Cognitive effects of treatment of depression with repetitive transcranial magnetic stimulation.

BACKGROUND AND OBJECTIVE: We previously reported a randomized, sham-controlled trial of 5 Hz dorsolateral prefrontal left- and right-side repetitive transcranial magnetic stimulation (rTMS) in 48 participants with a medically refractory major depressive disorder. Depression improved most with right-side cranial stimulation, both rTMS and sham, and to a lesser degree with left rTMS. Because depression is often associated with cognitive impairment, in this study we sought to determine whether our earlier participants had treatment-induced changes in cognition, which cognitive domains (language, executive, visuospatial, verbal episodic memory, attention) were affected, and whether treatment-induced cognitive changes were related either to improvement in depression or to other treatment variables, such as right versus left treatment and rTMS versus sham. METHODS: We used hierarchical regression analyses to determine how variables measured at baseline or associated with treatment affected changes in neuropsychological functions. The variables were neuropsychological function in the 5 domains, severity of depression, change in depression with treatment, rTMS versus sham, laterality of stimulation, and rTMS-laterality interaction. RESULTS: Compared to sham, right rTMS was associated with 1.24 standard deviations greater gain in language function, 1.09 standard deviations greater gain in visuospatial function, and 2.38 standard deviations greater gain in verbal episodic memory than left rTMS. These improvements did not appear to be directly related to the relief from depression. CONCLUSIONS: Our results suggest that disorders of cognition and mood in depression may have different mechanisms, but right rTMS may treat both. We propose potential mechanisms underlying the right-side rTMS effect. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT00711568.

Motor evoked potential depression following repetitive central motor initiation.

Prior reports have described a transient and focal decline in transcranial magnetic stimulation (TMS)-induced motor evoked potential (MEP) amplitude following fatiguing motor tasks. However, the neurophysiological causes of this change in MEP amplitude are unknown. The aim of this study was to determine whether post-task depression of MEPs is associated with repetitive central motor initiation. We hypothesized that MEP depression is related to repeated central initiation of motor commands in task-related cortex independent of motor fatigue. Twenty healthy adults had MEPs measured from the dominant first dorsal interosseous (FDI) muscle before and after six different tasks: rest (no activity), contralateral fatiguing hand-grip, ipsilateral fatiguing hand-grip, contralateral finger tapping, ipsilateral finger tapping, and imagined hand-grip (motor imagery). Changes in MEPs from baseline were assessed for each task immediately following the task and at 2-min intervals until MEPs returned to a stable baseline. Measures of subjective effort and FDI maximum voluntary contractions (MVC) were also recorded following each task. A statistically significant drop in MEP amplitude was noted only with contralateral finger tapping and imagined grip. Changes in MEP amplitude did not correlate with subjective fatigue or effort. There was no significant change in FDI MVCs following hand-grip or finger-tapping tasks. This study extends our knowledge of the observed decline in MEP amplitude following certain tasks. Our results suggest that central initiation of motor programs may induce a change in MEP amplitude, even in the absence of objective fatigue.

Right and left dorsolateral pre-frontal rTMS treatment of refractory depression: a randomized, sham-controlled trial.

We conducted a prospective, randomized, sham-controlled, double blind, parallel group study of right or left pre-frontal rTMS in 48 subjects with medication-resistant depression. Two thousand (50x8-s trains of 5Hz) stimuli at MEP threshold were delivered each weekday for 2weeks. We employed a sham coil and simultaneous electrical stimulation of the scalp to simulate rTMS. Mean (+/-S.D.) reductions in the HAMD-24 from baseline to 3-months were not significantly different between rTMS and sham treatment groups. However, right cranial stimulation (sham or rTMS) was significantly more effective than left cranial stimulation (sham or rTMS) (P=0.012). Mean (+/-S.D.) reductions in the HAMD from baseline to 3 months were: left: 28.1 (+/-5.36) to 19.2 (+/-11.2); and right 27.2 (+/-4.2) to 11.5 (+/-9.4). Left rTMS achieved a reduction in HAMD 9.5 points greater than that achieved by left sham, a benefit greater than that reported in a recent multi-center Phase III trial of rTMS (O'Reardon et al., 2007), albeit not statistically significant. These results suggest that somatosensory stimuli that repeatedly engage the left hemisphere may be important to the achievement of therapeutic effect.

The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee.

The review focuses on the clinical diagnostic utility of transcranial magnetic stimulation (TMS). The central motor conduction time (CMCT) is a sensitive method to detect myelopathy and abnormalities may be detected in the absence of radiological changes. CMCT may also detect upper motor neuron involvement in amyotrophic lateral sclerosis. The diagnostic sensitivity may be increased by using the triple stimulation technique (TST), by combining several parameters such as CMCT, motor threshold and silent period, or by studying multiple muscles. In peripheral facial nerve palsies, TMS may be used to localize the site of nerve dysfunction and clarify the etiology. TMS measures also have high sensitivity in detecting lesions in multiple sclerosis and abnormalities in CMCT or TST may correlate with motor impairment and disability. Cerebellar stimulation may detect lesions in the cerebellum or the cerebellar output pathway. TMS may detect upper motor neuron involvement in patients with atypical parkinsonism and equivocal signs. The ipsilateral silent period that measures transcallosal inhibition is a potential method to distinguish between different parkinsonian syndromes. Short latency afferent inhibition (SAI), which is related to central cholinergic transmission, is reduced in Alzheimer's disease. Changes in SAI following administration of cholinesterase inhibitor may be related to the long-term efficacy of this treatment. The results of MEP measurement in the first week after stroke correlate with functional outcome. We conclude that TMS measures have demonstrated diagnostic utility in myelopathy, amyotrophic lateral sclerosis and multiple sclerosis. TMS measures have potential clinical utility in cerebellar disease, dementia, facial nerve disorders, movement disorders, stroke, epilepsy, migraine and chronic pain.

Short Intracortical Inhibition During Voluntary Movement Reveals Persistent Impairment Post-stroke.

Objective: Short intracortical inhibition (SICI) is a GABAA-mediated phenomenon, argued to mediate selective muscle activation during coordinated motor activity. Markedly reduced SICI has been observed in the acute period following stroke and, based on findings in animal models, it has been posited this disinhibitory phenomenon may facilitate neural plasticity and contribute to early motor recovery. However, it remains unresolved whether SICI normalizes over time, as part of the natural course of stroke recovery. Whether intracortical inhibition contributes to motor recovery in chronic stroke also remains unclear. Notably, SICI is typically measured at rest, which may not fully reveal its role in motor control. Here we investigated SICI at rest and during voluntary motor activity to determine: (1) whether GABAA-mediated inhibition recovers, and (2) how GABAA-mediated inhibition is related to motor function, in the chronic phase post-stroke. Methods: We studied 16 chronic stroke survivors (age: 64.6 ± 9.3 years; chronicity: 74.3 ± 52.9 months) and 12 age-matched healthy controls. We used paired-pulse transcranial magnetic stimulation (TMS) to induce SICI during three conditions: rest, submaximal grip, and performance of box-and-blocks. Upper-extremity Fugl-Meyer Assessment and Box-and-Blocks tests were used to evaluate motor impairment in stroke survivors and manual dexterity in all participants, respectively. Results: At rest, SICI revealed no differences between ipsilesional and contralesional hemispheres of either cortical or subcortical stroke survivors, or healthy controls (P's > 0.05). During box-and-blocks, however, ipsilesional hemisphere SICI was significantly reduced (P = 0.025), especially following cortical stroke (P < 0.001). SICI in the ipsilesional hemisphere during box-and-blocks task was significantly related to paretic hand dexterity (r = 0.56, P = 0.039) and motor impairment (r = 0.56, P = 0.037). Conclusions: SICI during motor activity, but not rest, reveals persistent impairment in chronic stroke survivors indicating that inhibitory brain circuits responsible for motor coordination do not fully normalize as part of the natural history of stroke recovery. Observation that reduced SICI (i.e., disinhibition) is associated with greater motor impairment and worse dexterity in chronic hemiparetic individuals suggests the response considered to promote neuroplasticity and recovery in the acute phase could be maladaptive in the chronic phase post-stroke.

Ipsilateral motor activation during unimanual and bimanual motor tasks.

OBJECTIVE: To test for the presence and possible asymmetry of ipsilateral motor activation during unimanual and bimanual motor tasks. METHODS: Twelve right-handed healthy subjects underwent motor evoked potential (MEP) measurement of one hand (target-hand) while the other hand (task-hand) performed different motor tasks. The target-hand was either at rest (first experiment) or performed a Perdue PegBoard task (second experiment). The task-hand was either at rest, performed a simultaneous pegboard task, or rotated a coin (second experiment). RESULTS: In the first experiment, the motor task resulted in significant increase in MEP area in the target-hand, regardless which hand was the task-hand, with a greater increase when the left hand was the task-hand. In the second experiment, ipsilateral motor activation was not present for either hand, however, when the right hand was the task-hand, performance of continuous coin rotation by the right hand resulted in a significant decrease in the MEP area of the left hand. CONCLUSIONS: Hemispheric asymmetry and task-dependence of ipsilateral motor cortex activation supports the postulate that motor activity may start bilaterally with subsequent interhemispheric inhibition. Furthermore, in right-handers, the left motor cortex is either more active in ipsilateral hand movements or exerts more effective inhibitory control over the right motor cortex than vice versa. SIGNIFICANCE: We suggest that hemispheric asymmetry in ipsilateral motor control is a factor in determining motor dominance in right-handed individuals.

Immobilization dystonia.

The mechanisms underlying dystonia after injury are unclear. Pain has been implicated as an important factor. We report four patients who exhibited segmental dystonia following removal of a cast, only two of whom experienced pain during casting. Recent work implicates the cerebral cortex as an important site of neural plasticity underlying the development of dystonia. Cortical changes may be induced by peripheral stimuli that are repetitive, spatially and temporally proximate, stereotyped, and attended. Immobilization by casting may meet these requirements if there is sufficiently persistent sensation of the immobilized limb to assure that it is regularly attended. The fact that all of our patients were immobilized but only two experienced pain during casting suggests that pain is not necessary and immobilization alone may be sufficient for the development of segmental dystonia after peripheral injury, consistent with the implications of animal studies.

Corticosteroid treatment of mitochondrial encephalomyopathies.

BACKGROUND: Mitochondrial encephalopathy with lactic acidosis and stroke-like symptoms (MELAS) is a multisystem disorder characterized by stroke-like episodes, seizures, dementia, headaches,evidence of mitochondrial myopathy. Lactic acidosis and ragged red fibers are often present. A variety of therapies have been used with inconclusive and disappointing results. There have been very few cases of MELAS reported as corticosteroid responsive. SUMMARY: A 27-year-old healthy man was hospitalized with recurrent generalized tonic-clonic seizures, intractable headaches, and stroke-like symptoms. These symptoms improved after the initiation of corticosteroid treatment. Multiple attempts to taper corticosteroids were followed by clinical relapse. Genetic testing in this patient revealed a point mutation at nt 3243 of the mitochondrial tRNA gene, confirming the diagnosis of MELAS. The patient died 1 year later after an episode of status epilepticus. Corticosteroid therapy in individual MELAS patients has been associated with clinical improvement. Discrepancy exists with regard to corticosteroid type, dose, route of administration, length of therapy, patient population, and clinical and metabolic parameters to follow during corticosteroid therapy. CONCLUSIONS: Corticosteroid therapy may be beneficial during acute exacerbation of MELAS.

Does inhibitory repetitive transcranial magnetic stimulation augment functional task practice to improve arm recovery in chronic stroke?

Introduction. Restoration of upper extremity (UE) functional use remains a challenge for individuals following stroke. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive modality that modulates cortical excitability and is being explored as a means to potentially ameliorate these deficits. The purpose of this study was to evaluate, in the presence of chronic stroke, the effects of low-frequency rTMS to the contralesional hemisphere as an adjuvant to functional task practice (FTP), to improve UE functional ability. Methods. Twenty-two individuals with chronic stroke and subsequent moderate UE deficits were randomized to receive 16 sessions (4 times/week for 4 weeks) of either real-rTMS or sham-rTMS followed by 1-hour of paretic UE FTP. Results. No differences in UE outcomes were revealed between the real-rTMS and sham-rTMS intervention groups. After adjusting for baseline differences, no differences were revealed in contralesional cortical excitability postintervention. In a secondary analysis, data pooled across both groups revealed small, but statistically significant, improvements in UE behavioral measures. Conclusions. rTMS did not augment changes in UE motor ability in this population of individuals with chronic stroke. The chronicity of our participant cohort and their degree of UE motor impairment may have contributed to inability to produce marked effects using rTMS.

Use of transcranial magnetic stimulation to influence behavior.

Transcranial magnetic stimulation (TMS) is a noninvasive technique that allows researchers to induce electrical currents in focal areas of the cerebral cortex. These currents can transiently activate or inhibit focal cortical areas and thus influence behavior. In the 20 years since its introduction, TMS has been applied to the study and treatment of a wide variety of neurologic and psychiatric conditions. This review focuses particular attention on the use of TMS as a research tool for understanding brain-behavior relationships, an adjunct to traditional neurorehabilitation strategies, and a potential treatment option for depression and other psychiatric disorders.

Repetitive transcranial magnetic stimulation as an adjunct to constraint-induced therapy: an exploratory randomized controlled trial.

OBJECTIVE: To test the potential adjuvant effect of repetitive transcranial magnetic stimulation (rTMS) on motor learning in a group of stroke survivors undergoing constraint-induced therapy (CIT) for upper-limb hemiparesis. DESIGN: This was a prospective randomized, double-blind, sham-controlled, parallel group study. Nineteen individuals, one or more years poststroke, were randomized to either a rTMS + CIT (n = 9) or a sham rTMS + CIT (n = 10) group and participated in the 2-wk intervention. RESULTS: Regardless of group assignment, participants demonstrated significant gains on the primary outcome measures: the Wolf Motor Function Test (WMFT) and the Motor Activity Log (MAL)--Amount of Use, and on secondary outcome measures including the Box and Block Test (BBT) and the MAL--How Well. Participants receiving rTMS failed to show differential improvement on either primary outcome measure. CONCLUSIONS: Although this study provided further evidence that even relatively brief sessions of CIT can have a substantial effect, it provided no support for adjuvant use of rTMS.

Diagnosis and Treatment of Chronic Immune-mediated Neuropathies.

The chronic autoimmune neuropathies are a diverse group of disorders, whose diagnosis and classification is based on the clinical presentations and results of ancillary tests. In chronic inflammatory demyelinating polyneuropathy, controlled therapeutic trials demonstrated efficacy for intravenous gamma-globulins, corticosteroids, and plasmaphereis. In multifocal motor neuropathy, intravenous gamma-globulins have been shown to be effective. In the other immune-mediated neuropathies, there are no reported controlled therapeutic trials, but efficacy has been reported for some treatments in non-controlled trials on case studies. Choice of therapy in individual cases is based on reported efficacy, as well as severity, progression, coexisting illness, predisposition to developing complications, and potential drug interactions.

Lateralized asymmetry of facial motor evoked potentials.

BACKGROUND: There is considerable evidence that emotions are expressed more intensely on the left side of the face. This asymmetry could reflect a right hemisphere advantage in processing emotional material or an asymmetry in corticobulbar motor systems. Transcranial magnetic stimulation (TMS) was used to test for lateralized asymmetry in the cortical control of muscles of facial expression in the lower face. METHODS: We administered TMS to the motor cortex of 50 subjects during contraction of bilateral orbicularis oris muscles. We analyzed motor evoked potentials (MEPs) with a repeated measures analysis of variance (ANOVA) using hemisphere stimulated and orbicularis oris side recorded as within subject factors. RESULTS: TMS elicited contralateral MEPs in 42 of 50 subjects. Forty of these 42 subjects showed bilateral MEPs. The ANOVA showed a significant main effect of face side, such that MEPs elicited in left face were larger than in right face (p < 0.0001). The analysis also showed a significant interaction between the hemisphere stimulated and face side, such that the difference between contralateral and ipsilateral MEPs with right brain TMS was greater than with left brain TMS (p < 0.0001). CONCLUSIONS: The results provide evidence of lateralized asymmetry of corticobulbar projections to muscles of facial expression in the lower face.

Effect of repetitive transcranial magnetic stimulation on rate of memory acquisition.

Repetitive transcranial magnetic stimulation (rTMS) may temporarily accelerate knowledge acquisition by neural networks, possibly by promoting rapid Hebbian learning. The authors tested this hypothesis in 20 normal subjects by comparing the impact of 25 minutes of high-frequency left dorsolateral prefrontal rTMS with that of sham rTMS on subsequent knowledge acquisition in several procedural and declarative memory domains. No significant group effects, positive or negative, were noted for any memory acquisition test, but prefrontal rTMS did reduce motor evoked potential threshold.

Cerebral blood flow changes in depressed patients after treatment with repetitive transcranial magnetic stimulation: evidence of individual variability.

OBJECTIVE: To elucidate the neural mechanisms of depression. BACKGROUND: Despite extensive study, the neurophysiology of the brain's state(s) corresponding to depression remains uncertain. METHODS: HMPAO single photon emission computed tomographic (SPECT) scans were obtained from eight adults diagnosed with major depression resistant to medication (average age 51 years; 4 men) before and immediately after 10 days of 20 Hz repetitive transcranial magnetic stimulation (rTMS) (2000 stimuli/daily 30' treatment). To maximize the likelihood that SPECT scans reflected the state of depression, rather than uncontrolled responses of patients to poorly constrained environments, HMPAO was administered while subjects performed a simple task involving continuous monitoring of the direction of a large arrow on a computer screen and continuously tapping with the left or right index finger according to the direction of the arrow. Mean baseline Beck Depression Inventory (BDI) score was 27.4 (SD = 8.3) and mean posttreatment BDI score was 17.5 (SD = 8.5). RESULTS: Treatment responders (defined by reduction in BDI score of > or = 30%) had significantly less pretreatment blood flow in the left amygdala compared with nonresponders. Responders demonstrated two patterns of change in regional blood flow with treatment: a reduction in orbitofrontal blood flow and/or a reduction in anterior cingulate blood flow. Nonresponders did not demonstrate any regional changes in blood flow with treatment. CONCLUSIONS: These results suggest that there may be either more than one state of depression, or that depression may be associated with more than one pattern of psychologic activity, which in turn defines the depressive experience for individual patients.

Mental object rotation in Parkinson's disease.

Deficits in visual-spatial ability can be associated with Parkinson's disease (PD), and there are several possible reasons for these deficits. Dysfunction in frontal-striatal and/or frontal-parietal systems, associated with dopamine deficiency, might disrupt cognitive processes either supporting (e.g., working memory) or subserving visual-spatial computations. The goal of this study was to assess visual-spatial orientation ability in individuals with PD using the Mental Rotations Test (MRT), along with other measures of cognitive function. Non-demented men with PD were significantly less accurate on this test than matched control men. In contrast, women with PD performed similarly to matched control women, but both groups of women did not perform much better than chance. Further, mental rotation accuracy in men correlated with their executive skills involving mental processing and psychomotor speed. In women with PD, however, mental rotation accuracy correlated negatively with verbal memory, indicating that higher mental rotation performance was associated with lower ability in verbal memory. These results indicate that PD is associated with visual-spatial orientation deficits in men. Women with PD and control women both performed poorly on the MRT, possibly reflecting a floor effect. Although men and women with PD appear to engage different cognitive processes in this task, the reason for the sex difference remains to be elucidated.