Jameson K. Holden

Absence of stimulus-driven synchronization effects on sensory perception in autism: Evidence for local underconnectivity?

BackgroundA number of neurophysiological characteristics demonstrated in autism share the common theme of under-connectivity in the cerebral cortex. One of the prominent theories of the cause of the dysfunctional connectivity in autism is based on distinct anatomical structures that differ between the autistic and the neurotypical cortex. The functional minicolumn has been identified as occupying a much smaller space in the cortex of people with autism as compared to neurotypical controls, and this aberration in architecture has been proposed to lead to under-connectivity at the local or within-macrocolumn level, which in turn leads to dysfunctional connectivity globally across cortical areas in persons with autism. Numerous reports have indicated reduced synchronization of activity on a large scale in the brains of people with autism. We hypothesized that if the larger-scale aberrant dynamics in autism were due – at least in part – to a widespread propagation of the errors introduced at the level of local connectivity between minicolumns, then aberrations in local functional connectivity should also be detectable in autism.MethodsRecently, we reported a method for measuring the perceptual changes that are impacted by the presence of synchronized conditioning stimuli on the skin. In this study, the temporal order judgment (TOJ) and temporal discriminative threshold (TDT) of 10 adult autism subjects were assessed both in the absence and presence of synchronized conditioning vibrotactile stimuli.ResultsOur previous report demonstrated that delivering simultaneous and synchronized vibrotactile stimuli to near-adjacent skin sites decreases a subjects ability to determine temporal order by 3 to 4-fold. However, results presented in this report show that subjects with autism do not demonstrate such decreased capacity in temporal order judgment (TOJ) in the presence of synchronized conditioning stimuli, although these same subjects do have TOJ thresholds well above that of controls.ConclusionIt is speculated that the differences in sensory perceptual capacities in the presence of synchronized conditioning stimuli in autism are due to local under-connectivity in cortex at the minicolumnar organizational level, and that the above-average TOJ thresholds in autism could be attributed to structural differences that have been observed in the frontostrial system of this population.

Perceptual metrics of individuals with autism provide evidence for disinhibition

Adults with autism exhibit inhibitory deficits that are often manifested in behavioral modifications, such as repetitive behaviors, and/or sensory hyper‐responsiveness. If such behaviors are the result of a generalized deficiency in inhibitory neurotransmission, then it stands to reason that deficits involving localized cortical–cortical interactions—such as in sensory discrimination tasks—could be detected and quantified. This study exemplifies a newly developed method for quantifying sensory testing metrics. Our novel sensory discrimination tests may provide (a) an effective means for biobehavioral assessment of deficits specific to autism and (b) an efficient and sensitive measure of change following treatment. The sensory discriminative capacity of ten subjects with autism and ten controls was compared both before and after short duration adapting stimuli. Specifically, vibrotactile amplitude discriminative capacity was obtained both in the presence and absence of 1 sec adapting stimuli that were delivered 1 sec prior to the comparison stimuli. Although adaptation had a pronounced effect on the amplitude discriminative capacity of the control subjects, little or no impact was observed on the sensory discriminative capacity of the subjects with autism. This lack of impact of the adapting stimuli on the responses of the subjects with autism was interpreted to be consistent with the reduced GABAergic‐mediated inhibition described in previous reports. One significant aspect of this study is that the methods could prove to be a useful and efficient way to detect specific neural deficits and monitor the efficacy of pharmacological or behavioral treatments in autism.

Altered Central Sensitization in Subgroups of Women With Vulvodynia

ObjectiveTo investigate the clinical correlates of central nervous system alterations among women with vulvodynia. Altered central sensitization has been linked to dysfunction in central nervous system-inhibitory pathways (eg, &ggr;-aminobutyric acidergic), and metrics of sensory adaptation, a centrally mediated process that is sensitive to this dysfunction, could potentially be used to identify women at risk of treatment failure using conventional approaches. MethodsTwelve women with vulvodynia and 20 age-matched controls participated in this study, which was conducted by sensory testing of the right hands index and middle fingers. The following sensory precepts were assessed: (1) vibrotactile detection threshold; (2) amplitude discrimination capacity (defined as the ability to detect differences in intensity of simultaneously delivered stimuli to 2 fingers); and (3) a metric of adaptation (determined by the impact that applying conditioning stimuli have on amplitude discriminative capacity). ResultsParticipants did not differ on key demographic variables, vibrotactile detection threshold, and amplitude discrimination capacity. However, we found significant differences from controls in adaptation metrics in 1 subgroup of vulvodynia patients. Compared with healthy controls and women with a shorter history of pain [n=5; duration (y)=3.4±1.3], those with a longer history [n=7; duration (y)=9.3±1.4)] were found to be less likely to have adaptation metrics similar to control values. DiscussionChronic pain is thought to lead to altered central sensitization, and adaptation is a centrally mediated process that is sensitive to this condition. This report suggests that similar alterations exist in a subgroup of vulvodynia patients.

Effects of stimulus-driven synchronization on sensory perception

BackgroundA subjects ability to differentiate the loci of two points on the skin depends on the stimulus-evoked pericolumnar lateral inhibitory interactions which increase the spatial contrast between regions of SI cortex that are activated by stimulus-evoked afferent drive. Nevertheless, there is very little known about the impact that neuronal interactions – such as those evoked by mechanical skin stimuli that project to and coordinate synchronized activity in adjacent and/or near-adjacent cortical columns – could have on sensory information processing.MethodsThe temporal order judgment (TOJ) and temporal discriminative threshold (TDT) of 20 healthy adult subjects were assessed both in the absence and presence of concurrent conditions of tactile stimulation. These measures were obtained across a number of paired sites – two unilateral and one bilateral – and several conditions of adapting stimuli were delivered both prior to and concurrently with the TOJ and TDT tasks. The pairs of conditioning stimuli were synchronized and periodic, synchronized and non-periodic, or asynchronous and non-periodic.ResultsIn the absence of any additional stimuli, TOJ and TDT results obtained from the study were comparable across a number of pairs of stimulus sites – unilateral as well as bilateral. In the presence of a 25 Hz conditioning sinusoidal stimulus which was delivered both before, concurrently and after the TOJ task, there was a significant change in the TOJ measured when the two stimuli were located unilaterally on digits 2 and 3. However, in the presence of the same 25 Hz conditioning stimulus, the TOJ obtained when the two stimuli were delivered bilaterally was not impacted. TDT measures were not impacted to the same degree by the concurrent stimuli that were delivered to the unilateral or bilateral stimulus sites. This led to the speculation that the impact that the conditioning stimuli – which were sinusoidal, periodic and synchronous – had on TOJ measures was due to the synchronization of adjacent cortical ensembles in somatosensory cortex, and that the synchronization of these cortical ensembles could have been responsible for the degradation in temporal order judgment. In order to more directly test this hypothesis, the synchronized 25 Hz conditioning stimuli that were delivered during the initial TOJ test were replaced with asynchronous non-periodic 25 Hz conditioning stimuli, and these asynchronous conditioning stimuli did not impact the TOJ measures.ConclusionThe results give support to the theory that synchronization of cortical ensembles in SI could significantly impact the topography of temporal perception, and these findings are speculated to be linked mechanistically to previously reported co-activation plasticity studies. Additionally, the impact that such synchronizing conditioning stimuli have on TOJ – which can be measured relatively quickly – could provide an effective means to assess the functional connectivity of neurologically compromised subject populations.

Somatosensory information processing in the aging population.

While it is well known that skin physiology – and consequently sensitivity to peripheral stimuli – degrades with age, what is less appreciated is that centrally mediated mechanisms allow for maintenance of the same degree of functionality in processing these peripheral inputs and interacting with the external environment. In order to demonstrate this concept, we obtained observations of processing speed, sensitivity (thresholds), discriminative capacity, and adaptation metrics on subjects ranging in age from 18 to 70. The results indicate that although reaction speed and sensory thresholds change with age, discriminative capacity, and adaptation metrics do not. The significance of these findings is that similar metrics of adaptation have been demonstrated to change significantly when the central nervous system (CNS) is compromised. Such compromise has been demonstrated in subject populations with autism, chronic pain, acute NMDA receptor block, concussion, and with tactile–thermal interactions. If the metric of adaptation parallels cortical plasticity, the results of the current study suggest that the CNS in the aging population is still capable of plastic changes, and this cortical plasticity could be the mechanism that compensates for the degradations that are known to naturally occur with age. Thus, these quantitative measures – since they can be obtained efficiently and objectively, and appear to deviate from normative values significantly with systemic cortical alterations – could be useful indicators of cerebral cortical health.

A novel device for the study of somatosensory information processing.

Current methods for applying multi-site vibratory stimuli to the skin typically involve the use of multiple, individual vibrotactile stimulators. Limitations of such an arrangement include difficulty with both positioning the stimuli as well as ensuring that stimuli are delivered in a synchronized and deliberate manner. Previously, we reported a two-site tactile stimulator that was developed in order to solve these problems (Tannan et al., 2007a). Due to both the success of that novel stimulator and the limitations that were inherent in that device, we designed and fabricated a four-site stimulator that provides a number of advantages over the previous version. First, the device can stimulate four independent skin sites and is primarily designed for stimulating the digit tips. Second, the positioning of the probe tips has been re-designed to provide better ergonomic hand placement. Third, the device is much more portable than the previously reported stimulator. Fourth, the stimulator head has a much smaller footprint on the table or surface where it resides. To demonstrate the capacity of the device for delivering tactile stimulation at four independent sites, a finger agnosia protocol, in the presence and absence of conditioning stimuli, was conducted on seventeen healthy control subjects. The study demonstrated that with increasing amplitudes of vibrotactile conditioning stimuli concurrent with the agnosia test, inaccuracies of digit identification increased, particularly at digits D3 and D4. The results are consistent with prior studies that implicated synchronization of adjacent and near-adjacent cortical ensembles with conditioning stimuli in impacting TOJ performance (Tommerdahl et al., 2007a,b).

Functional deficits in carpal tunnel syndrome reflect reorganization of primary somatosensory cortex.

Carpal tunnel syndrome, a median nerve entrapment neuropathy, is characterized by sensorimotor deficits. Recent reports have shown that this syndrome is also characterized by functional and structural neuroplasticity in the primary somatosensory cortex of the brain. However, the linkage between this neuroplasticity and the functional deficits in carpal tunnel syndrome is unknown. Sixty-three subjects with carpal tunnel syndrome aged 20-60 years and 28 age- and sex-matched healthy control subjects were evaluated with event-related functional magnetic resonance imaging at 3 T while vibrotactile stimulation was delivered to median nerve innervated (second and third) and ulnar nerve innervated (fifth) digits. For each subject, the interdigit cortical separation distance for each digits contralateral primary somatosensory cortex representation was assessed. We also evaluated fine motor skill performance using a previously validated psychomotor performance test (maximum voluntary contraction and visuomotor pinch/release testing) and tactile discrimination capacity using a four-finger forced choice response test. These biobehavioural and clinical metrics were evaluated and correlated with the second/third interdigit cortical separation distance. Compared with healthy control subjects, subjects with carpal tunnel syndrome demonstrated reduced second/third interdigit cortical separation distance (P < 0.05) in contralateral primary somatosensory cortex, corroborating our previous preliminary multi-modal neuroimaging findings. For psychomotor performance testing, subjects with carpal tunnel syndrome demonstrated reduced maximum voluntary contraction pinch strength (P < 0.01) and a reduced number of pinch/release cycles per second (P < 0.05). Additionally, for four-finger forced-choice testing, subjects with carpal tunnel syndrome demonstrated greater response time (P < 0.05), and reduced sensory discrimination accuracy (P < 0.001) for median nerve, but not ulnar nerve, innervated digits. Moreover, the second/third interdigit cortical separation distance was negatively correlated with paraesthesia severity (r = -0.31, P < 0.05), and number of pinch/release cycles (r = -0.31, P < 0.05), and positively correlated with the second and third digit sensory discrimination accuracy (r = 0.50, P < 0.05). Therefore, reduced second/third interdigit cortical separation distance in contralateral primary somatosensory cortex was associated with worse symptomatology (particularly paraesthesia), reduced fine motor skill performance, and worse sensory discrimination accuracy for median nerve innervated digits. In conclusion, primary somatosensory cortex neuroplasticity for median nerve innervated digits in carpal tunnel syndrome is indeed maladaptive and underlies the functional deficits seen in these patients.

Effects of the N-methyl-D-Aspartate receptor antagonist dextromethorphan on vibrotactile adaptation

BackgroundPrevious reports have demonstrated that short durations of vibrotactile stimuli (less than or equal to 2 sec) effectively and consistently modify both the perceptual response in humans as well as the neurophysiological response in somatosensory cortex. The change in cortical response with adaptation has been well established by a number of studies, and other reports have extended those findings in determining that both GABA- and NMDAR-mediated neurotransmission play a significant role in the dynamic response of somatosensory cortical neurons. In this study, we evaluated the impact that dextromethorphan (DXM), an NMDAR antagonist, had on two distinct vibrotactile adaptation tasks.ResultsAll subjects, both those that ingested 60 mg DXM and those that ingested placebo, were evaluated for their amplitude discriminative capacity between two simultaneously delivered vibrotactile stimuli both with and without 3 conditions of pre-exposure to adapting stimulation. The results demonstrated that the perceptual metrics of subjects who ingested 60 mg DXM were significantly altered from that of controls when the amplitude discrimination task followed one of the conditions of adapting stimulation. Without the condition of pre-exposure to an adapting stimulus (or stimuli), there was little difference between the observations obtained from the subjects that ingested DXM and controls. Peak impact on subject response occurred at 60 min post-ingestion, whereas the scores of controls who ingested placebo were not impacted.ConclusionThe results – that DXM blocks vibrotactile adaptation – is consistent with the suggestion that NMDAR-mediated neurotransmission plays a significant role in the perceptual adaptive response. This finding is also consistent with neurophysiological findings that report observations of the effects of NMDAR block on the SI cortical response to repetitive vibrotactile stimulation.

Centrally-mediated sensory information processing is impacted with increased alcohol consumption in college-aged individuals.

Alcohol consumption can have an impact on a variety of centrally-mediated functions of the nervous system, and some aspects of sensory perception can be altered as a result of long-term alcohol use. In order to assess the potential impact of alcohol intake on sensory information processing, metrics of sensory perception (simple and choice reaction time; static and dynamic threshold detection; amplitude discrimination with and without pre-exposure to conditioning stimulation) were tested in college-aged subjects (18 to 26 years of age) across a broad range of levels of alcohol consumption. The analysis indicated no detectable associations between reaction time and threshold measures with alcohol consumption. However, measures of adaptation to short duration (0.5s) conditioning stimuli were significantly associated with alcohol consumption: the impact of a confounding conditioning stimulus on amplitude discriminative capacity was comparable to values reported in previous studies on healthy controls (28.9±8.6) for light drinkers while the same adaptation metric for heavy drinkers (consuming greater than 60 drinks per month) was significantly reduced (8.9±7.1). The results suggest that while some of the sensory perceptual metrics which are normally impacted in chronic alcoholism (e.g., reaction time and threshold detection) were relatively insensitive to change with increased alcohol consumption in young non-alcoholic individuals, other metrics, which are influenced predominantly by centrally-mediated mechanisms, demonstrate a deviation from normative values with increased consumption. Results of this study suggest that higher levels of alcohol consumption may be associated with alterations in centrally-mediated neural mechanisms in this age group.

Vibrotactile discriminative capacity is impacted in a digit-specific manner with concurrent unattended hand stimulation.

Abstract A number of perceptual and neurophysiological studies have investigated the effects of delivering unilateral versus bilateral tactile sensory stimulation. While a number of studies indicate that perceptual discrimination degrades with opposite-hand stimulation, there have been no reports that examined the digit specificity of cross-hemispheric interactions to discriminative capabilities. The purpose of this study was to determine whether unattended hand (UH) stimulation significantly degraded or improved amplitude discriminative capacity on the attended hand (AH) in a digit-specific manner. The methods are based on a sensory perceptual task (vibrotactile amplitude discriminative capacity on the tips of the fingers D2 and D3 of the left hand) in the absence and presence of conditioning stimuli delivered to D2 and D3 of the right hand. Non-specific equal-amplitude stimulation to D2 and D3 of the UH significantly worsened amplitude discrimination (AD) performance, while delivering unequal-amplitude stimuli to D2 and D3 of the UH worsened task performance only under the condition in which the unattended stimuli failed to appropriately match the stimulus parameters on the AH. Additionally, delivering single-site stimuli to D2 or D3 of the UH resulted in degraded performance on the AD task when the stimulus amplitude did not match the amplitude of the stimulus applied to homologous digits of the AH. The findings demonstrate that there is a reduction in performance under conditions where UH stimulation least matched stimulation applied to the AH, while there was little or no change in performance when stimulus conditions on the homologous digit(s) of the contralateral sites were similar. Results suggest that bilateral interactions influence perception in a context-dependent manner that is digit specific.