes Duchenne muscular dystrophy (DMD) may alter REE, this has not been extensively investigated.nnnMETHODSnWe studied REE in 77 patients with DMD ranging in age from 10 to 37 years using a portable indirect calorimeter, together with several clinical parameters (age, height, body weight (BW), body mass index (BMI), vital capacity (VC), creatine kinase, creatinine, albumin, cholinesterase, prealbumin), and assessed their influence on REE. In addition, in 12 patients maintaining a stable body weight, the ratio of energy intake to REE was calculated and defined as an alternative index for the physical activity level (aPAL).nnnRESULTSnREE (kcal/day, mean±SD) in DMD patients was 1123 (10-11 years), 1186±188 (12-14 years), 1146±214 (15-17 years), 1006±136 (18-29 years) and 1023±97 (≥30 years), each of these values being significantly lower than the corresponding control (p<0.0001). VC (p<0.001) was the parameter most strongly associated with REE, followed by BMI (p<0.01) and BW (p<0.05). The calculated aPAL values were 1.61 (10-11 years), 1.19 (12-14 years), 1.16 (15-17 years), and 1.57 (18-29 years).nnnCONCLUSIONnThe REE in DMD patients was significantly lower than the normal value in every age group, and strongly associated with VC. Both the low REE and PAL values during the early teens, resulting in a low energy requirement, might be related to the obesity that frequently occurs in this age group. In contrast, the high PAL value in the late stage of the disease, possibly due to the presence of respiratory failure, may lead to a high energy requirement, and thus become one of the risk factors for development of malnutrition.

Ataxic hemiparesis: neurophysiological analysis by cerebellar transcranial magnetic stimulation.

The aim of this study was to investigate physiological mechanisms underlying ataxia in patients with ataxic hemiparesis. Subjects were three patients with ataxic hemiparesis, whose responsible lesion was located at the posterior limb of internal capsule (case 1), thalamus (case 2), or pre- and post-central gyri (case 3). Paired-pulse transcranial magnetic stimulation (TMS) technique was used to evaluate connectivity between the cerebellum and contralateral motor cortex. The conditioning cerebellar stimulus was given over the cerebellum and the test stimulus over the primary motor cortex. We studied how the conditioning stimulus modulated motor evoked potentials (MEPs) to the cortical test stimulus. In non-ataxic limbs, the cerebellar stimulus normally suppressed cortical MEPs. In ataxic limbs, the cerebellar inhibition was not elicited in patients with a lesion at the posterior limb of internal capsule (case 1) or thalamus (case 2). In contrast, normal cerebellar inhibition was elicited in the ataxic limb in a patient with a lesion at sensori-motor cortex (case 3). Lesions at the internal capsule and thalamus involved the cerebello-thalamo-cortical pathways and reduced the cerebellar suppression effect. On the other hand, a lesion at the pre- and post-central gyri should affect cortico-pontine pathway but not involve the cerebello-thalamo-cortical pathways. This lack of cerebello-talamo-cortical pathway involvement may explain normal suppression in this patient. The cerebellar TMS method can differentiate cerebellar efferent ataxic hemiparesis from cerebellar afferent ataxic hemiparesis.

Bidirectional modulation of sensory cortical excitability by quadripulse transcranial magnetic stimulation (QPS) in humans.

OBJECTIVEnQuadripulse transcranial magnetic stimulation (QPS) is a newly designed patterned repetitive transcranial magnetic stimulation (TMS). Previous studies of QPS showed bidirectional effects on the primary motor cortex (M1), which depended on its inter-stimulus interval (ISI): motor evoked potentials (MEPs) were potentiated at short ISIs and depressed at long ISIs (homotopic effects). These physiological characters were compatible with synaptic plasticity. In this research, we studied effects of QPS on the primary sensory cortex (S1).nnnMETHODSnOne burst consisted of four monophasic TMS pulses at an intensity of 90% active motor threshold. The ISI of four pulses was set at 5 ms (QPS-5) or at 50 ms (QPS-50). Same bursts were given every 5s for 30 min. QPS-5 and QPS-50 were performed over three areas (M1, S1 and dorsal premotor cortex (dPMC)). One sham stimulation session was also performed. Excitability changes of S1 were evaluated by timeline of somatosensory evoked potentials (SEPs).nnnRESULTSnQPS-5 over M1 or dPMC enhanced the P25-N33 component of SEP, and QPS-50 over M1 depressed it. By contrast, QPSs over S1 had no effects on SEPs.nnnCONCLUSIONSnQPSs over motor cortices modulated the S1 cortical excitability (heterotopic effects). Mutual connections between dPMC or M1 and S1 might be responsible for these modulations.nnnSIGNIFICANCEnQPSs induced heterotopic LTP or LTD-like cortical excitability changes.

Cortical hemoglobin concentration changes underneath the coil after single-pulse transcranial magnetic stimulation: a near-infrared spectroscopy study

Using near-infrared spectroscopy (NIRS) and multichannel probes, we studied hemoglobin (Hb) concentration changes when single-pulse transcranial magnetic stimulation (TMS) was applied over the left hemisphere primary motor cortex (M1). Seventeen measurement probes were centered over left M1. Subjects were studied in both active and relaxed conditions, with TMS intensity set at 100%, 120%, and 140% of the active motor threshold. The magnetic coils were placed so as to induce anteromedially directed currents in the brain. Hb concentration changes were more prominent at channels over M1 and posterior to it. Importantly, Hb concentration changes at M1 after TMS differed depending on whether the target muscle was in an active or relaxed condition. In the relaxed condition, Hb concentration increased up to 3-6 s after TMS, peaking at ∼6 s, and returned to the baseline. In the active condition, a smaller increase in Hb concentrations continued up to 3-6 s after TMS (early activation), followed by a decrease in Hb concentration from 9 to 12 s after TMS (delayed deactivation). Hb concentration changes in the active condition at higher stimulus intensities were more pronounced at locations posterior to M1 than at M1. We conclude that early activation occurs when M1 is activated transsynaptically. The relatively late deactivation may result from the prolonged inhibition of the cerebral cortex after activation. The posterior-dominant activation at higher intensities in the active condition may result from an additional activation of the sensory cortex due to afferent inputs from muscle contraction evoked by the TMS.

Quadri-pulse stimulation induces stimulation frequency dependent cortical hemoglobin concentration changes within the ipsilateral motor cortical network.

BACKGROUNDnImaging studies investigating repetitive transcranial magnetic stimulation (rTMS) mediated hemodynamic consequences revealed inconsistent results, mainly due to differences in rTMS parameters and technical difficulties with simultaneous recordings during rTMS.nnnOBJECTIVE/HYPOTHESISnQuadri-pulse rTMS (QPS) induces bidirectional long-term plasticity of the human primary motor cortex (M1). To evaluate its on-line effects, near infrared spectroscopy (NIRS) recordings were performed during QPS. We hypothesized that on-line effects during QPS are different from long-term aftereffects.nnnMETHODSnUsing a novel TMS - on-line multi-channel NIRS setup we recorded hemoglobin concentration [Hb] changes at the stimulated M1 and adjacent sensory-motor areas during QPS protocols inducing oppositely directed aftereffects (QPS-5: interstimulus interval (ISI) 5xa0ms, potentiation; QPS-50: ISI 50xa0ms, depression). In two experiments we studied NIRS changes during either single or repeated QPS bursts.nnnRESULTSnThe repetitive QPS-5 bursts significantly decreased oxyhemoglobin concentration ([oxy-Hb]) in the ipsilateral M1. A single QPS-5 burst decreased [oxy-Hb] in the M1 and premotor cortex. QPS-50 induced no significant NIRS changes at any sites.nnnCONCLUSIONSnQPS can significantly alter cortical hemodynamics depending on the stimulation frequency. While bidirectional long-term aftereffects of QPS reflect synaptic efficacy changes, unidirectional on-line effects during QPS may represent pure electrophysiological property changes within the cell membrane or synapse. Since neuronal postexcitatory inhibitory postsynaptic potentials typically peak within the first 10-20xa0ms, only pulses delivered at higher frequencies may lead to summation of the inhibitory effects, resulting in [oxy-Hb] decrease only after QPS-5. Our new TMS-NIRS setup may be valuable to investigate TMS induced neurovascular coupling mechanisms in humans.

On-line effects of quadripulse transcranial magnetic stimulation (QPS) on the contralateral hemisphere studied with somatosensory evoked potentials and near infrared spectroscopy

To evaluate on-line effects of quadripulse stimulation (QPS) over the primary motor cortex (M1) on cortical areas in the contralateral hemisphere. QPS consisted of 24 bursts of transcranial magnetic stimulation (TMS) pulses with an inter-burst interval of 5xa0s for 2xa0min (for on-line effect study) or 360 bursts for 30xa0min (for after-effect study). Each burst consisted of four TMS pulses (i.e. QPS) separated by an interstimulus interval of 5 or 50xa0ms (QPS-5 or QPS-50). QPSs were delivered over the left M1. Experiment 1 [on-line effect on somatosensory evoked potential (SEP)]: Left median nerve SEPs were recorded before, during and after QPS. Experiment 2 (after effect on SEP): After-effects of QPS were evaluated by following up SEPs after the QPS sessions. Experiment 3 (on-line effect on NIRS): Near infrared spectroscopy (NIRS) was also recorded at the right hemisphere during all QPS paradigms. Both QPS-5 and QPS-50 enlarged a cortical component of the contralateral SEP during stimulation. On the other hand, concerning the after effects, QPS-5 over M1 potentiated the contralateral SEP and QPS-50 tended to depress it. In NIRS study, both QPS-5 and QPS-50 induced a significant oxy-Hb decrease (deactivation pattern) at the right hemisphere during stimulation whereas sham stimulations unaffected them. We have shown the unidirectional on-line effects evoked by QPS-5 and QPS-50 on both SEP and NIRS, and bidirectional after effects on SEP at the contralateral hemisphere. The discrepancy between on-line effect and after effect may be explained by the differences in the underlying mechanisms between them. The former may be mainly explained by pure electrophysiological property changes in the membrane or synapses. The latter may be explained by synaptic efficacy changes which need some protein syntheses at least partly. Another discrepancy shown here is the direction of on-line effects. Electrophysiological (SEP) function was potentiated by both QPSs whereas hemodynamic (NIRS) function was depressed. This may be explained by which sensory areas contribute to NIRS or SEP generation.