Change in EEG Activity is Associated with a Decrease in Tinnitus Awareness after rTMS.

OBJECTIVE: To examine how 1Hz and 10Hz rTMS temporarily influence ratings of tinnitus loudness, annoyance, and awareness. The thalamocortical dysrhythmia (TCD) model of tinnitus was tested by examining changes in spectral power and coherence of resting state EEGs from baseline to each phase of treatment and correlating these data with change in tinnitus. METHODS: Nineteen participants completed a double-blind, placebo (sham rTMS) controlled, within-subjects study with crossover between the two active rTMS treatment conditions. An imposed order effect, sham rTMS first, eliminated drift of active treatment into the placebo condition. The primary outcome measures were analogue ratings of tinnitus loudness, annoyance, and awareness, assessed repeatedly at baseline and during treatment, and 64 channel, resting state EEGs collected at baseline and the end of each treatment phase. Active rTMS consisted of 1800 pulses at 110% of motor threshold over temporal cortex delivered at 1Hz and 10Hz over four days. The research design also examined the effect of rTMS immediately following stimulation, regression to the mean in tinnitus ratings made over multiple days, and differences between treatment responders and non-responders. RESULTS: There was no immediate effect of rTMS on tinnitus during a single rTMS session. Regression to the mean in tinnitus ratings occurred over three days of baseline and four days of treatment (both sham and active rTMS). After accounting for regression to the mean in the statistical model, 1Hz rTMS led to a significant decrease in tinnitus awareness from baseline and 10Hz rTMS trended in the same direction, whereas sham rTMS showed little change from baseline other than regression to the mean. Changes from baseline in spectral power of the resting state EEG provided partial support for predictions based on TCD model of tinnitus for active 1 and 10Hz rTMS but not sham rTMS. However, only an increase in beta coherence correlated significantly with a decrease in tinnitus awareness. Changes in the EEG were robust in treatment responders but absent among non-responders and during sham rTMS. CONCLUSIONS: A positive response to rTMS for tinnitus is associated with an rTMS-induced change in beta coherence of the EEG. Increased beta coherence may be a biomarker of the rTMS effect; a "top-down" modulation of the EEG that promotes habituation to tinnitus. Participants whose tinnitus did not improve after rTMS did not show any changes in the EEG.

Neural activity during attentional conflict predicts reduction in tinnitus perception following rTMS.

BACKGROUND: Subjective idiopathic tinnitus is an intrusive, distracting, and potentially disabling disorder characterized by phantom perception of sounds. Although tinnitus has no approved pharmacologic treatment, recent evidence supports the use of repetitive transcranial magnetic stimulation (rTMS) to alleviate tinnitus symptoms. OBJECTIVE/HYPOTHESIS: Repetitive TMS delivered over the middle superior temporal gyrus (STG) may alter ratings of tinnitus awareness and annoyance more than loudness due to change in attentional processing. STG has reciprocal connections to regions of the prefrontal cortex that mediate attention. To probe the hypothesized influence of STG stimulation on attention, a subset of patients with tinnitus enrolled in an rTMS clinical trial [n = 12, 9 male, mean (sd) age = 49 (15) years] underwent an attentional conflict task before and after rTMS treatment in a repeated-measures functional magnetic resonance imaging (fMRI) study. METHODS: The Multi-Source Interference Task (MSIT), a Stroop-based visual attentional conflict fMRI task, was used to map participants' neural processing of attentional conflict prior to rTMS intervention (Baseline) and after three rTMS intervention arms: Sham, 1 Hz, and 10 Hz (four sessions per arm, 1800 pulses per session, delivered @110% of the motor threshold over the posterior superior temporal gyrus). RESULTS: All measures of tinnitus severity (awareness, loudness, and annoyance) improved with 1 Hz rTMS intervention; however, the greatest and most robust changes were observed for ratings of tinnitus awareness (mean 16% reduction in severity from Baseline, p < 0.01). The MSIT elicited a similar pattern of neural activation among tinnitus participants at Baseline compared to an independent sample of 43 healthy comparison adults (r = 0.801, p = 0.001). Linear regression with bootstrap resampling showed that greater recruitment of bilateral prefrontal and bilateral parietal regions by MSIT at Baseline corresponded with poorer treatment response. Individual regions' activities explained 37-67% variance in participant treatment response, with left dorsolateral prefrontal cortex's MSIT activity at Baseline explaining the greatest reduction in tinnitus awareness following 1 Hz stimulation. Although left dorsolateral prefrontal cortex activity at Baseline also predicted reduction in tinnitus loudness and annoyance (∼50% variance explained), these symptoms were more strongly predicted by right middle occipital cortex (∼70% variance explained) - suggesting that the neural predictors of symptom-specific treatment outcomes may be dissociable. CONCLUSION: These candidate neural reactivity markers of treatment response have potential clinical value in identifying tinnitus sufferers who would or would not therapeutically benefit from rTMS intervention.

Oral perception of liquid volume changes with age.

Bolus volume has been widely studied, and research has demonstrated a variety of physiological impacts on swallowing and swallowing disorders. Oral perception of bolus volume has not, to our knowledge, been investigated in association with normal ageing processes. Research suggests many sensory changes with age, some within the oral cavity, and changes in swallowing function with age have been defined. The role of perception in oropharyngeal deglutition with age requires further investigation. The purpose of this study was to establish the psychophysical relationship between liquid volume and oral perception and examine changes with age. Healthy young and older adults were prospectively assessed using a magnitude estimation task differentiating five volumes of water delivered randomly to the oral cavity. Results suggest a fourfold increase in liquid volume is required by older participants to perceive an approximate twofold increase in the perception of volume compared with younger healthy adults. Sensory receptors in the oral cavity provide a feedback loop that modulates the swallowing motor response so that it is optimal for the size and consistency of the bolus. Changes in perception of bolus volume with age are consistent with other perceptual changes and may provide valuable information regarding sensorineural rehabilitation strategies in the future.

Laterality, frequency and replication of rTMS treatment for chronic tinnitus: pilot studies and a review of maintenance treatment.

This manuscript reports on findings of three open-label, pilot studies and it reviews studies using rTMS as a maintenance treatment for any disorder. The first pilot study examined whether a patient's original treatment response to 1 Hz rTMS over temporal cortex could be replicated by stimulating a homologous region of the opposite hemisphere. The second study examined whether a patient's response to 1 Hz rTMS could be replicated by applying 10 Hz rTMS over the same treatment site. The third study applied a 3-day course of maintenance rTMS, either at 1 or 10 Hz, when subjects indicated that the benefit of their last course of treatment was waning. Patients with bilateral subjective tinnitus of at least 6 months duration were recruited from a prior, sham controlled study with treatment crossover that applied 1 Hz rTMS over temporal cortex. Both treatment responders and non-responders were recruited. Results indicated, first, that the original treatment response, both positive and negative, is replicated after stimulating a homologous region of the opposite hemisphere; second, patients respond similarly to 1 and 10 Hz stimulation of the same treatment site (an exception was one patient who initially failed 1 Hz stimulation but responded positively to 10 Hz stimulation); and, third, maintenance rTMS had a sustained and additive benefit for tinnitus among treatment responders. Conclusions are that rTMS-induced effects on tinnitus are neither hemisphere specific nor frequency dependent; although, different frequencies of rTMS may have greater potency for a given subject. Maintenance treatment is a well tolerated approach with demonstrated feasibility for managing chronic tinnitus in persons who respond positively to an initial course of treatment.

Sham Transcranial Magnetic Stimulation Using Electrical Stimulation of the Scalp.

BACKGROUND: Most methods of sham, repetitive transcranial magnetic stimulation (rTMS) fail to replicate the look, sound, and feel of active stimulation in the absence of a significant magnetic field. OBJECTIVE/HYPOTHESIS: To develop and validate a new method of sham rTMS appropriate for a double-blind, placebo-controlled study with subject crossover. METHODS: The look and sound of active rTMS was replicated using a matched, air-cooled sham TMS coil. Scalp muscle stimulation associated with rTMS was replicated using large rubber electrodes placed over selected muscles. The intensity and pulse width of electrical stimulation necessary to match 1-Hz rTMS was developed in one sample of normal subjects. The sham technique was validated in back-to-back comparisons with active rTMS in new samples of normal subjects who were either naïve or experienced with rTMS. RESULTS: Subjects naïve to TMS could not tell which type of stimulation was active or sham or which was electrical or magnetic. Naïve subjects incorrectly picked sham stimulation as active, when forced to choose, because electrical stimulation felt more focused than magnetic stimulation. Subjects experienced with TMS could correctly identify sham and active stimulation. Experimenters could detect subtle differences between conditions. CONCLUSIONS: This method of sham rTMS closely mimics the look, sound, and feel of active stimulation at 1Hz without creating a significant magnetic field. It is valid for use with naïve subjects and in crossover studies. It can accommodate differences in scalp muscle recruitment at different sites of stimulation, and it could potentially be used with higher frequency stimulation.

Perception of motor strength and stimulus magnitude are correlated in stroke patients.

The authors examined whether perception of contralateral limb strength is altered and whether perception of strength correlates with perception of stimulus intensity (magnitude) in a prospective sample of patients with unilateral right (RHL: n = 13) and left (LHL: n = 6) hemisphere lesions due to stroke. Patients with RHL tended to overestimate strength and patients with LHL tended to underestimate strength; both patterns were highly correlated with altered perception of stimulus magnitude.

Disorganized search on cancellation is not a consequence of neglect.

BACKGROUND: Some studies have suggested that in stroke patients, spatial inattention on the cancellation test is closely related to disorganized visual search. However, methods to assess spatial aspects of search organization on cancellation tests have not been well developed. In this study the authors design and evaluate new methods to quantify strategies of spatial exploration on the cancellation test in stroke patients who showed a broad range of spatial attentional abilities, and test whether disorganization and inattention are related. METHODS: Twenty stroke patients were videotaped while they performed a cancellation test. Several variables that reflect spatial aspects of search organization were measured through subsequent video playback. Two patients with severe neglect were excluded from further analysis to avoid constraining the spatial expression of search organization. Spearman correlations were used to assess whether severity of spatial inattention correlated with the individual search organization measures. RESULTS: Of the 18 remaining patients, 10 had mild-moderate spatial neglect (pathologic inattention), while the other 8 omitted at most one target (normal performance). There were no significant correlations between the number of targets omitted and any of the search organization measures. CONCLUSIONS: Spatial inattention on cancellation due to neglect following stroke is not closely related to the organization of visual search. Instead, search disorganization during cancellation may reflect disturbance of an unspecified executive control mechanism.

Just thinking about targets can aggravate neglect on cancellation tests.

While many studies investigate how the visual features of targets influence cancellation performance in neglect, few, if any, even consider that thought processes, such as the use of an algorithm to identify targets, might similarly aggravate neglect. This single-case study of a patient with chronic neglect compared cancellation performance after manipulating (1) ease of visual target identification, (2) the use of an algorithm to identify targets, and (3) the material-specific nature of target cancellation. Neglect severity was defined by the number and location of target omissions. While each manipulation had a differential impact on neglect severity, the novel and interesting finding occurred during the second condition, when a math algorithm was used to identify targets. In this condition, target omissions increased relative to other tests and target cancellations were confined to the right half of the page. This is the first report, to our knowledge, that neglect on cancellation tests can be aggravated by an internal thought process, a math algorithm, as opposed to external manipulations of visual stimuli and procedural characteristics of cancellation tests. An important characteristic of the algorithm used in this study is that it appeared to activate the intact left cerebral hemisphere.

Crossover by line length and spatial location.

It is well known that line length has a systematic influence on line bisection error in neglect. Most patients with neglect misbisect long lines on the same side of true center as their brain lesion but then cross over on short lines, misbisecting them on the opposite side (i.e., crossover by line length). What is less recognized is that the spatial location of lines relative to the viewer can similarly induce a crossover effect when one considers line bisection error scores that have been averaged across individual line lengths. Patients with right hemisphere injury and neglect classically make averaged line bisection errors that fall right of true center on lines located either at midline or to the left of the viewer; however, we observed that the averaged line bisection error can fall left of true center when lines are located to the right of the viewer (i.e., crossover by spatial location). We hypothesized that crossover by both line length and spatial location stem from systematic errors in magnitude estimation, i.e., perceived line length. We tested predictions based on this hypothesis by examining how the crossover effect by line length is altered by the spatial location of lines along a horizontal axis relative to the viewer. Participants included patients with unilateral lesions of the right and left cerebral hemispheres and age-appropriate normal subjects. All groups demonstrated a crossover effect by line length at the midline location but the effect was altered by placing lines to the right and left of the viewer. In particular, patients with right hemisphere injury and neglect crossed-over across a broader range of line lengths when the lines were located to the right of the viewer rather than at either midline or left of the viewer. It is proposed that mental representations of stimulus magnitude are altered in neglect, in addition to mental representations of space, and that traditional accounts of neglect can be enhanced by including the psychophysical concept of magnitude estimation.

Variability not ability: another basis for performance decrements in neglect.

OBJECTIVE: To determine reaction time (RT) and its variability, as a function of horizontal spatial position, in subjects with neglect. BACKGROUND: In neglect, performance is frequently reported a as mean and a decreased ability to perform the task inferred by comparison to control groups. Few studies have examined how consistency and optimal performance relate to spatial neglect. METHODS: Ten subjects with brain damage, five with and five without spatial neglect, were assessed on a RT task. Subjects responded by pushing a computer key to the onset of a white square appearing on a black screen. The locations of stimuli were randomly varied along the horizontal meridian. RESULTS: For three of five neglect subjects, optimal RT showed no or little relation to horizontal location. Four of five neglect subjects demonstrated an increased variability in RT that correlated with spatial position and which was not present in our brain damaged subjects without neglect. The relationship was not an artifact of left sided stimuli, in general, being processed differently. For the two neglect subjects with the most trials, a significant correlation between RT variability and spatial position existed for left-sided trials alone. Increased variability was not a consequence of simply looking left proportionately less often, nor could a model of multiple compensatory systems operating in parallel explain the enhanced variability. Neither hemianopsia alone nor brain damage per se could account for the spatial modulation of RT variability. CONCLUSIONS: That neglect subjects perform the RT task normally on some trials, even in their 'neglected field', challenges the notion that neglect must reflect an irreparably damaged cognitive system. Performance decrements in neglect can reflect an inability to consistently detect and respond. Evaluating optimal performance and variability of performance can indicate if a capacity has been lost absolutely or merely degraded such that normal performance cannot be sustained.

A search for the optimal stimulus.

How do stimulus size and item number relate to the magnitude and direction of error on center estimation and line cancellation tests? How might this relationship inform theories concerning spatial neglect? These questions were addressed by testing twenty patients with right hemisphere lesions, eleven with left hemisphere lesions and eleven normal control subjects on multiple versions of center estimation and line cancellation tests. Patients who made large errors on these tests also demonstrated an optimal or pivotal stimulus value, i.e., a particular size center estimation test or number of lines on cancellation that either minimized error magnitude relative to other size stimuli (optimal) or marked the boundary between normal and abnormal performance (pivotal). Patients with right hemisphere lesions made increasingly greater errors on the center estimation test as stimuli were both larger and smaller than the optimal value, whereas those with left hemisphere lesions made greater errors as stimuli were smaller than a pivotal value. In normal subjects, the direction of errors on center estimation stimuli shifted from the right of true center to the left as stimuli decreased in size (i.e., the crossover effect). Right hemisphere lesions exaggerated this effect, whereas left hemisphere lesions diminished and possibly reversed the direction of crossover. Error direction did not change as a function of stimulus value on cancellation tests. The demonstration of optimal and pivotal stimulus values indicates that performances on center estimation and cancellation tests in neglect are only relative to the stimuli used. In light of other studies, our findings indicate that patients with spatial neglect grossly overestimate the size of small stimuli and underestimate the size of large stimuli, that crossover represents an "apparent" shift in error direction that actually results from normally occurring errors in size perception, and that the left hemisphere is specialized for one aspect of size estimation, whereas the right performs dual roles.

Thalamic thought disorder: on being "a bit addled".

Humans can generate and maintain relatively coherent trains of thought in natural discourse. The neural mediation of this ability and the phenomenology of its breakdown are not well understood. We report a case of a woman with paramedian thalamic strokes involving the mammillothalamic tract, intralaminar nuclei, parts of the dorsomedial and ventral lateral nuclei bilaterally. She presented with a dense amnesia and confusion typical of the syndrome of bilateral paramedian thalamic infarcts. Her Tc-99m HMPAO brain SPECT scan showed decreased thalamic and basal ganglia blood flow. General diminution of cerebral blood flow and areas of further diminution in the right frontal, left temporal and left temporoparietal regions were also observed. Although her amnesia was characteristic of diencephalic amnesia, her most striking clinical feature was a bizarre, disconnected and at times incoherent speech output. Analysis of her speech revealed relatively preserved lexical and morpho-syntactic linguistic production. By contrast, analysis of the macrostructure of her discourse revealed frequent unpredictable topic shifts that were completely unconstrained by contextual factors. Many of her shifts were intrusions from previous topics. We interpret her severely disordered speech output as representing the surface manifestations of a thought disorder (rather than as a language disorder per se) characterized by an inability to maintain and appropriately shift themes that normally guide discourse. Median and intralaminar thalamic nuclei appear to be critical for the neurophysiologic regulation of thalamocortical and striatocortical circuits, which in turn may be critical for the functional regulation of contextually appropriate transitions of thought.

Contributions of the left and right cerebral hemispheres to line bisection.

Thirty-one right-hemisphere lesioned (RHL) patients, 11 left-hemisphere lesioned patients (LHL) and 10 normal controls (NC) bisected lines in three spatial location and four directional cuing conditions. The error direction and error size were analyzed as separate and combined variables. Seventy-seven percent of RHL patients and 45% of LHL patients made abnormally large errors in line bisection. Right-hemisphere lesioned patients were more sensitive to spatial location and directional cuing than NC subjects. In contrast, LHL patients were less sensitive to either condition than NCs. The error direction and error size emerged as dissociable components of line bisection. Right-hemisphere lesioned patients and NC subjects bisected lines consistently to one side of the true center. Left-hemisphere lesioned patients bisected lines equally often on both sides of the true center. Both RHL and LHL patients made larger absolute bisection errors than NC subjects, but the RHL patient's errors were larger than those of the LHL patients. We propose that the greater sensitivity of RHL patients to spatial location and directional cues and the directional consistency of their bisection errors represent contributions of the intact left cerebral hemisphere to line bisection. In contrast, the LHL patient's unrestrained ability to orient to both ends of the line reflects a contribution of the intact right cerebral hemisphere to line bisection. The failure of both groups to accurately bisect lines reflects a common visuospatial processing deficit that is more pronounced following RHLs than LHLs.

Tapping, talking and the thalamus: possible influence of the intralaminar nuclei on basal ganglia function.

A patient with a discrete lesion of the left, intralaminar thalamic, nuclei exhibited a paradoxical finding with regard to finger-tapping. Normal subjects typically reduce their tapping rate when performing simultaneous verbal activity. Tapping was impaired in our patient's contralesional hand on baseline trials; however, performing the controlled oral word association (COWA) task, while finger-tapping, normalized her deficit. Subsequent experiments showed that motoric tasks rather than cognitive aspects of the COWA task were critical in potentiating finger-tapping performance. A SPECT study performed at rest revealed focal perfusion asymmetries in motor and premotor cortices. Because the caudal intralaminar nuclei project heavily to the striatum, striatal deafferentiation may account for these asymmetries. These observations provide some insight into the influences of the caudal intralaminar thalamic nuclei on basal ganglia function and the basal ganglia's influence on motor gating.

A comparison of the influences of body and environment centred reference frames on neglect.

Extrapersonal space can be defined by coordinate systems, or frames of reference, that are centred on the body (viewer) or on the environment. Although these frames are identical in the upright position, when the body is placed in positions orthogonal to gravity, the frames may be dissociable. We compared the influences of environmental and body-centred frames on line bisection in two patients with neglect who, when upright, neglected opposite dimensions of space. Through certain combinations of line placement and body orientation, the body and environmental frames were brought into opposition, and each frame predicted line bisection errors in an opposite direction. When the patients were positioned so that predictions of the two frames contrasted, both bisected lines as predicted by the environmental rather than the body-centred frame.

Contributions of the parietal and frontal lobes to sustained attention and habituation.

The parietal cortex may be important in sustaining attention toward visual stimuli in peripheral space whereas the frontal cortex may mediate selective attention through habituation to peripheral stimuli. To test this hypothesis, patients with focal lesions of either the parietal or frontal cortex or both and normal controls were studied using a paradigm known as Troxler fading. Accordingly, if one fixates on a centrally located stimulus and attends to a stationary stimulus in peripheral vision, the peripheral stimulus quickly fades from awareness (i.e. Troxler fading: Troxler [Verschwinden, unseres, Opthal, Vol. 2, pp. 51-53. Fromann, Jena, 1804]). Movement of the peripheral stimulus on the retina normally prevents Troxler fading. Results indicated that patients with parietal lesions not only reported accelerated Troxler fading but also reported fading of moving peripheral stimuli contralateral to their brain lesion. In contrast, patients with frontal lesions rarely reported Troxler fading. In one patient with a left parietal and a right frontal lobe lesion fading was hemi-spatially dissociated, being accelerated in right hemispace but absent in left hemispace. These observations suggest that the parietal and frontal cortices play complementary roles in attentional processing.

The psychophysical power law and unilateral spatial neglect.

The relationship between objective measures and subjective experiences of sensory stimuli is described by a power law, psi = K phi beta, in which psi represents the psychological value and phi the physical value. The constant (K) and the exponent (beta) are empirically derived. This relationship is often assumed to correspond to properties of peripheral receptor sensory transduction. Patients with left-sided spatial neglect tend to bisect lines to the right of the objective midline. Line bisection bias was used as the dependent variable in how a patient with neglect and five normal subjects bisected lines of varying lengths. Analyzing these data as a power function accounted for over 99% of the variance in five different experimental conditions. The normal exponent matched the value expected from traditional psychophysical experiments of line length estimation, whereas the patient's exponent was diminished. The patient's data provide evidence for central nervous system participation in computations underlying psychophysical relationships. The notion that attentional and perceptual processes are closely linked was supported by the influence of attentional cuing on the power functions obtained in normal subjects. The descriptive precision of the power function uncovered qualitative variability in how normal subjects allocate attention across different spatial reference frames and demonstrated that this patient had a quantitative defect in directing attention across an allosteric reference frame, but a qualitative defect in directing attention across a viewer/environment reference frame.

Memory, mood and measurement in hypothyroidism.

A 63-year-old female exhibited primary hypothyroidism, both upon clinical examination and laboratory tests. A full neuropsychological exam and repeated, multiple measures of affect, memory, concentration, and problem solving were used to establish baselines prior to treatment and to assess change during the first 7 months of thyroid hormone replacement therapy. Additionally, thyroid hormone and metabolites T3, T4, TSH, and T3 (resin uptake) were regularly assessed. Results indicated that establishing stable baselines before treatment, long-term repeated assessments during treatment, and the use of control subjects are crucial to understanding the neuropsychological changes associated with hypothyroidism. Certain measures of depression, anxiety, attention, and concentration changed from severely impaired to normal levels following an explanation of the diagnosis but before actual treatment. Baseline memory functions were impaired before treatment and remained impaired relative to normals during replacement therapy in spite of improvement with repeated testing. However, replacement therapy may have arrested the progression of memory deterioration as no further decline was evident at a 7-month follow-up. Our data suggest that the memory changes associated with primary hypothyroidism may not be reversed by thyroid hormone replacement therapy.

A stimulus-response relationship in unilateral neglect: the power function.

We have previously suggested that patients with unilateral neglect may be limited in their ability to sequentially attend or act upon stimuli. To assess the nature of this capacity limitation, we examined the relationship between number of stimuli presented on cancellation arrays and how many targets a patient with neglect cancelled. This relationship was systematic and described by a power function: targets cancelled = K (targets presented)B, in which the constant and exponent were derived empirically. Density of targets and time taken to cancel targets did not account for the relationship. Improvement on subsequent testing was reflected in an increase in the constant. However, the exponent of the power function did not change, suggesting that some critical aspect of her dysfunction remained the same. These data also imply that she had implicit knowledge of quantity of stimuli presented, and that this knowledge systematically influenced her explicit behavior.