Temporal discrimination thresholds (TDT) for recognition of paired sensory (tactile, auditory and visual) stimuli given over a wide range of time intervals were assessed in 44 patients with Parkinson's disease (PD) and 20 age-matched normal subjects. A significant increment in TDT for all three sensory modalities was found in PD patients compared with controls. This abnormality was greatly attenuated for about 2 h by a single levodopa/carbidopa (250/25 mg) tablet. A significant correlation was found between disease severity as assessed clinically and TDT. Patients with more severe PD had higher TDT values. The study of the peripheral median nerve and cortical somatosensory evoked potential recovery curves following double electrical stimulation of the index finger showed no differences between patients and control subjects, nor changes from ‘off’ to ‘on’ motor state which could explain the findings. These results indicate the existence of an abnormality of timing mechanisms in PD.

We compared the performance of 44 patients with Parkinson's disease (PD), tested 12–24 h after withdrawal of dopaminergic medication, with 20 age-matched controls, on a verbal test for time estimation and in several time reproduction tasks.

Flicker stimuli of variable frequency (2-90 Hz) elicit a steady-state visual-evoked response (SSVER) in the electroencephalogram (EEG) with the same frequency as the stimulus. In humans, the amplitude of this response peaks at ∼15 Hz, decreasing at higher stimulation frequencies. It was not known whether this peak response corresponds to increased synaptic activity in the visual cortex or to other mechanisms [for instance, the temporal coherence (phase summation) of evoked responses]. We studied the SSVER in 16 normal volunteers by means of visual stimulation at 14 different frequencies (from 5 to 60 Hz) while recording the EEG. In nine subjects of the group, we measured regional cerebral blood flow (rCBF) with positron emission tomography (PET)-H₂¹⁵O at rest and during visual stimulation at five different frequencies: 5, 10, 15, 25, and 40 Hz. We confirmed that the amplitude of the SSVER in occipital regions peaks at 15 Hz stimulation. Applying to the PET rCBF data a contrast weighted by the amplitude of the SSVER, we determined that the primary visual cortex rCBF follows an activation pattern similar to the SSVER. This finding suggests that the amplitude of the SSVER corresponds to increased synaptic activity, specifically in Brodmann9s area 17. Additionally, this study showed that visual stimulation at 40 Hz causes selective activation of the macular region of the visual cortex, and that a region in the dorsal aspect of the Crus I lobule of the left cerebellar hemisphere is activated during repetitive visual stimulation.

We used functional brain imaging with positron emission tomography (PET)-H₂¹⁵O to study a remarkable neurophysiological finding in the normal brain. Auditory stimulation at various frequencies in the gamma range elicits a steady-state scalp electroencephalographic (EEG) response that peaks in amplitude at 40 Hz, with smaller amplitudes at lower and higher stimulation frequencies. We confirmed this finding in 28 healthy subjects, each studied with monaural trains of stimuli at 12 different stimulation rates (12, 20, 30, 32, 35, 37.5, 40, 42.5, 45, 47.5, 50, and 60 Hz). There is disagreement as to whether the peak in the amplitude of the EEG response at 40 Hz corresponds simply to a superimposition of middle latency auditory evoked potentials, neuronal synchronization, or increased cortical synaptic activity at this stimulation frequency. To clarify this issue, we measured regional cerebral blood flow (rCBF) with PET-H₂¹⁵O in nine normal subjects at rest and during auditory stimulation at four different frequencies (12, 32, 40, and 47 Hz) and analyzed the results with statistical parametric mapping. The behavior of the rCBF response was similar to the steady-state EEG response, reaching a peak at 40 Hz. This finding suggests that the steady-state amplitude peak is related to increased cortical synaptic activity. Additionally, we found that, compared with other stimulation frequencies, 40 Hz selectively activated the auditory region of the pontocerebellum, a brain structure with important roles in cortical inhibition and timing.

Phosphatase and tensin homolog-induced putative kinase 1 gene mutations have been associated with autosomal recessive early-onset Parkinson’s disease. To date, no neuropathological reports have been published from patients with Parkinson’s disease with both phosphatase and tensin homolog-induced putative kinase 1 gene copies mutated. We analysed the coding region of phosphatase and tensin homolog-induced putative kinase 1 gene in a large Spanish family with six members with parkinsonism. The phenotype was characterized by an early-onset (mean: 31.6, standard deviation: 9.6 years, range: 14–45 years), slowly progressive levodopa-responsive parkinsonism, initial gait impairment and psychiatric symptoms. We identified two segregating pathogenic phosphatase and tensin homolog-induced putative kinase 1 mutations that were either in homozygous or heterozygous compound state in all affected family members. We found an exon 7 deletion (g.16089_16383del293; c.1252_1488del) and a novel + 1U1-dependent 5′ splice-site mutation in exon 7 (g.16378G > A; c.1488 + 1G > A). Leukocyte-derived messenger RNA analysis showed that both mutations caused exon 7 skipping and c.1488 + 1G > A also lead to an in-frame transcript with a 33 base-pair deletion (p.L485_R497del) resulting from activation of a 5′ cryptic exon 7 splice site. Single photon emission computed tomography quantification of striatal dopamine transporter binding (¹²³I-Ioflupane) revealed a posterior–anterior gradient similar to that of idiopathic Parkinson’s disease, but there was no correlation between striatal reduced uptake and disease duration. Post-mortem neuropathological examination of an early-onset Parkinson’s disease carrier of two heterozygous compound phosphatase and tensin homolog-induced putative kinase 1 mutations showed neuronal loss in the substantia nigra pars compacta, Lewy bodies and aberrant neurites in the reticular nuclei of the brainstem, substantia nigra pars compacta and Meynert nucleus, but the locus ceruleus and the amygdala were spared. This is the first neuropathological report of the brain from an early-onset phosphatase and tensin homolog-induced putative kinase 1-linked parkinsonism showing that mutated phosphatase and tensin homolog-induced putative kinase 1 protein induces Lewy body pathology. Unbalanced preservation of the locus ceruleus may well play a role in the slow evolution of motor symptoms and, probably, in the psychiatric symptoms often encountered in Parkinson’s disease associated with phosphatase and tensin homolog-induced putative kinase 1 mutation.